January 2019 Clinical Advisor by The Clinical Advisor

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■■ NICU Nursing Workload and Missed Care ■■Probiotic for Infant Colic ■■Digital Obesity Treatment CASE STUDY

An Incidental Finding of Hypercalcemia LEGAL ADVISOR

Fired for Refusing a Flu Shot CONFERENCE ROUNDUP

SABCS 2018

DERMATOLOGY CLINIC

Erythematous, Scaly Scalp Lesions

FEATURE

Irritable Bowel Syndrome and Vitamin D

JANUARY 2019

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CME: GENOMIC MEDICINE

Advances in Management of Breast Cancer With Whole Genome Sequencing WGS analyzes the entire genomic DNA sequence of an organism.

Vice president, content, medical communications, editor Kathleen Walsh Tulley editor@clinicaladvisor.com Associate editor Madeline Morr Assistant editor Rita Aghjayan Contributing editors Mark P. Brady, PA-C; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP; Sharon Dudley-Brown, PhD, FNP; Abimbola Farinde, PharmD; Laura A. Foster, CRNP, FNP; Abby A. Jacobson, PA; Maria Kidner, DNP, FNP; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Mary Newberry, CNM, MSN; Claire Babcock O’Connell, MPH, PA; Kathy Pereira, DNP, FNP; Sherril Sego, DNP, FNP; Ann Walsh, PA-C, SCT(ASCP); Kim Zuber, PA-C Production editor Kim Daigneau Group art director, Haymarket Medical Jennifer Dvoretz Senior production manager Krassi Varbanov Assistant manager, audience development Ashley Noelle Director of audience insights Paul Silver National accounts manager Alison McCauley, 973.224.6414 alison.mccauley @ haymarketmedical.com Publisher Kathleen Hiltz, 201.774.1078 kathleen.hiltz@haymarketmedia.com General manager, medical communications Jim Burke, RPh President, medical communications Michael Graziani CEO, Haymarket Media, Inc. Lee Maniscalco All correspondence to: The Clinical Advisor 275 7th Avenue, 10th Floor, New York, NY 10001 For advertising sales, call 646.638.6085. For reprints, contact Wright’s Reprints at 877.652.5295. Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Features” are not the actual individuals mentioned in the articles. They appear for illustrative purposes only. The Clinical Advisor ® (USPS 017-546, ISSN 1524-7317),Volume 22, Number 1, Published 12 times a year, monthly, by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. For Advertising Sales & Editorial, call (646) 638-6000 (M–F, 9am–5pm, ET). The Clinical Advisor is available on a paid subscription basis at the following annual rates: $75 USA, $85 Canada, $110 for all other foreign, in U.S. dollars, Single copy price: USA $20, Foreign $30. To order or update a paid subscription visit our website at www. ClinicalAdvisor.com or call (800) 436-9269. Periodicals postage rate paid at NewYork, NY, and additional mailing offices. Postmaster: Send changes of address to The Clinical Advisor, c/o Direct Medical Data, 10255 W. Higgins Rd., Suite 280, Rosemont, IL 60018. All rights reserved. Reproduction in whole or in part without permission is prohibited. Copyright © 2019

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EXPERTS If a patient has you stumped, write us and we’ll forward your query to one of our consultants and publish the response in Advisor Forum.You can also use this space to contribute a clinical pearl of your own or comment on another letter.

Advisor Forum These are letters from practitioners around the country who want to share their clinical problems and successes, observations, and pearls with their colleagues. Responding consultants are identified below. We invite you to participate.

CLINICAL PEARLS

It cannot be beat.—TERRI JORDAN, ARNP, Daytona Beach, Fla. (202-2)

NEUTROPHILS AND LYMPHOCYTES In interpreting a complete blood count with differential, anytime the neutrophils and lymphocytes are numerically close, it is a viral cause; when the neutrophils and lymphocytes are numerically distant, it is a bacterial cause. This is very helpful in determining treatment.—DONNA CARTER, FNP-C, Scottsburg, Ind. (202-1) GENERIC “CAINE” IS EFFECTIVE FOR WOUND CARE For pain relief, most pharmacies offer a “caine” at 2-510%, and basically nothing higher, for between $5 and $30 per tube. I work in wound care and use Walmart’s

INTRA-ARTICULAR INJECTIONS FOR SEVERE OSTEOARTHRITIS Patients with severe osteoarthritis in the knees seem to do better with intra-articular injections if you have them sit up and dangle their legs off the examination table and distract the knee slightly when administering the injection.—ROSEMARY LEDBETTER, PhD, PA, Troy, Ill. (202-3)

YOUR COMMENTS SLIPPED CAPITAL FEMORAL EPIPHYSIS IN OBESE ADOLESCENTS I just read the CME/CE article by Marilou Shreve, DNP, APRN, entitled, “Assessing and treating pediatric obesity” [ June 2015]. I was concerned regarding the oversight of a critical issue in obese adolescents: the increased risk of slipped capital femoral epiphysis (SCFE). This was not addressed in the article. The case study (p. 55) gave incomplete advice regarding the evaluation of an obese adolescent male with knee pain. The most common etiology of the insidious onset of knee pain in children is the hip, due to referred pain from the

Equate brand—vagicaine 20% benzocaine. When using this before debriding a wound, give it three minutes to sedate the nerves, then perform the procedure. I get good results, as patients say. It relieves pain and burning for $1.88.

Advisor F

Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001. You may contact us by e-mail at editor@ clinicaladvisor.com. If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter. No anonymous contributions will be accepted.

orum

These are lette and successe rs from practitioners s, observat around the below. We ions, and country who OUR CONSULTANTS pearls with invite you want to shar to participa their colle e their clinic agues. Resp te. al problems onding cons ultants are identified CON SULTAT IONS

TREATM ENT FOR INFECT URINAR ION SGLT2 REC MALE CHI S IN THE UNC Y TRACT IRCUMCI LD FOR DIA EPTOR BLOCKE If a male SED child conti Deborah L. Cross, MPH, CRNP, Laura A.BET Foster,ES CRNP, FNP, Abby A. Jacobson, PA-C, RS Abimbola Farinde, PhD, PharmD, With the nues toassociate ANP-BC, is practices family medicine is a physician assistant is a professor redevprogram adven t ofPrimary circu SGLT2 recep at Delaware Valley urinaryattract director, Gerontology NP elop Program, mcisi Columbia Southern moda litywith Palmetto on be perfo for type tor infecUniversity of Pennsylvania School Physicians Dermatology blockersGroup University 2 diabe rmed? regarding inCare as a treatm in Wilmington, Del. in Orange Beach, Ala. useCharleston, S.C. tes, is there ent urology is of Nursing, Philadelphia. any evide NATHAN in patients with to protect the is well advise nce or data type 1 diabe GARDNE d tes mellitus?— R, PA-C, continues to to recommend a circum upper tracts, the kidne CPAAPA, ys. develo cision•on It p recurr•ent 44 THE ADVISOR AUGUST 2015 www.ClinicalAdvisor.com Castleton, severaCLINICAL l consideration urinary tract the male child who As it currently stands N.Y. , SGLT2 s that enter infections. for glycemic impede the recept into There or blockers control in ability to cleans this decisio adults are FDA-appr n. Poor hygien are with diet and should the e and quell oved child have exercise, but with type 2 diabet e may appro phimosis, simpl infection potential. es appropriate the in ved for use in conjun 2:38 PM FDA has Moreover, AdvisorForum_CA0815.indd urine 44 e cathet patients with stated that 9/29/15ction culture can ketoacidosi steroid cream they are not type be a challenge. erization to obtain s, or those may tempo an FAR with severe 1 diabetes, patients with Having a short tion of the rarily solve renal functi diabetic steroid the trial of informINDE, PhD, Pharm these issues tenden , though after for infection D (See bottom on.—ABIMBOL ation about once again.—C cy redevelops, placin cessaA Dr. Farinde.) of this page Milwaukee g (203-2) for more , Wis. (203- OLEEN ROSEN, the child at risk 1) DNP, FNP -C, CLI Philip R. Cohen, MD,

is clinicaltions associate professor , shou ld of dermatology, University a of Texas Medical Center, The focus of Houston.

NICAL

Send us your letter Advisor Forum, The s with questions New York, and comm Clinical Advisor ents to: , 114 clinicaladvisoNY 10001. You may contacWest 26th Street , please indicatr.com. If you are writing in t us by e-mail at 4th Floor, each item. e so by including response editor@ to a the Letters are policy is edited for number in parent published letter, to heses at length and contribution print the author ’s name with clarity. The Clinicathe end of s will be accepted. l Advisor the letter. No anonym ’s ous

Write us today.

OUR CO

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PEARLS

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VAGINA L RESULT DISCHARGE AND ING FRO If a female M TAMPON ODOR patient has USE a ask if she uses tamp history of vaginal disch ons. If she the pelvic arge with says “yes,” exam when cond odor, that you woul , do not enter ucting the rotating of d to take a pap smea vagina in the same the specu way r. Instead, the cervix. lum Most retain from side to side start shallow until reach ed tampons ing are lodge d in the fold

Philip R.

Cohen, MD, is clinical associa te profess of dermat or ology, of Texas MedicaUniversity l Center, Houston.

SEND TO The Clinical Advisor 275 7th Avenue, 10th floor New York, NY 10001

62 THE CLINI

Deborah L. Cross, MPH, ANP-B

CRNP, C, is associa te program director, Geronto logy NP Program University of Pennsyl vania School , of Nursing , Philadelphia.

CAL ADVI

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Abimbo la Farinde

, PhD,

is a profess PharmD, or at Columb ia Souther n Univers in Orange ity Beach, Ala.

• www.Clinic

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Laura A.

Foster,

practices familyCRNP, FNP, with Palmett medicine o Primary Care Physicia ns in Charles ton, S.C.

Abby A.

Jacobso

is a physicia n, PA-C, n at Delawa assistant re Dermatology Valley in Wilmington,Group Del.

.indd 62

9/29/15

2:44 PM

E-MAIL editor@clinicaladvisor.com

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2019 5

CONTENTS JANUARY 2019

NEWS

12 Missed Care in the NICU

12 Newsline ■■Increased Neonatal Intensive Care Unit Workload Linked to Missed Care ■■Oral Immunomodulatory Therapy for Pediatric Peanut Allergy ■■Probiotic Found to Be Effective for Colic in Breastfed Infants ■■Diabetes Outcomes With PA, NP, or Physician Provider ■■Digital Obesity Treatment May Help Disadvantaged Patients

15 Incidental Hypercalcemia

41 Conference Roundup: 2018 SABCS ■■Mastectomy Often Chosen Over Breast-Conserving Surgery ■■Chemotherapy-Induced Peripheral Neuropathy in Breast Cancer ■■Massage for Chemotherapy-Induced Peripheral Neuropathy ■■Increased Breast Cancer Risk for African American Veterans ■■Metastatic vs Early-Stage HR+/HER2- Breast Cancer Mutations Identified ■■Pregnancy and Quality of Life in Women With Breast Cancer ■■Black Women Experience Worse Breast Cancer Outcomes

FEATURES 18 Irritable Bowel Syndrome and Vitamin D Deficiency: Is There a Connection? Research suggests a possible inflammatory response in the gut when vitamin D levels are low, making the connection between vitamin D and IBS a feasible speculation. 38 Flu Shot Refusal

Continues on page 8

41 News From SABCS

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CONTENTS JANUARY 2019

FEATURES (cont’d)

Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com Case Study: Endocrinology An Incidental Finding of Hypercalcemia in a Postmenopausal Woman Dermatology Clinic ■ Erythematous, Scaly Scalp Lesions ■ Nonblanching, Irregularly Shaped Plaques Legal Advisor Fired for Refusing a Flu Shot

CASE STUDY

An Incidental Finding of Hypercalcemia LEGAL ADVISOR

Fired for Refusing a Flu Shot

NEWSLINE CME: CASE STUDY

■ Screening for alcohol

| www.ClinicalAdvisor.com

MULTIPLE SYSTEM ATROPHY

FEATURE

in Myasthenia Gravis

WGS analyzes the entire genomic DNA sequence of an organism.

ADPKD can have a ALT MEDS effect UPDATE devastating on patients. Wound care treatments

CASE STUDY: PEDIATRICS

A Case of Floppy Baby Syndrome

MSA is notable for accumulation of α-synuclein in glial cells.

LEGAL ADVISOR LEGAL ADVISOR

SABCS 2018

Terminated for Taking FMLA?

DERMATOLOGY CLINIC

Erythematous, Scaly Scalp Lesions

Irritable Bowel Syndrome and Vitamin D

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS | NOVEMBER 2018 A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS | DECEMBER 2018 | www.ClinicalAdvisor.com JANUARY 2019 | www.ClinicalAdvisor.com

and depression ■ HBV Guideline Adherence A Common Form of ADPKD: Promising Advances in Management ■ VVA management barriers ■ Ovarian Cancer Screening ■ Sexual assault effects ■ Cesarean Delivery Rates forAtypical a Rare, Parkinsonism of Breast Cancer With Treatment Micronutrients for optimizing Whole Genome Sequencing Inherited Disorder Guidance for Antibiotic Use pregnancy outcomes

CONFERENCE ROUNDUP

FEATURE

CME: GENOMICNEWSLINE MEDICINE ■ Flu Vaccine in Pregnancy

A patient’s death following hospital discharge

DERMATOLOGY CLINIC

Pigmented Growth on the Upper Back

Painful, recurrent rash on the fingers

FEATURE

Effect of Artificial Sweeteners on Obesity Risk in Children

FREE CME COURSE

Minimally invasive total laparoscopic hysterectomy

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“Every Thursday I do her nails.”

DEPARTMENTS

■ NICU Nursing Workload and Missed Care ■ Probiotic for Infant Colic ■ Digital Obesity Treatment

VOLUME 21, NUMBER 11

CME Feature Posttest

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

THE CLINICAL ADVISOR • NOVEMBER 2018

and Breast Cancer in Primary Care Understanding the purpose and use of whole-genome sequencing in breast cancer screening and management can strengthen the evidence-based delivery of womancentered care.

VOLUME 21, NUMBER 12

CME Addressing Whole-Genome Sequencing

THE CLINICAL ADVISOR • DECEMBER 2018

EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com

NEWS ClinicalAdvisor.com/News

Curcumin Not Beneficial for Inflammation, Complications Following Elective Abdominal Aneurysm Repair

THE WAITING ROOM

Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Jim Anderson, MPAS, PA-C, DFAAPA Obesity Medicine: Time for a Paradigm Shift? Overweight patients often experience bias from the medical community, which may prevent them from seeking medical attention, even when it’s necessary.

Researchers found that, compared with placebo, perioperative oral curcumin did not affect the inflammatory response and risk of postoperative complications after elective abdominal aortic aneurism repair.

Gender Differences in ASCVD Care, Quality of Life, and Outcomes Women with arteriosclerotic cardiovascular disease are at increased risk for poor patient experience, lower health-related QOL, and inferior perception of their health compared with men.

Mediterranean Diet, Physical Activity Effective for Weight Loss, Decreased Cardiovascular Events A 12-month intensive lifestyle intervention including an energy-restricted Mediterranean diet, increased physical activity, and behavioral support for overweight/obese patients was found to be beneficial in decreasing adiposity and cardiovascular events.

Parental Chronic Spinal Pain May Affect Prognosis in Adult Offspring

CASE STUDY Clinical Advisor.com/CaseStudy Brady Pregerson, MD White Paste Found After Ankle Aspiration A 53-year-old man with a history of diabetes and hypertension presents to the emergency department with 1 month of migratory bilateral ankle pain that is worse on the left side. He has seen many clinicians, underwent radiographic examination, and has been using orthotics, but the pain persists. Read the full case here: ClinicalAdvisor.com/CaseWhitePaste

MY PRACTICE ClinicalAdvisor.com/MyPractice

In a prospective study, individuals with chronic spinal pain, particularly those who were overweight or obese, were found to be less likely to experience pain relief if both of their parents also had chronic spinal pain.

10 THE CLINICAL ADVISOR • JANUARY 2019 • www.ClinicalAdvisor.com

The Future of Robot Physicians: Is Artificial Intelligence Poised to Take Over Medicine? Clinicians debate the potential for this new technology to contribute to the practice of medicine.

Advisor Dx Interact with your peers by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit ClinicalAdvisor.com/AdvisorDx. Check out some of our latest cases below!

DERM DX

Swelling in the Finger Following a Cat Scratch A 61-year-old woman presents with swelling in the second digit of her left hand of 3 days’ duration. Five days earlier she experienced a cat scratch at the site that resulted in profuse bleeding. She complains of slight malaise but no fever. CAN YOU DIAGNOSE THIS CONDITION?

• Sporotrichosis • Cat scratch disease

• Candidiasis • Buerger disease

● See the full case at ClinicalAdvisor.com/DermDx_Jan19

In partnership with

ORTHO DX

TheJopa.org

Journal of Orthopedics for Physician Assistants

Chronic Pain and Stiffness After Total Hip Replacement An 80-year-old man presents to the office with complaints of chronic right hip pain and stiffness after undergoing total hip replacement 4 years earlier. The procedure was without complication, and the patient had an uneventful recovery. He denies significant loss of function and can still mobilize quite well. Anteroposterior radiograph of the pelvis is performed. WHAT IS THE RECOMMENDED TREATMENT FOR THIS PATIENT?

• Observation • Indomethacin

• Radiation therapy • Surgical excision

● See the full case at ClinicalAdvisor.com/OrthoDx_Jan19

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2019 11

Newsline

Measures of workload included staffing ratio and infant acuity scores.

Increased Neonatal Intensive Care Unit Workload Linked to Missed Care NURSE STAFFING RATIOS and subjective workload were found to be directly associated with missed care in a neonatal intensive care unit (NICU), according to a study published in JAMA Pediatrics. Researchers collected data from a 52-bed level IV NICU. Eligibility criteria included registered nurses who completed unit orientation, provided direct patient care for >80% of their clinical effort, and were permanently employed in the NICU. Data were included from all infants during active NICU cycles. Missed care was assessed by asking nurses to report the omission of 11 essential neonatal nursing care practices. Nurses reported the frequency of missed care based on a Likert-type scale: never, rarely,

occasionally, or frequently missed, or not applicable.The researchers then created a dichotomous missed care indicator for each infant on each shift if a nurse reported missing any of the 11 practices during a shift. Objective measures of workload included infant-to-nurse staffing ratio and infant acuity scores. Infant acuity scores were estimated based on clinical indicators of nursing care intensity such as ventilation modality, frequency and mode of feedings, number and type of infusions, and procedures. Higher acuity scores were indicative of a greater degree of nursing care intensity. Of 202 eligible nurses, 136 (67.3%) reported care for 418 infants during 332 shifts of 12 hours each, resulting

12 THE CLINICAL ADVISOR • JANUARY 2019 • www.ClinicalAdvisor.com

in 10,428 nurse-infant shifts of workload and missed care data available for analysis. Mean infant-to-nurse ratio was approximately 2:1 and ranged from 1 to 4 infants per nurse. Missed care was reported on 326 (98.2%) of the 332 shifts and in 2502 (24.0%) of 10,428 corresponding nurse-infant shifts.The most frequently reported missed nursing care involved hourly checks of intravenous line sites (1066 [20.4%] of applicable shifts) and adherence to the central-line associated bloodstream infection prevention bundle (695 [15.5%]). Least frequently reported were missing standard safety checks of alarms and equipment (188 [1.8%] of applicable shifts). Out of 12 ratio models of missed care outcomes, 7 showed a statistically significant worsening effect of an increased infant-to-nurse ratio on the odds of missed care; these effects were more prominent when nurses cared for 3 or more infants during a shift compared with a 1:1 assignment (ie, nurses caring for ≥3 infants were 2.51 times more likely to report missing any care during the shift). All 12 models demonstrated worsening effects of increased subjective workload ratings on the odds of missed care (ie, a 5-point increase in a nurse’s NASA-TLX rating during a shift was associated with a 34% increase in the likelihood of missing an infant assessment). Increased staffing ratios were associated with a worsening effect of missed care in 9 of 12 models; small increases in acuity were found in 5 models, including any missed care (1.07), missed patient assessment (1.03), missed parent involvement (1.05), and missed verification of 6 rights of medication administration (1.05).

Oral Immunomodulatory Therapy for Pediatric Peanut Allergy

AR101, an investigational biologic oral immunotherapy drug derived from peanuts, reduced symptom severity and induced desensitization in children and adolescents with peanut allergies, according to research published in the New England Journal of Medicine. A team of researchers for the Peanut Allergy Oral Immunotherapy Study of AR101 for Desensitization (PALISADE, ClinicalTrials.gov Identifier: NCT02635776) conducted an international, randomized, double-blind, placebo-controlled, phase 3 clinical trial to determine the efficacy and safety of AR101 in reducing allergic symptoms associated with peanut allergy in children and adolescents. The investigators screened 842 patients aged 4 to 55 years with allergic doselimiting symptoms at ≤100 mg of peanut protein for eligibility; 750 of these patients were aged 4 to 17 years. A total of 551 eligible participants were then randomly assigned in a 3:1 ratio to be

AR101 reduced symptom severity associated with peanut allergy in children and adolescents.

administered either AR101 or placebo; 496 participants were aged 4 to 17 years. Over the course of 12 months, dose increased throughout the study in phases: the initial phase involved supervised dose escalation of AR101 from 0.5 mg to 6 mg occurring on 1 day; the increasing-dose phase, during which the dose of AR101 was increased every 2 weeks from 3 mg to 300 mg; and a 24-week maintenance phase with a steady dose of 300 mg. Of the 372 pediatric participants in the AR101 group, 250 individuals (67.2%) were able to ingest ≥600 mg of peanut protein without dose-limiting symptoms compared with 5 of the 124 (4.0%) of the pediatric participants in the placebo group (difference, 63.2 percentage points). Maximum symptom severity during the exit food challenge was reported as moderate in 25% and severe in 5% of participants in the AR101 group and moderate in 59% and severe in 11% of participants in the placebo group. More than 95% of pediatric participants experienced adverse events: mild events were reported in 34.7% of the AR101 group and in 50.0% of the placebo group, while moderate events were reported in 59.7% of the AR101 group and in 44.4% of the placebo group. Severe events were reported in 4.3% of the AR101 group and in 0.8% of the placebo group. No significant efficacy was reported in participants aged ≥18 years. “In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo,” the authors concluded.

Probiotic Found to Be Effective for Colic in Breastfed Infants BREASTFED infants administered the probiotic Lactobacillus reuteri for colic were found to demonstrate a reduction in duration of crying and fussing, according to a meta-analysis published in Pediatrics.These findings were not demonstrated in formula-fed infants given L reuteri. An international team of investigators reviewed 4 double-blind randomized controlled trials involving 345 infants with colic who were randomly assigned to probiotic treatment (n=174) or placebo (n=171) to determine the efficacy of L reuteri DSM17938 for reducing the duration of crying and/or fussing and if feeding type could influence treatment outcomes. Probiotic and placebo were orally administered and consistent for probiotic product manufacturer and dosage across all 4 trials, all of which included breastfed infants (n=246) and 1 that included formula-fed infants (n=99). Within the 21-day trial, average crying/fussing duration was less in the probiotic cohort than the placebo cohort at all time points (day-21 adjusted average difference in change from baseline, -25.4 min), with the probiotic cohort demonstrating nearly twice the likeliness of treatment success than the placebo group (day-21 adjusted incidence ratio, 1.71). Significant intervention effects were seen in breastfed infants (number needed to treat for day-21 success, 2.6); no significant results were noted for probiotic use in formulafed infants.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2019 13

Newsline Diabetes Outcomes With PA, NP, or Physician Provider NO SIGNIFICANT differences in intermediate diabetes outcomes were reported among patients managed by physician assistants (PAs), nurse practitioners (NPs), or physicians, according to a study published in Annals of Internal Medicine. A team of researchers from Duke University and the DurhamVeterans Affairs Health Care System in North Carolina conducted a cohort study using data from the US Department ofVeteran Affairs (VA) electronic health record to analyze intermediate diabetes outcomes among patients who were managed by PAs, NPs, and physician primary care providers (PCPs). The investigators collected data from 368,481 adults with medication-treated diabetes managed at 568 VA primary care facilities and measured the association between the PCP profession and continuous and dichotomous control of glycated hemoglobin (HbA1c), systolic

No clinically significant differences were seen in intermediate diabetes outcomes.

blood pressure (SBP), and low-density lipoprotein cholesterol (LDL-C). A total of 3487 physicians, 1445 NPs, and 434 PAs treated 74.9%, 18.2%, and 6.9% of patients, respectively. Compared with measurements in patients managed by physicians, the differences in HbA1c values were -0.05% for NPs and 0.01% for PAs; the differences for SBP were -0.08 mm Hg

for NPs and 0.02 mm Hg for PAs; and the differences in LDL-C were 0.01 mmol/L for NPs and 0.03mol/L for PAs. “In conclusion, we found no clinically significant differences in intermediate diabetes outcomes,” the authors wrote. “As a result, this study provides further evidence that using NPs and PAs as PCPs may represent a mechanism for expanding access to primary care while maintaining quality standards.” In a corresponding editorial published in Annals of Internal Medicine, Anne L. Peters, MD, of Keck School of Medicine of the University of Southern California, wrote that “although the results validate that NPs and PAs can provide primary care, they are hardly surprising,” adding that “the time has come to embrace many different approaches to providing primary care, particularly for persons with a chronic disease, such as diabetes.”

Digital Obesity Treatment May Help Disadvantaged Patients Individuals were randomly assigned to usual primary care (n=175) or to a 12-month digital weight loss intervention (n=176) within a community health center system.The intervention was defined as an “app-based self-monitoring of behavioral change goals with tailored feedback, a

group lost more weight within 6 months (net effect, -4.4 kg) and 12 months (net effect, -3.8 kg). The investigators noted that individuals in the intervention group were more likely to lose ≥5% of weight from baseline to 6 months (43% vs 6%) and 12 months (40% vs 17%) compared

Clinically meaningful weight loss was found to be possible in disadvantaged, vulnerable patients with increased cardiovascular risk. smart scale, dietitian-delivered counseling calls, and clinician counseling informed by app-generated recommendations.” This information was transcribed through an electronic health record system. Compared with members in the control group, members in the intervention

14 THE CLINICAL ADVISOR • JANUARY 2019 • www.ClinicalAdvisor.com

with participants in the usual-care group. In addition, individuals in the intervention group who completed ≥80% of their self-monitoring episodes, counseling calls, or self-weighing days reported significantly more weight loss than those who were less engaged. ■

SOCIOECONOMICALLY disadvantaged individuals with obesity and elevated cardiovascular risk may benefit from a primary care digital obesity treatment combined with health system resources, according to a study published in the American Journal of Preventive Medicine. A team of researchers participating in the New Media Obesity Treatment in Community Health Centers study invited 351 adults (aged 21-65 y; 68% women) with obesity, hypertension, diabetes, and hyperlipidemia to participate in the randomized controlled trial. Participants were identified from a health system service area in which the majority of patients are impoverished and either uninsured or receiving public insurance.The primary outcome measured was change in weight over 12 months.

Case Study | ENDOCRINOLOGY

An Incidental Finding of Hypercalcemia in a Postmenopausal Woman A visit to a primary care provider for routine evaluation uncovers an incidental finding of hypercalcemia.

DENISE M. LINTON, DNS, FNP-BC

Ms M is a college graduate and a reliable historian. She has never been married or pregnant, is not sexually active, and has no history of sexually transmitted infections. Ms M reported short-term use of contraception during perimenopause and transdermal hormone replacement therapy due to severe vasomotor symptoms. She has infrequent night sweats and does not wish to resume hormone replacement therapy. Her last menstrual period was 7 years earlier. Ms M has never smoked. She drinks one cup of coffee per day and does not drink alcohol. She neither abuses prescription medications nor uses illicit drugs. She has no known drug or food allergies and takes no prescription or overthe-counter medications. Her medical history is significant for multiple uterine fibroids for which she underwent myomectomy.Although she does not recall the date or year of her surgery, she does recall that the procedure and hospital stay were uneventful. She underwent colonoscopy at 49 years of age because of rectal bleeding and constipation. Benign polyps were identified, and the gastroenterologist recommended follow-up in 10 years as she had no family history of colorectal cancer. Her family history is significant for her mother having an abnormal Papanicolaou test result that was managed with “freezing of her cervix.” Her maternal grandaunt died in her late 50s after a diagnosis of late-stage breast cancer. Ms M received all her childhood immunizations, the hepatitis B vaccine series, and the hepatitis A vaccine. She undergoes annual influenza vaccination. She is unsure of the date of her last tetanus vaccine.

PHYSICAL EXAMINATION AND PLAN

THE CASE Ms M is a 52-year-old postmenopausal African American woman who reported to the family practice clinic as a new patient for her Papanicolaou test and referral for a screening mammogram. She had no complaints and reported no history of abnormal findings on prior diagnostic tests, although she was uncertain when these tests were last performed.

Ms M’s blood pressure is measured at 122/72 mm Hg. Her height is 5 ft 8 in and her weight is 185.6 lb; body mass index (BMI) is calculated at 28.2 kg/m2.The remainder of her physical examination is unremarkable. Her plan of care included a Papanicolaou test, since she was unable to recall when she last underwent testing, comprehensive

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2019 15

Case Study metabolic panel, lipids, thyroid-stimulating hormone, urinalysis, and referral for screening mammogram. She received tetanus vaccine at this visit.

ABNORMAL LABORATORY RESULTS Two weeks after her initial visit, Ms M’s primary care provider (PCP) called and informed her that her test results were within normal limits except for serum calcium, which was elevated at 10.6 mg/dL (reference range, 8.5-10.0 mg/dL). Because of her hypercalcemia, a parathyroid hormone (PTH) level was requested and was found to be elevated at 136.4 pg/ dL (reference range, 14.0-72.0 pg/dL). When asked about possible symptoms of primary hyperparathyroidism (Table), Ms M admitted experiencing fatigue, which she attributed to her work schedule and personal problems. As a result of her elevated calcium and PTH levels, Ms M was referred for osteoporosis screening and consultation with an endocrinologist, who advised that she undergo a sestamibi scan of her parathyroid.The result of the dual x-ray absorptiometry test was osteopenia of L1 to L4 and the femoral necks bilaterally. She was instructed to increase her daily intake of calcium to 1200 mg, take over-the-counter vitamin D3 1000 IU/d, and undergo repeat dual x-ray absorptiometry testing in 2 years. Following further laboratory testing, Ms M was found to be deficient in vitamin D at 13.3 ng/mL (reference range, 30-80 ng/mL); she was prescribed ergocalciferol (vitamin D2) 50,000 IU weekly for 8 weeks, followed by 3000 IU/d.Three months later, repeat vitamin D level was 16.9 ng/mL and TABLE. Symptoms Associated With Primary Hyperparathyroidism1 System

Symptoms

Neurologic

Reduced concentration, memory impairment, irritability, anxiety, confusion, fatigue, stupor, mild depression

Cardiovascular

Sinus bradycardia, hypertension, shortened QT interval

Gastrointestinal

Anorexia, nausea, vomiting, gastrointestinal reflux, peptic ulcer disease, hypomotility of the bowel, constipation, pancreatitis

Renal

Polyuria, polydipsia, nephrolithiasis, nephrocalcinosis, acute and chronic renal insufficiency

Musculoskeletal

Muscle weakness, bone pain, osteopenia, osteoporosis, fracture

calcium was normal at 9.4 ng/mL. She was advised to repeat her regimen of ergocalciferol 50,000 IU once per week for 8 weeks followed by 3000 IU/d. Sestamibi scan of the parathyroid gland revealed a suspected right lower pole adenoma measuring <1 cm. Ultrasound of the parathyroid and thyroid confirmed the parathyroid adenoma and revealed thyroid cysts and nodules that were not considered suspicious. Ms M was advised to return for follow-up in one year. She kept her appointment with the endocrinologist. As there was no sign of lymphadenopathy on physical examination, the endocrinologist recommended repeat thyroid ultrasound and follow-up only if she experienced changes in her condition.The endocrinologist agreed with the PCP’s plan that Ms M should undergo removal of the parathyroid adenoma. Ms M followed up with a surgical oncologist and was scheduled for excision of the parathyroid adenoma.

OUTCOME Ms M underwent right lower pole parathyroidectomy approximately 4 months after her initial visit to her PCP. Intact PTH immediately before surgery was 138.8 pg/dL (reference range, 23.6-123.6 pg/dL). Intact PTH repeated intraoperatively after excision of the parathyroid gland was within normal limits at 48.2 pg/dL. Ms M continues to follow up with her PCP for her vitamin D deficiency, osteopenia, and thyroid nodules.

DISCUSSION This case demonstrates a stepwise multidisciplinary management approach of a seemingly asymptomatic patient who was diagnosed with primary hyperparathyroidism after the incidental finding of mild hypercalcemia on screening laboratory testing. The decision to refer a patient with primary hyperparathyroidism for surgical intervention is controversial; therefore, it is important for PCPs to make appropriate referrals. Ms M recalls that she understood that surgery was her only option when her parathyroid hormone level was elevated, before she was diagnosed with osteopenia and vitamin D deficiency. During her consultation with the surgeon, she was informed that it was best to have the surgery as soon as possible instead of waiting. The surgeon wanted to ensure that the parathyroid adenoma was not malignant, and he informed her that watchful waiting could result in worsening hypercalcemia and increasing size of the parathyroid adenoma. Women should be informed that parathyroidectomy is usually indicated in patients who are symptomatic1 and those who meet the criteria for surgery.2 Although the necessity of surgery in the management of patients with primary

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SURGICAL VS MEDICAL MANAGEMENT Parathyroidectomy is recommended for patients who have severe renal or bone signs and symptoms of hyperparathyroidism,4 those with symptomatic primary hyperparathyroidism, and asymptomatic patients who are at risk for disease progression.3 With the exception of patients with presentation at age <50 years, it is difficult to predict those patients who will experience disease progression.3 Surgery cures the disease by removing the source of the hyperactivity, reduces the risk of kidney stones, and improves bone mineral density.3 The mortality rate after parathyroidectomy is 0%, and the worrisome complication of injury to the recurrent laryngeal nerve is <1%.4 Patients who choose to not undergo surgery should be monitored.Their serum calcium and creatinine levels should be checked annually to assess for worsening hypercalcemia and renal impairment. Bone density of the hip, spine, and forearm should be requested every 1 to 2 years to evaluate potential bone loss.3 There are some patients who may be symptomatic and/ or have severe hypercalcemia, but they may have comorbid contraindications to surgery or make the personal decision not to have surgery. Patients without bone loss should receive cinacalcet 30 mg twice per day, while those with bone loss or osteoporosis should receive a bisphosphonate, preferably alendronate.3 Calcimimetics such as cinacalcet inhibit parathyroid hormone secretion by activating calcium-sensing receptors in the parathyroid gland.3 Serum calcium level should be measured 1 week after initiation of therapy and any dose adjustment(s).3 Dose adjustments may occur every 2 weeks to every month and may be increased from 30 mg twice per day to 60 mg twice per day followed by 90 mg twice per day.5 If calcium levels are not within normal range, the patient can receive cinacalcet 90 mg 3 or 4 times per day.5 Combination bisphosphonate and cinacalcet is indicated in patients with chronic hypercalcemia and osteoporosis.Vitamin D supplementation should be administered to patients with reduced vitamin D levels.3 High-dose vitamin D was prescribed for this patient; however, the recommendation is for patients to take 600 IU/d to 1000 IU/d to prevent exacerbation of hypercalciuria and hypercalcemia.3

in their patients. In this case, the quick action of the initial practitioner with whom Ms M came in contact resulted in the early identification and treatment of primary hyperparathyroidism and the complication of vitamin D deficiency and osteopenia. As demonstrated in this case, an incidental finding of mildly elevated calcium is not always benign. ■ Denise M. Linton, DNS, FNP-BC, is associate professor, nurse practice coordinator, and holds the Dudley Joseph Plaisance, Sr./ BORSF Professorship in Nursing at the University of Louisiana at Lafayette College of Nursing and Allied Health Professions. References 1. Turner JJO. Hypercalcemia – presentation and management. Clin Med. 2017;17(3):270-273. 2. Bilezikian JP, Bandeira L, Khan A, Cusano NE. Hyperparathyroidism. Lancet. 2018;391(10116):168-178. 3. Silverberg SJ, Fuleihan GE. Primary hyperparathyroidism: management. UpToDate website. Available at: https://www.uptodate.com/contents/primaryhyperparathyroidism-management?search=primary-hyperparathyroidismmanagement.&source=search_result&selectedTitle=1~108&usage_ type=default&display_rank=1. Updated September 6, 2017. Accessed December 13, 2018. 4. Udelsman R, Akerstrom G, Biagini C, et al. The surgical management of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinolol Metab. 2014;99(10):3595-3606. 5. Sensipar® (cinacalcet hydrochloride) [product monograph]. Mississauga, Ontario, Canada: Amgen Canada, Inc.; 2018.

CONCLUSION It is important for PCPs to conduct appropriate follow-up of abnormal testing results in order to prevent adverse outcomes www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2019 17

hyperparathyroidism who are asymptomatic is controversial, the Fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism provides evidence-based criteria for surgery.2

FEATURE: MARY E. POLLOCK, DNP, CRNP, FNP-BC; COLLEEN BESSETTI-BARRETT, DNP, CRNP, FNP-BC

Irritable Bowel Syndrome and Vitamin D Deficiency: Is There a Connection? The gut microbiota is an area of increased interest due to its effect on the gastrointestinal tract that can lead to chronic gastrointestinal diseases.

There is currently no specific diagnostic testing for IBS.

18 THE CLINICAL ADVISOR • JANUARY 2019 • www.ClinicalAdvisor.com

rritable bowel syndrome (IBS) is the most common functional bowel disorder in the general population, affecting approximately 25 to 45 billion people in the United States.1 There is no known etiology, which makes identifying treatment for IBS a frustrating task for healthcare providers. Common symptoms of IBS are constipation, diarrhea, or alternating diarrhea and constipation with or without abdominal pain. Approximately 10% to 15% of the western population is affected by IBS, which results in an increase in direct and indirect health costs through loss of work productivity, frequent office and hospital visits, and testing to rule out more serious diseases.2 The total cost of IBS in the United States is approximately $30 billion annually, with an estimated $1.6 to $10.5 billion in direct costs and $20 billion in indirect costs.3 IBS can be lifealtering for patients and often leads to avoidance of social situations and emotional distress. It is not life-threatening, has different degrees of severity, and treatment is based on symptomology. Due to no known cause of IBS, treatment may not be successful and patients may experience a lifetime of frustration and depression. Vitamin D deficiency symptoms can be vague and may lead to underdiagnosis of the condition. Low vitamin D levels have been linked to multiple diseases including some cancers, neurologic disorders, decrease in bone density, and cognitive decline in the elderly. There is research that suggests a possible inflammatory response in the gut

IBS AND VITAMIN D

Common symptoms of IBS include constipation, diarrhea, or alternating diarrhea and constipation with or without abdominal pain. when vitamin D levels are low, making the connection between vitamin D and IBS a feasible speculation. Vitamin D is most often acquired through sunlight, which can vary throughout the United States. The stronger the radiation, the longer an individual is exposed to radiation, and the more body area exposed to radiation, the more vitamin D that can be produced.4 Due to research noting the benefits of vitamin D, healthcare professionals are more aware of the importance of maintaining normal vitamin D levels in their patients. What Is IBS?

IBS is a functional bowel disorder that was first documented 150 years ago.5 A functional bowel disorder is defined as changes in intestinal motility, intestinal nerve sensitivity, and the way the brain controls the normal function of the gut.1 As mentioned, there is no known etiology for IBS, nor is there specific testing to secure the diagnosis. The diagnosis of IBS is determined through application of the Rome criteria for functional bowel disorders. The Rome classification system was introduced by an international group of gastrointestinal experts at the University of Rome, Italy, and is used in daily practice for patients with gastrointestinal complaints (Sidebar).6 The Rome IV criteria were introduced in May 2016 and are currently used to diagnose IBS by healthcare providers in daily practice today.7 The Rome IV criteria consist of recurrent abdominal pain on at least 1 day a week over the previous 3 months accompanied by 2 or more of the following symptoms: abdominal pain related to defecation, associated with a change in stool frequency, and associated with a change in stool form. All symptoms should be present for the past 3 months with the onset of symptoms occurring 6 months prior.8 By meeting these criteria, a diagnosis of IBS can be established.

Rome IV Diagnostic Criteria6 Recurrent abdominal pain on average at least 1 day per week in the last 3 months associated with 2 or more of the following*: 1. Related to defecation 2. Associated with a change in frequency of stool 3. Associated with a change in form of stool *All symptoms must have started at least 6 months prior

Symptoms of IBS include diarrhea, constipation, and a mix of diarrhea alternating with constipation.The Rome IV diagnoses for bowel disorders include IBS constipation (IBS-C), IBS diarrhea (IBS-D), IBS mixed (IBS-M), IBS unclassified (IBS-U), functional constipation, functional diarrhea, functional abdominal bloating and distension, unspecified functional bowel disorder, and opioid-induced constipation.7 Treatment for IBS consists of prescription and over-the-counter medications, dietary modifications, and behavioral therapy.Treatment is based on a patient’s symptoms and may need to be altered according to a patient’s needs. Stating this, changes in treatment can be costly and time-consuming due to lost days of work and adjustments in medication or behavioral therapy. Studies have been conducted that investigate the cognitive and emotional aspects of IBS. Up to 50% of patients with IBS meet the criteria for a psychiatric diagnosis including depression, anxiety, hostility, phobia, somatization, and paranoia.9 Due to symptoms of IBS, avoidance of certain foods, eating out with others, social situations, work situations where a toilet may not be available, intimate relationships, and personal relationships that would entail others finding out about IBS are common and significant concerns.10 The American College of Gastroenterology Functional GI Disorders Task Force recommends against extensive testing for IBS because these patients do not seem to have a higher prevalence of organic disease.5 However, there are alarm features outside of the Rome IV criteria that should alert the healthcare provider to investigate for more serious diseases.These alarm features include anemia, nocturnal symptoms, rectal bleeding, weight loss, recent antibiotic use, onset of symptoms after age 50, family history of colon cancer, inflammatory bowel disease, or celiac sprue disease.11 It is not uncommon for patients with IBS to wander through the medical system for years with multiple diagnoses because of lack of interest or frustration by the healthcare provider due to lack of treatment; the psychiatric component of the disease; or lack of clinical, physical, and/or laboratory criteria for the diagnosis.5 Vitamin D Deficiency

Vitamin D is a hormone that is mainly produced in the skin as a response to sunlight.12 The dominant form of vitamin D that circulates throughout the body is 25- hydroxyvitamin D (25[OH]D).13 According to the Institute of Medicine (IOM), vitamin D deficiency is defined as a serum 25(OH)D level <12 ng/mL.14 The Endocrine Society defines vitamin D deficiency as 25(OH)D levels ranging from 21 to 29 ng/mL.15

20 THE CLINICAL ADVISOR • JANUARY 2019 • www.ClinicalAdvisor.com

Symptoms of deficient vitamin D levels include fatigue, muscle weakness, chronic musculoskeletal pain, leg heaviness, and joint pain. The recommended measurement of vitamin D is the 25(OH) D level using a reliable assay.15 Vitamin D deficiency in the general population has numerous causes, including lack of sunlight, poor dietary choices, and comorbidities such as diabetes, inflammatory bowel disease, or gastric bypass. In the United States, milk, orange juice, yogurts, cheese, breads, and cereals are fortified with vitamin D.15 Foods that naturally contain vitamin D include fatty fish, eggs, mushrooms, and fish oil.14 Individuals with IBS often admit to food avoidance due to unpleasant IBS symptoms, resulting in a general nutritional deficit and a diet that may exclude food sources high in calcium and vitamin D.16 It is also known that individuals with IBS commonly have lactose intolerance and are more likely to avoid all dairy products. Although diet plays a small role in maintaining normal vitamin D levels, it continues to be an important aspect in maintaining daily recommended levels. Ultraviolet B (UVB) is a medium wavelength radiation that is emitted by the sun.17 Most vitamin D is produced from UVB that is absorbed through the epidermal layer of the skin where 7-dehydrocholesterol is present.4 According to the IOM, a few minutes of exposure to sunlight each day is enough to obtain sufficient vitamin D levels.14 This guidance can be conflicting for individuals, especially when they are advised to avoid the sun or to wear sunscreen due to the damaging effects of the sun that can lead to skin cancer. Other barriers to obtaining enough sunlight to maintain sufficient vitamin D levels exist, such as geography, time of day, cloud coverage, smog, season, pollution, glass filters, and an individual’s mobility to access the outdoors.14 In 2009, the American Academy of Dermatology made a strong statement that advised protection from the sun at all times by using sunscreen and wearing protective clothing, and in 2014, a statement from Brett Colidron, MD, president of the American Academy of Dermatology, reinforced the recommendation of photoprotection.18 Due to the potential benefits of vitamin D, weighing the risk vs the benefits of sun exposure is a challenge for healthcare providers. Symptoms of deficient vitamin D levels include fatigue, muscle weakness, chronic musculoskeletal pain, leg heaviness, and joint pain, all of which are common complaints in a primary care setting.19Vitamin D deficiency has been linked to an increased risk of colon cancer, ovarian cancer, and prostate cancer.4 According to the US Preventive Services Task Force, there is currently insufficient evidence to assess the risks and benefits of screening for vitamin D deficiency in asymptomatic adults.20 As a result of this, healthcare providers often order vitamin D

levels only when a patient has complaints related to vitamin D deficiency.There are no set recommendations on daily dosing of vitamin D supplementation; however, the IOM reports the upper limit of safe supplementation to be 4000 IU/d and that too much vitamin D can place an individual at risk for cancer, cardiovascular disease, falls, fractures, and mortality.14 Monitoring blood levels in patients taking a vitamin D supplement is essential.Vitamin D supplements can be purchased as over-the-counter agents, but prescription doses can also be prescribed by healthcare providers.The National Kidney Foundation provides the following guidance: severe vitamin D insufficiency at <5 ng/mL requires supplementation with vitamin D (ergocalciferol) 50,000 IU weekly for 12 weeks followed by monthly dosing thereafter; moderate vitamin D insufficiency at 5 ng/mL to 15 ng/mL requires vitamin D (ergocalciferol) 50,000 IU weekly for 4 weeks followed by monthly dosing; and mild vitamin D insufficiency at 16 ng/mL to 30 ng/mL requires monthly supplementation with vitamin D (ergocalciferol) 50,000 IU.21 Vitamin D (ergocalciferol) at a dose of 50,000 IU is available via prescription only and cannot be purchased over the counter. Is There a Correlation Between Low Vitamin D Levels and IBS?

Studies suggest a correlation between IBS and an inflammatory response in the gut. The gut microbiota is an area of increased interest and research mostly because of the effect the gut microbiota has on the gastrointestinal tract that can lead to chronic gastrointestinal diseases.22 Inflammation, gut motility, and brain-gut axis disturbances may explain triggering and continuation of bowel symptoms along with visceral sensitivity due to bowel sensation and afferent nerve signaling.23 Histologic examination in individuals with IBS suggests an increase in mast cells, lymphocytes, and other cell types in parts of the colon and small intestine leading to increased sensitivity in the nervous system and visceral hypersensitivity along with altered perception of abdominal pain.24 This suggests that inflammation in the gut triggers an increase in sensitivity and pain perception. The relationship between a patient’s perception of symptoms has also been an interesting area of relevance. Studies note that individuals with IBS show a lower tolerance to balloon distension in the large and small bowel compared with healthy subjects.9 In one study, magnetic resonance imaging was performed on male patients with IBS and healthy male controls at the rectal balloon distension threshold.The investigators noted an increase in activation of common

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2019 21

IBS AND VITAMIN D

POLL POSITION Which of the following foods are not a source of naturally occurring vitamin D? 8.57% ■ Eggs ■ Fatty fish ■ Mushrooms ■ Whole grain breads

10% 44.29% 37.14%

For more polls, visit ClinicalAdvisor.com/Polls.

neural regions in the brain with rectal balloon distension in the male patient with IBS.25 Two specific changes in gut motility noted in the patient with IBS — changes in gut transit and increased motility — may be associated with specific stimuli such as psychological stress and meals.9 The stress that occurs due to a patient’s thought process may lead to worsening of the patient’s symptoms. Research suggests that low vitamin D levels may be a cause or effect of mental illness such as depression.26 If this is the case, then is it possible that low vitamin D has a larger role in thought processes and can lead to IBS symptoms? Vitamin D has been known to inhibit T-cell proliferation, thereby decreasing the potential for an immune response.27 Interestingly, 70% to 80% of vitamin D absorption in the gut occurs in the ileum with most vitamin D receptors (VDRs) and regulatory mechanisms in the cecum and large intestine.27 VDR is a protein that regulates physiologic processes and is present in most tissues of the body.28 The presence of VDRs in the gut suggests that vitamin D is needed to maintain normal function. The effects of vitamin D on gut function may be due toVDR expression in the gut and the neurologic system that regulate the epithelium barrier, neurotransmitters, and serotonin synthesis, causing a decrease in visceral hypersensitivity and abdominal pain.24 A study in 2016 recognized a benefit of vitamin D 50,000 IU every 2 weeks on IBS symptoms, severity, and quality of life.24 In an article published in 2015, VDRs were found to play an important protective role in the mucosal barrier, and an increased risk of dysfunctional mucosal barrier and inflammation was identified with a reduction in VDR.29 The same article reported that increasing the epithelial VDR level with

vitamin D therapy will result in a decrease in inflammation and a decrease in the risk of colitis and inflammation in the colon.29 In an article by Klampfer, decreased levels of VDR in the intestinal epithelium were correlated with low levels of vitamin D and inflammation in the gut.30 Diet may also have an effect on the enteric microbial community in the gut, resulting in an alteration in composition and function.31 Studies have explored the possible correlation of IBS and vitamin D with results favoring further research. In a study conducted by Khayyat and Attar, 49 out of 60 participants with IBS were found to have low vitamin D levels compared with 31 of 100 healthy individuals having low vitamin D levels.27 A separate case study reported on cessation of symptoms in a patient with IBS taking vitamin D 3000 IU daily; the patient’s symptoms returned upon discontinuation of the vitamin D supplementation.2 An analysis of blogs of 37 patients with IBS noted 70% improvement with vitamin D supplementation in those with low vitamin D levels.32 In a recent randomized control trial, 112 individuals aged 14 to 18 years who met the Rome III criteria for IBS with vitamin D levels <20 ng/mL were followed from April 2015 to April 2017.33 Out of the 112 study participants, 56 received vitamin D supplementation and 56 received a placebo; results showed improvement in symptom severity and quality of life in the patients who received vitamin D supplementation.33 Conclusion

Research into the correlation between vitamin D and IBS is certainly compelling, and the need for further investigation is recommended by previous studies. The diagnosis of IBS is based strictly on the Rome IV criteria, and treatment can be frustrating for both the patient and the healthcare provider. Due to the increase in direct and indirect healthcare costs associated with IBS and the impact that IBS has on an individual’s daily life and psychiatric health, improving a patient’s outcome is certainly a goal for clinicians who provide direct care to these patients. Knowledge of the Rome IV criteria is essential for appropriate diagnosis and can help to determine whether further testing is warranted.Vitamin D deficiency has been recognized as a possible cause of some cancers and other diseases.With the identification of VDRs in the gut and a possible inflammatory response from lack of vitamin D, the correlation between IBS and vitamin D is plausible. However, there is currently no evidence-based practice recommendations for ordering vitamin D levels for patients with IBS. Further research into vitamin D insufficiency and IBS is necessary to prove a correlation between the 2 conditions and ultimately improve patient outcomes. ■ Mary E. Pollock, DNP, CRNP, FNP-BC, is currently practicing in a private gastroenterology practice. Colleen Bessetti-Barrett, DNP,

22 THE CLINICAL ADVISOR • JANUARY 2019 • www.ClinicalAdvisor.com

CRNP, FNP-BC, is assistant professor of nursing at Edinboro University of Pennsylvania and director of the Edinboro-Clarion University DNP Consortium Program; she is currently practicing at a Veterans’ Administration community-based outpatient clinic.

18. Colidron B. American Academy of Dermatology statement on Journal of Internal Medicine study on sun exposure, vitamin D levels and mortality. American Academy of Dermatology website. Available at: https://www. newswise.com/articles/american-academy-of-dermatology-statement-onjournal-of-internal-medicine-study-on-sun-exposure-vitamin-d-levels-and-

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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2019 23

CME

Christina Murphey, PhD, RNC-OB Texas A&M University Corpus Christi, Texas

Release Date: January 10, 2019 Expiration Date: January 10, 2020 Estimated Time to Complete: 45 minutes Maximum Credits: 0.75 AMA PRA Category 1 Credit(s)TM

FEATURED COURSE LEARNING OBJECTIVES After completing this activity, the participant should be better able to: • Summarize familial whole-genome sequencing genetic mutations associated with breast cancer • Describe evidencebased screening and treatment recommendations for clinicians and patients alike COMPLETE THE POSTTEST: Page 31

Accredited Provider: This activity is provided by Haymarket Medical Education. Program Description: A goal of whole-gene sequencing (WGS) is to provide clinicians with data that can support diagnostic and treatment guidance not possible before; primary care clinicians are now able to use it to educate and counsel patients regarding disease risks and treatment options, so that patients and families can participate in the decision-making process to facilitate optimal care. The purpose of this article is to educate and equip primary care clinicians to understand and implement clinical practice guidelines and to guide decisionmaking involving WGS on the part of patients undergoing breast cancer treatment. Intended Audience: This activity has been designed to meet the educational needs of primary care health care professionals who will treat patients with or at risk for breast cancer. Conflict of Interest Disclosure Policies: In accordance with the ACCME Standards for Commercial Support, Haymarket Medical Education (HME) requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. HME resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational activities. Faculty Tammy Walker-Smith, DNP, MHA, MSN, APRN, FNP Texas A&M University Corpus Christi, Texas

Jessica L. Peck, DNP, APRN, CPNP-PC, CNE, CNL Texas A&M University Corpus Christi, Texas All faculty have no relevant financial relationships to disclose. Nick Zittell Director, Grant and Content Development Haymarket Medical Education Paramus, NJ Mr. Zittell has no financial relationships with commercial interest(s). HME staff involved in the review of this activity have no relevant financial relationships to disclose. Accreditation Statement: Haymarket Medical Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Designation Statement: Haymarket Medical Education designates this enduring material for a maximum of 0.75 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Disclosure of Unlabeled Use: This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical education purposes only and is not meant to substitute for the independent medical judgment of a clinician relative to diagnostic and treatment options for a specific patient’s medical condition.

Provided by

CME FEATURED COURSE: TAMMY WALKER-SMITH, DNP, MHA, MSN, APRN, FNP; CHRISTINA MURPHEY, PHD, RNC-OB; JESSICA L. PECK, DNP, APRN, CPNP-PC, CNE, CNL

Addressing Whole-Genome Sequencing and Breast Cancer in Primary Care Whole-genome sequencing data collection includes the identification of disease processes, such as breast cancer, linked to well-known phenotypes.

he National Institutes of Health Human Genome Project, initiated in April 1999, was the first collaborative research initiative to map and sequence a reference human genome completely.1,2 Currently, the whole-genome sequencing (WGS) program continues to collect data from participants with specific clinical outcomes of interest and previously identified phenotypes in the database.1,3 The objectives of ongoing WGS data collection include, for example, the identification of disease processes linked to well-known phenotypes among 62,000 study participants with breast cancer.4 WGS provides clinicians with data that can support diagnostic and treatment guidance not possible before; primary care clinicians are now able to use it to educate and counsel patients regarding disease risks and treatment options, so that patients and families can participate in the decision-making process to facilitate optimal care. The purpose of this article is to educate and equip primary care clinicians to understand and implement clinical practice guidelines and to guide decision-making involving WGS on the part of patients undergoing breast cancer treatment. Whole-Genome Sequencing: Process and Evolution

WGS provides clinicians with data to support diagnosis and treatment.

To understand WGS, it is important to know that a genome consists of a complete set of deoxyribonucleic acid (DNA), found in every cell that has a nucleus.The DNA construct includes 4 nitrogen bases, and the order of these bases encodes the

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2019 25

CME FEATURED COURSE

TABLE 1. Breast Cancer Biomarkers and Molecular Subtypes13 HR Status (HR+/–)

Molecular Subtype

Tumor Growth

Prognosis

Grade of Cancer Cell

HR+ (ER+)

Luminal A: HER2– (without increased HER2 levels)

Slow

Good

Low

Luminal B: HER2+ (may or may not have PR)

Fast

Poor

High

HR–

HER2 enriched (HER2+)

Very fast

Poor

High

HR–

Triple negative (ER–, HER2–, and PR–) (basal cell subtype)

Limited information

Poorest (target therapy not available for this subtype)

Based on cancer stage

ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; HR = hormone receptor; PR = progesterone receptor.

biological information that makes each individual unique.5,6 Genetic expression and genotypes are identified through laboratory testing in which the bases of the genome are sequenced during several steps: (1) Bacterial cells and chemicals are used to break down DNA sufficiently for extraction, and the DNA is released and purified; (2) the DNA is sheared with enzymes or mechanically cut, after which a polymerase chain reaction produces DNA fragment copies for the sequencing library; and (3) DNA is sequenced through special placement identification in which a computer assembles and combines the sequences.7 This process was originally called “shotgun sequencing” but is now known as WGS.8 Quality assurance data for the completed human genome sequence indicate 99.99% accuracy for more than 95% of the human genome.2 The initial phase of the WGS effort, completed in 2003, cost $2.7 billion.6 The costs are attributed to the extensive testing and analyses required to read a human diploid genome, which has around 6 billion bases.2 On average, the cost in late 2015 was less than $1500 per reading.2 Because of the intensive work required to sequence a whole genome, a more targeted process, called whole exome sequencing, has been developed to sequence key genetic segments of an individual’s DNA, called exons, which provide instructions (or coding) for making proteins.2 (All the exons in a genome are known as the exome.) Because whole-exome sequencing is less labor-intensive and requires only about 1.5% of the effort that an entire WGS process entails in reading sequence bases, whole-exome sequencing is the least expensive option for patients with financial constraints.2 These advances in sequencing has led to BRCA mutation testing to identify patients who may carry a mutated form of this gene, and clinicians can use the information for early detection of the disease and to develop individualized treatment plans.9

Familial Genetic Link to Disease Processes

Pedigree analysis contributed to the initial identification of breast cancer as an inherited disease. By studying different families with a history of breast cancer, researchers determined in clustering studies a link between genetic mutations and familial breast cancer.10 BRCA1- and BRCA2-related breast cancers have been identified through WGS, and high-penetrance mutations of BRCA1 and BRCA2 have been studied extensively.10 Providers who are competent in genomics use evidence-based clinical practice to initiate WGS testing for the early detection and treatment of breast cancer, which allows a better quality of life for patients with a genetic mutation linked to breast cancer.11,12 WGS technology comes with both advantages and disadvantages. Primary care clinicians, who are well positioned to identify patients with family histories that indicate a potential for genetic diseases,12 can test and identify patients early so that personalized plans of care can be prepared, environmental exposure risks identified, and educational information on newly available treatment options provided.9 Disadvantages include the inability of many clinicians to translate genetic test findings into comprehensive genetic counseling, as well as the difficulties of supporting and offering guidance to patients who may fear the unknown when faced with a potential disease-causing genetic mutation.11 Effect of the BRCA Mutation

The national breast cancer mortality rates per 100,000 women identified between 2011 and 2015 according to ethnicity are: non-Hispanic black, 29.5; non-Hispanic white, 20.8;American Indian, 14.3; Hispanic/Latino, 14.2; and Asian/Pacific Islander, 11.3.13 Breast cancers associated with an inherited mutation accounted for between 5% and 10% of all breast cancers.14 Early studies had shown that the cumulative lifetime risk for breast cancer among women identified as carriers of an allele

26 THE CLINICAL ADVISOR • JANUARY 2019 • www.ClinicalAdvisor.com

mutation was 92%; this risk was determined from an analysis of a research data collection in which 4730 patients who had a diagnosis of breast cancer were compared with a control group of 4688 women who did not have breast cancer.15 Those who did not have a breast cancer allele mutation and did not have breast cancer were identified as having a lifetime risk for breast cancer of 10% related to nongenetic factors.15 The germline BRCA1 mutation is considered the most common cause of hereditary breast cancer of early onset, in addition to ovarian cancer syndrome.16 More than 80% of cancers with a BRCA1 mutation do not express the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) (Table 1).16 The loss of BRCA1 functionality causes an estrogen receptor-negative type of breast cancer due to the loss of breast stem cell differentiation.16 Per Online Mendelian Inheritance in Man (OMIM), BRCA1-related susceptibility to breast cancer is attributed to the phenotype-gene relationship and the gene location (17q21.31); inheritance is most commonly autosomal dominant and/or multifactorial in nature, especially in postmenopausal women (Table 2).15 BRCA2 carriers have a higher incidence of ovarian cancer, with an overall lifetime risk of between 10% and 20%; however, studies have shown that those with a BRCA1 or BRCA2 gene mutation were found to have a lower risk for gynecologic or breast cancers if an oophorectomy was performed preventively.17 BRCA2-related susceptibility to breast cancer is attributed to the phenotype-gene relationship and gene location (13q13.1), and inheritance is most commonly autosomal dominant in nature.17 BRCA1 carriers have a 54% cumulative risk for a breast cancer diagnosis by age 60, whereas BRCA2 carriers have a 71% cumulative risk.15 Implications of Genetic Testing and Diagnosis

WGS has been used for the last 20 years to test for BRCA1 and BRCA2 gene mutations. In one study from the University of Michigan, research was focused on genetic testing for patients with breast cancer, aged 20 to 79 years, who had undergone surgical intervention 2 months before being surveyed through the

mail.The response rate was 71%, with 2529 responses in total.18 Of the respondents, 66% wanted to undergo genetic testing and 29% had already done so. Of the high-risk patients who declined genetic testing, 56.1% said their care provider did not encourage genetic testing, 13.7% cited cost constraints, 10% were not interested in testing, and 0.2% cited family disapproval of testing.18 Evidence-based breast cancer screening and treatment recommendations are provided by the National Comprehensive Cancer Network (NCCN) and made available to clinicians to ensure quality patient care, education, and resource management regarding identified cancers. The NCCN also provides guidance for patients in a clinically rigorous and verifiable online environment, explaining genetic testing, options, and new advances in technology.18,19 The NCCN guidelines for breast cancer risk assessment provide information about more in-depth genetic testing for patients with any the following: diagnosis of breast or ovarian cancer; known Ashkenazi Jewish origin17 (1 of every 9 women with recurring BRCA2 genetic mutations); one or multiple first-degree relatives with cancer of the breast or ovaries; known family genetic mutation (ie, BRCA1/2); and/or personal or family history of pancreatic cancer.19 Testing for BRCA1 and BRCA2 rather than WGS can be discussed with patients if cost is an issue.20 Cancer originates from either germline or somatic mutations.These pathways signal activation and must be deactivated through the targeted treatment of cancer cells identified by genetic sequencing.21 New treatments of breast cancer based on somatic mutation profiling can be individualized according to the findings of genetic sequencing and analysis.12 Advances in Targeted Gene Therapy

The Trans-Omics for Precision Medicine (TOPMed) Program is using data collected from new techniques combined withWGS data from previous research studies and clinical outcome findings to expand activities geared to precision medicine. The goal is to initiate new research, establish repository databases, and ensure that precision medicine is fully supported to allow additional advances in treatments and genetic understanding.22 Since 2010,

TABLE 2. Breast Cancer Phenotype-Gene Relationships15,17 Chromosomal Location

Phenotype

Phenotype MIM Number

Inheritance

Phenotype Mapping Key

Gene

Gene/Locus MIM Number

17q21.31

Breast-ovarian cancer, familial, 1

604370

Multifactorial; AD

BRCA1

113705

13q13.1

Breast-ovarian cancer, familial, 2

612555

BRCA2

600185

AD = autosomal dominant; MIM = Mendelian inheritance in man.

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CME FEATURED COURSE

Whole-genome sequencing has revolutionized our understanding of genetic mutations and the application of genetic testing to treatment options. two tests based on specific genetic markers and gene expression have been approved by the Food and Drug Administration (FDA) for patients with breast cancer: MammaPrint and Oncotype DX.23 MammaPrint identifies gene profiles that may help patients and providers decide if adjuvant therapy is warranted. Oncotype DX formulates a recurrence score based on the expression of 21 genes; the assay was validated in 2 different studies that tested outcomes when tamoxifen was administered alone (n = 227) and together with cyclophosphamide or methotrexate plus 5-fluorouracil (n=424). In the 10-year survival study, the survival rates increased from 60% in the patients given tamoxifen alone to 88% in the patients given tamoxifen with adjuvant therapy.23 During genetic profiling, breast cancers are grouped into molecular subtypes through the identification of biological markers.24 One such biological marker is estrogen receptor gene expression (ER+); cancers that are ER+ are then subdivided into luminal A and luminal B cancers.24 The identification of a cancer as luminal A or luminal B helps to determine the type of cancer, the prognosis, and the most effective targeted treatment plan.24 ER+ luminal A cancers respond well to antihormonal treatments and do not grow as fast as other breast cancers, features that suggest a favorable prognosis.13 The outcomes of ER+ luminal B cancers are less favorable because these cancers exhibit a lesser degree of cell differentiation and a more aggressive growth rate.13 Clinicians and their patients with breast cancer can use the results of genetic testing performed before surgical intervention to make decisions regarding possible sequential and/or alternative therapies.20 The gene activation signatures for 4510 breast cancer gene expression profiles were analyzed with the Denoising Algorithm based on Relevance network Topology (DART) to predict gene activation status in 1733 selected models.25 The Absolute Inference of the Patient Signature (AIPS) was able to distinguish luminal A from luminal B cancer types in 74.5% (1291/1733) of the models.25 One study found that WGS of a breast tumor provided a lead time of 11 months for the identification of metastasis in 86% of the participants. In another study, the detection of circulating tumor DNA (ctDNA) in the bloodstream after treatment was linked to the identification of metastatic recurrence with a lead time of 7.9 months.11 These findings indicate that additional lead time/warning of metastasis obtained with WGS does influence patient treatment choice(s).12 WGS makes it possible to predict medication sensitivity and therapeutic response, and to identify patients who cannot tolerate cancer treatments without toxic side effects.12 This is done by identifying patients with dihydropyrimidine dehydrogenase (DPD) deficiency, which is due to mutations in the DYPD gene located

at chromosome 1p22. Individuals with DPD deficiency cannot metabolize certain pyrimidine analog cancer treatments.12 Management: What Is the Role of Genomics in Primary Care?

Primary care clinicians are uniquely well positioned to integrate cutting edge genetic breakthroughs into treatment, to provide information about new technologies and advances in genomics in a way that laypersons can understand, and to give patients the tools they need to make informed decisions about care.9 The ethical and professional dilemma is to maintain balance, respect, and objectivity and to provide information without bias.9 On an organizational level, advanced practice clinicians are change agents leading the way to create a genetic vision enabling collaboration and a platform for patient advocacy with the goal of improved health outcomes.26 One approach to consider is screening patients during an annual office visit with a Breast Cancer Risk Assessment Tool (BCRAT), which assists clinicians in identifying patients with a family history of breast cancer and/or additional risk factors for breast cancer (Table 3).27 TABLE 3. Components of the National Cancer Institute’s Breast Cancer Risk Assessment Tool27 Assessing Patient Eligibility

• Does the woman have a medical history of any breast cancer, ductal carcinoma in situ or lobular carcinoma in situ, or has she received previous radiation therapy to the chest for treatment of Hodgkin lymphoma? • Does the woman have a mutation in either the BRCA1 or BRCA2 gene, or does she have a diagnosis of a genetic syndrome that may be associated with elevated risk of breast cancer?

Demographic Information

• What is the patient’s age? (Note that this tool calculates risk for women between the ages of 35 and 85.) • What is the patient’s race/ethnicity? • If Hispanic/Latina or Asian American, what is the sub-race/ethnicity or place of birth?

Patient and Family History

• Has the woman ever had a breast biopsy? • If yes, how many breast biopsies (both positive and negative) has the woman had? • Has the woman ever had a breast biopsy with atypical hyperplasia? • What was the woman’s age at the time of her first menstrual period? • What was the woman’s age when she gave birth to her first child? • How many of the woman’s first-degree relatives (mother, sisters, daughters) have had breast cancer?

28 THE CLINICAL ADVISOR • JANUARY 2019 • www.ClinicalAdvisor.com

Genetic and genomic science and technology have evolved to complement each other and improve patient outcomes through genetic testing. The BCRAT is calibrated to provide an accurate 5-year breast cancer prediction score for women of all ethnicities.28 The risk assessment tool allows clinicians to determine whether genetic counseling, genetic testing, additional diagnostics, and/or referral to an oncologist may be warranted while at the same time providing collaboration and social support to the patient.29 With the nurse practitioner role in mind, the American Nurses Association (ANA) sent a letter to representatives of the Presidential Commission for the Study of Bioethical Issues highlighting the ability of the nursing profession to contribute to the development of an ethical and responsible approach to genomics. In addition, the ANA recommended the development of an advisory body for bioethical practices to assist in establishing a multidisciplinary approach in biomedical advancement/technology.30 The Susan G. Komen Foundation is a key stakeholder and supports a website providing resources to the public with the mission of educating patients about cancer and treatment options.31 This is a potential reference to which primary care clinicians can direct patients who want to learn more about cutting edge treatments, studies, testing, and the survival rates achieved with specific combination treatment modalities.The website has a section presenting information from peer-reviewed clinical trials and preeminent researchers regarding efficacy and success rates of treatment and survival rates 10 years after the completion of treatment.31 With these data, primary care clinicians can provide credible and tangible information written in a way that the layperson can understand. Future Benefits of Genomics

The transition to health care with advancements in genomic technology has made it possible to offer preventive care to patients before the appearance of a breast lump or dimpling or the puckering of breast tissue, signs of disease progression.14 Past breakthroughs from genomics and WGS have provided the foundation for endless possibilities, such as healthy autologous skin grafts or possibly breast tissue implants with one’s own genetic makeup.11 Policy Implications

The ethical, legal, and social implications of learning one’s risk for specific disease patterns have legal ramifications related to the misuse of such information for discriminatory purposes.32 Once people know their genetic makeup and are aware of any genetic risk, there is a real concern that employers with access to that information will have the leverage to deny employment for a prospective candidate, or that health

insurance companies will deny coverage.33 The US Equal Employment Opportunity Commission enforces the federal Genetic Information Nondiscrimination Act (GINA) of 2008, which included the creation of a Genetic Nondiscrimination Study Commission 6 years after passage of the law to ensure that new technologies in genetics would be reviewed to determine the need for potential revisions and/or additions to GINA.34 The provisions include protection from health insurance denials on the basis of genetic makeup and from denial or termination of employment on the basis of genetic findings. Genetic information, including an employee’s or an employee’s family member’s health history or the results of genetic monitoring, cannot be shared with employers. Harassment related to genetic health information is also prohibited and unlawful.33 Because certain treatment modalities are still very new, some oncology institutions have created “molecular tumor boards” to review decisions about patient drug therapy based on nextgeneration sequencing and genetic findings.12 The precision medicine initiative reflects the FDA goal to streamline the approval of genetic treatments as medical care tailored according to each patient’s genetic makeup.35 To advance research further, it has been recommended that international clinical trials be conducted by teams of experts in multiple disciplines. The FDA has also granted several new cancer drugs “expedited approval” based on the results of phase 2 “basket trials,” with specific stipulations attached.12 The primary care clinician is in a unique position to educate, guide, and counsel patients about undergoing genetic testing, interpreting the results, and translating the genetic information received.The ability of these providers to help patients calm their fears, understand the significance of their family history, and make informed decisions is integral in planning patient care.9 The fear of carrying the BRCA mutation among women whose relatives have a history of breast cancer is very real.9 The ability to rule out the presence of this mutation or to know and prepare in advance is an advantage that women did not have 30 years ago. One dilemma that patients face is what to tell other family members if the results of testing for the BRCA mutation are positive. Physician assistants, nurses, nurse practitioners, and nurse navigators in particular, are ideally suited to help patients navigate these valid concerns and issues.2 The questions of whether to share genetic information and the diagnosis of a disease process carry social implications and privacy concerns. Confidentiality and the consent for such testing are at the forefront of the issues regarding

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CME FEATURED COURSE

ensuring ethical practices in the healthcare field.9 The cost of genetic testing may be a barrier for some patients, but this has decreased significantly since the introduction of WGS. The availability of next-generation sequencing, and its attendant lower costs, may provide a viable alternative for patients with financial constraints.2

7. The whole genome sequencing (WGS) process. https://www.cdc.gov/pulsenet/ pdf/genome-sequencing-508c.pdf. [ND]. Accessed September 19, 2018. 8. NHGRI policy for release and database deposition of sequence data. National Human Genome Research Institute. https://www.genome. gov/10000910. Published December 21, 2000. Reviewed February 24, 2012. 9. Huddleston K. Ethics: the challenge of ethical, legal, and social implications (ELSI) in genomic nursing. Online J Issues Nurs. 2013;19:6.

Conclusion

10. Sokolenko AP, Suspitsin EN, Kuligina ESh, Bizin IV, Frishman D,

The impact of WGS on the role of primary care in cancer prevention and management, patient options for testing, and, importantly, the implications for selection of treatment modalities, has changed the landscape for patients who may have a genetic predisposition for breast cancer. Moreover, our understanding of genetics and genetic sequencing is continually expanding to provide better guidance for the prevention and treatment of the spectrum of other solid tumors and hematologic malignances. As technology becomes more advanced, primary care clinicians will play an increasingly important role not only in advising patients but also in detecting those who are most likely to benefit from genetic testing.2 The goal of promoting optimal health outcomes by preventing disease and planning for future patient needs is already part of the nursing process.9 Scientific boundaries will continue to expand, so that primary care clinicians who are competent in this emerging field and who adhere to Ethical, Legal, and Social Implications (ELSI) for new and exciting healthcare practices/guidelines will be essential in shaping the overall direction of genomics.9 The WGS technology and database will be expanded further in the hope of identifying additional disease processes to ensure improved patient outcomes among diverse groups of people.4 ■

Imyanitov EN. Identification of novel hereditary cancer genes by whole exome sequencing. Cancer Lett. 2015;369:274-288. 11. Huston C. The impact of emerging technology on nursing care: warp speed ahead. Online J Issues Nurs. 2013;18:1. 12. Niravath P, Cakar B, Ellis M. The role of genetic testing in the selection of therapy for breast cancer: a review [published online August 25, 2016]. JAMA Oncol. doi: 10:1001:jamaoncol.2016.2719. 13. Breast cancer facts & figures 2017-2018. American Cancer Society. https:// www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/ breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2017-2018.pdf. Accessed September 19, 2018. 14. Breast cancer treatment (PDQ®)-patient version. National Cancer Institute. https://www.cancer.gov/types/breast/patient/breast-treatment-pdq. Updated April 12, 2018. Accessed September 19, 2018. 15. McKusick VA, Kniffin CL. Breast-ovarian cancer, familial, susceptibility to, 1; BROVCA1. OMIM entry # 604370. http://omim.org/entry/604370? search=BRCA1&highlight=brca1. Created December 17, 1999. Updated December 16, 2009. Accessed September 19, 2018. 16. Natrajan R, Mackay A, Lambros MB, et al. A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers. J Pathol. 2012;227:29-41. 17. Kniffin CL. Breast-ovarian cancer, familial, susceptibility to, 2; BROVCA2. OMIM entry # 612555.http://omim.org/entry/612555?search= BRCA2&highlight=brca2. Created January 27, 2009. Updated December 16,

References

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biology and medicine. Genome Med. 2013;5:79.

among patients with newly diagnosed breast cancer. JAMA. 2017;317:531-534.

2. The cost of sequencing a human genome. National Human Genome

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Research Institute. https://www.genome.gov/sequencingcosts. Updated

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https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf.

3. Manolio TA, Collins FS. The HapMap and genome-wide association studies

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4. Whole-genome sequencing (WGS) project. National Heart, Lung, and

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21. Tran DDH, Saran S, Koch A, Tamura T. mRNA export protein THOC5

medicine-topmed-program. Accessed December 4, 2018.

as a tool for identification of target genes for cancer therapy. Cancer Lett.

5. DNA sequencing. National Human Genome Research Institute.

2016;373:222-226.

https://www.genome.gov/10001177/dna-sequencing-fact-sheet. Updated

22. Trans-Omics for Precision Medicine (TOPMed) program. National Heart,

December 18, 2015. Accessed September 19, 2018.

Lung, and Blood Institute. https://www.nhlbi.nih.gov/science/trans-omics-

6. The human genome project completion: frequently asked questions.

precision-medicine-topmed-program. [ND]. Accessed September 19, 2018.

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23. Breast cancer treatment (PDQ®)-health professional version. National

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questions. Updated October 30, 2010. Accessed September 19, 2018.

pdq. Updated May 31, 2018. Accessed September 19, 2018.

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24. Akoz G, Diniz G, Ekmekci S, Ekin ZY, Uncel M. Evaluation of human

30. ANA advises federal agencies. American Nurses Association. http://www.

epididymal secretory protein 4 expression according to the molecular

nursingworld.org/MainMenuCategories/Policy-Advocacy/Federal/Agencies/

subtypes (luminal A, luminal B, human epidermal growth factor receptor

ANA-Advises-Federal-Agencies. [ND]. Accessed September 19, 2018.

2-positive, triple-negative) of breast cancer. Indian J Pathol Microbiol. 2018;61:

31. Research table topics. Susan G. Komen. http://ww5.komen.org/

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BreastCancer/ResearchTableTopics.html. Updated January 25, 2018. Accessed

25. Paquet ER, Lesurf R, Tofigh A, Dumeaux V, Hallett MT. Detecting gene

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signature activation in breast cancer in an absolute, single-patient manner.

32. Genetic information discrimination. U.S. Equal Employment Opportunity

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26. Naccarella L, Butterworth I, Moore T. Transforming health professionals

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into population health change agents. J Public Health Res. 2016;5:643.

33. Genetic discrimination. National Human Genome Research Institute.

27. The breast cancer risk assessment tool. National Cancer Institute.

https://www.genome.gov/10002077. Updated August 29, 2017.

https://www.cancer.gov/bcrisktool/Default.aspx. [ND]. Accessed September

34. The Genetic Nondiscrimination Act of 2008. U.S. Equal Employment

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Opportunity Commission. https://eeoc.gov/laws/statutes/gina.cfm. Approved

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35. Precision medicine. U.S. Food and Drug Administration. https://www.fda.

29. Gabram SG, Dougherty T, Albain KS, et al. Assessing breast cancer risk and

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Accessed September 19, 2018.

CME

POSTTEST Expiration date: January 10, 2020

A statement of credit will be issued only upon receipt of a completed preassessment test, activity evaluation form, and posttest with a score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/Jan19feature. CREDITS: 0.75 | Addressing Whole-Genome Sequencing and Breast Cancer in Primary Care

1. Which of the following familial genetic mutations are associated with breast cancer? a. APB24 c. BRCA2 b. BRCA1 d. BRCA1 and BRCA2

4. The Breast Cancer Risk Assessment Tool is calibrated to predict a woman’s risk of getting breast cancer in the next: a. 1 year c. 5 years b. 3 years d. 7 years

2. Which of the following programs applies precision medicine principles to collect WGS and other genomic data to generate new scientific resources? a. Trans-Omics for Precision Medicine (TOPMed) b. Germline mutation study c. Sequencing DNA study d. None of the above

5. Primary care clinicians have a unique opportunity to provide patients with key information on genetic testing, resources, and new treatment modalities. Increased clinician competency in genetics will help shape the direction of genomics by addressing what essential healthcare practice? a. Nursing process b. Ethical, legal, and social implications c. Case management d. All of the above

3. What is the cumulative lifetime risk for women who are carriers of the genetic allele mutation? a. 50% c. 87% b. 65% d. 92%

TO TAKE THE POSTTEST please go to: ClinicalAdvisor.com/Jan19feature

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Dermatology Clinic CASE #1

Erythematous, Scaly Scalp Lesions JOY TAN, BS;TALIA NOORILY, BA; CHRISTOPHER RIZK, MD

A 49-year-old man presents to the clinic with a 2-year history of lesions on his scalp. The lesions began as scaly, red spots that slowly expanded to cover his scalp. He still gets new spots, and he noticed that the older lesions eventually fade and stop growing. He loses hair wherever the lesions appear. On examination, multiple erythematous, indurated, coalescing plaques with adherent scale are noted on the vertex and occipital scalp. Several hypopigmented, depressed, atrophic patches are also visualized. What is your diagnosis? Turn to page 34

CASE #2

Nonblanching, Irregularly Shaped Plaques ANNA POLINER, BSA;TALIA NOORILY, BA; CHRISTOPHER RIZK, MD

A 42-year-old man presents to the clinic with a rash on his right thigh that he first noticed 4 months earlier. The rash originally had a red color but was asymptomatic. The patient reports being otherwise healthy. He denies taking any medications. He has never had a similar rash in the past. On examination, multiple brown, irregular, nonblanching plaques are noted on the patient’s right upper leg. On dermoscopy, multiple tiny red puncta are seen within the plaques. What is your diagnosis? Turn to page 35 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2019 33

Dermatology Clinic CASE #1

Discoid Lupus

The term lupus, which is Latin for wolf, dates back to the 10th century, when it was first used to describe aggressive skin lesions resembling a wolf ’s bite. Later, lupus was found to be a multisystem autoimmune disease with numerous diverse symptoms. Lupus erythematosus (LE) can be categorized as systemic lupus erythematosus (SLE) or cutaneous lupus erythematosus (CLE). CLE is further differentiated into acute (ACLE), subacute (SCLE), and chronic (CCLE) subtypes.1,2 Discoid lupus erythematosus (DLE) is the most common subtype of CCLE. Discoid lupus accounts for the majority of CLE skin lesions (80%), followed by SCLE (15%).1 DLE most commonly affects women in the third or fourth decade of life and is seen most frequently in African American individuals; however, it is also seen in a multitude of ethnic groups.1,3,4 Lupus erythematosus involves a group of illnesses caused by autoimmunity to self antigens (nucleosomes and ribonucleoproteins).5 Cutaneous disease can exist independently or with systemic disease. Simply, one can think of LE on a spectrum: mild disease may manifest only with discoid skin lesions, and severe disease may manifest with severe systemic manifestations such as nephritis and vasculitis. Of the cutaneous lupus subtypes, ACLE is nearly always associated with visceral involvement, SCLE meets SLE criteria in approximately 50% of cases, and CCLE usually presents with skin-only or skin-predominant disease. Fortunately, only 5% to 10% of patients with DLE will go on to develop SLE. Still, discoid lupus is often disfiguring and permanent, and can significantly affect a patient’s quality of life.3 Discoid rashes most often affect sun-exposed areas, including the face, scalp, ears, neck, upper chest, and extensor surfaces of the arms. Occasionally, the rash can present as a symmetric, hyperkeratotic, butterfly-shaped plaque across the malar areas of the face and the bridge of the nose. Less often, it presents as a generalized discoid rash with cutaneous involvement above and below the neck.1,3,6 In its early form, DLE is characterized by erythematous macules or papules that rapidly grow and coalesce into hyperkeratotic plaques. Classically, early DLE lesions grow into larger indurated, round plaques with peripheral scale that eventually progress to become atrophic scars. When DLE lesions expand, they develop erythema and hyperpigmentation at the periphery, with atrophic scarring, hypopigmentation, and telangiectasia

in the center.Thus, DLE lesions are more notable in darkerskinned individuals.When expanding, DLE lesions can also merge, forming confluent and disfiguring plaques. DLE lesions can affect hair-bearing regions such as the scalp and eyebrows, causing a scarring alopecia. Extension of lesions into hair follicles, also known as follicular plugging, is a classic finding associated with DLE lesions. Keratin can accumulate in the hair follicle; when peeled back, a keratotic spike seen under the scaly surface is known as the carpet-tack sign.1,6 The differential diagnosis for discoid lupus includes basal cell carcinoma, actinic keratosis, lichen planus, tinea faciei, secondary syphilis, sarcoidosis, cutaneous tuberculosis, leprosy, scars, and other subtypes of CLE such as SCLE.1 As DLC classically presents as a coin-shaped plaque with hyperpigmented or erythematous borders and central scarring, these features help to differentiate it from other diseases. As mentioned, hyperkeratosis and extension into hair follicles is common. The most frequent locations for DLE presentation include the face, scalp, and ears.3,7 Early active

Discoid lupus classically presents as a coinshaped plaque with hyperpigmented or erythematous borders and central scarring. lesions of DLE look similar to other subtypes of CLE, such as ACLE and SCLE. However, induration is more common in DLE and can be useful in differentiating it from other subtypes of CLE.8 The diagnosis of cutaneous lupus is often made in the context of known underlying SLE. Skin biopsy confirms the diagnosis. Histopathology of CLE is similar across many subtypes; therefore, although helpful in diagnosis of DLE, it is not definitive. Some shared histopathologic findings in CLE include hyperkeratosis, thickening of the basement membrane, follicular damage, leukocytic infiltration, interface dermatitis, liquefactive damage to the basal cell layer, and deep dermal involvement. Of those listed, findings more suggestive of DLE than other CLE subtypes include hyperkeratosis, follicular plugging, and basement membrane thickening. Direct immunofluorescence and antibodies have unclear value in confirming the diagnosis. In direct immunofluorescence, granular deposits of immunoglobulins and complement may be visualized along the basement membrane zone in lesions. However, these findings are not unique to LE and can be found in other skin disorders. In addition, these findings are only positive in sun-involved skin; therefore,

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immunofluorescence in sun-protected skin will almost always be negative in patients with DLE.1,8 There is no cure for discoid lupus, but multiple therapies are available for symptom management. Initial management requires ruling out systemic involvement. Patients should be advised to discontinue smoking and limit sun exposure with both broadspectrum sunscreen and wearing sun-protective clothing to avoid triggers.They should also be instructed to avoid drugs that cause photosensitivity such as tetracycline, griseofulvin, hydrochlorothiazide, and piroxicam. First-line medical therapies include high-potency topical corticosteroids, intralesional corticosteroids applied to active lesions monthly, and topical calcineurin inhibitors. Hydroxychloroquine and acitretin have also been shown to have approximately 50% efficacy in treatment of cutaneous lupus and should be considered in those with systemic symptoms.3,9,10 In patients with refractory symptoms, second-line therapies such as retinoids, methotrexate, thalidomide, mycophenolate, azathioprine, and dapsone have shown some efficacy.2,10 The patient in the case described above was diagnosed with discoid lupus and was advised to limit sun exposure.Treatment with hydroxychloroquine and intralesional corticosteroids applied to his scalp lesions was initiated monthly. At 3-month follow-up, notable regression of the lesions was noted. Joy Tan, BS, is a medical student; Talia Noorily, BA, is a medical student; and Christopher Rizk, MD, is a dermatology fellow at Baylor College of Medicine, Houston,Texas. References 1. Grönhagen CM, Nyberg F. Cutaneous lupus erythematosus: an update. Indian Dermatol Online J. 2014;5(1):7-13. 2. Sontheimer RD, Thomas JR, Gilliam JN. Subacute cutaneous lupus erythematosus: a cutaneous marker for a distinct lupus erythematosus subset. Arch Dermatol. 1979;115(12):1409-1415. 3. Costner MI, Sontheimer RD. Lupus erythematosus. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. eds. Fitzpatrick’s Dermatology in General Medicine, 8th ed. New York, NY: McGraw-Hill; 2012. 4. Lateef A, Petri M. Unmet medical needs in systemic lupus erythematosus. Arthritis Res Ther. 2012;14(Suppl 4):S4. 5. Janeway CA, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th ed. New York: Garland Science; 2001. 6. Cardinali C, Caproni M, Bernacchi E, Amato L, Fabbri P. The spectrum of cutaneous manifestations in lupus erythematosus-the Italian experience. Lupus. 2000;9(6):417-423. 7. Obermoser G, Sontheimer RD, Zelger B. Overview of common, rare and atypical manifestations of cutaneous lupus erythematosus and histopathological correlates. Lupus. 2010; 19(9):1050-1070. 8. Haber JS, Merola JF, Werth VP. Classifying discoid lupus erythematosus: background, gaps, and difficulties. Int J Womens Dermatol. 2017;3(1 Suppl):S62-S66.

9. Sontheimer RD. Skin manifestations of systemic autoimmune connective tissue disease: diagnostics and therapeutics. Best Pract Res Clin Rheumatol. 2004;18(3):429-462. 10. Jessop S, Whitelaw DA, Grainge MJ, Jayasekera P. Drugs for discoid lupus erythematosus. Cochrane Database Syst Rev. 2017:CD002954.

CASE #2

Pigmented Purpuric Dermatoses

Pigmented purpuric dermatoses (PPD) are a group of chronic, relapsing skin conditions that typically present with symmetrical bronze discoloration, petechiae, and pigmented macules on the lower extremities.1-3 There are 5 main subcategories of PPD based on varying clinical presentation: progressive pigmented purpuric dermatosis (Schamberg disease), purpura annularis telangiectodes (Majocchi disease), lichen aureus, pigmented purpuric lichenoid dermatosis (PPLD) of Gougerot-Blum, and eczematid-like purpura of Doucas-Kapetanakis.1,4 Other rare presentations include itching purpura of Loewenthal, as well as linear, quadrantic, transitory, granulomatous, and familial forms.Although many clinical variants have been described, those with related histopathology are typically managed in a similar manner.1,2 Besides experiencing rash, patients are generally asymptomatic, although some may experience slight itching with Schamberg disease and more severe itching with eczematid-like purpura of Doucas-Kapetanakis.1 Schamberg disease is a chronic, persistent subtype of PPD characterized by orange or brown irregular plaques formed by small reddish puncta. The color occurs as a result of hemosiderin deposition. Although this type of PPD mainly affects the lower limbs, it may occur on any part of the body and may display a slow, proximal extension. Venous insufficiency likely plays a role in localization of this variant. Majocchi disease is associated with bluish-red annular macules and telangiectatic puncta; atrophy of the central area is also frequently identified. Similar to that seen with Schamberg disease, Majocchi disease begins on the lower limbs and may extend to the upper extremities. However, unlike the presentation of Schamberg disease, there is an absence of venous stasis in patients with Majocchi disease. Lichen aureus is more localized and associated with lichenoid papules, intensely purpuric lesions, and

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Dermatology Clinic golden-brown plaques that may occasionally affect the trunk and face. PPLD of Gougerot-Blum is also characterized by lichenoid papules that convulse to form plaques.This subtype is primarily localized to the legs and is rarely seen on the trunk and thighs. The presentation of eczematid-like purpura of Doucas-Kapetanakis is similar to that of Schamberg disease with extensive lesions; the differentiating characteristic is the severe pruritus that accompanies the lesions in the former. This subtype often spontaneously improves, although recurrences are not uncommon.1 PPD is a rather rare condition in the United States.1,3 Schamberg disease is the most common subtype and has been reported in all age groups.1,3-5 In general, PPD can present in all ages and races, with certain clinical subtypes presenting more frequently in specific age and racial groups. Itching purpura, PPLD, and the granulomatous variant occur predominantly in middle-aged individuals, while lichen aureus and Majocchi disease are more commonly seen in childhood or adolescence.1 Although PPD appears more commonly in men overall,1,3,4 individual clinical variants, such as Majocchi disease, seem to predominantly affect women.1

In addition to experiencing rash, patients with a pigmented purpuric dermatosis may present with varying degrees of itching. The etiology of PPD is unknown; however, a number of conditions and drugs have been implicated as cofactors in disease development.1 These conditions include chronic venous hypertension, exercise, capillary fragility, focal infections, chemical ingestion, and gravitational dependency.1 Associations with diabetes mellitus, rheumatoid arthritis, lupus erythematosus, thyroid dysfunction, hereditary spherocytosis, hematologic disorders, hepatic disease, porphyria, malignancies, hyperlipidemia, and hypercholesterolemia have been described.1,3 Although an association between PPD and hepatitis B and C infection had been reported, recent studies have cast doubt on a potential relationship.6 The most notable risk factors for the development of PPD seem to be venous insufficiency and long periods of standing during daily activities.3,4 Histomorphologic examination of PPD reveals superficial CD3+, CD4+, and CDIA+ lymphocytic infiltration, erythrocyte extravasations, and hemosiderin deposition.1,2 Cell-mediated immunity as well as immune complexes have been implicated in disease evolution.1 Clinically, PPD

is distinguished based on history, blood counts, biopsy, and if necessary, genetic testing.1,7,8 PPD is most frequently misdiagnosed as vasculitis, thrombocytopenia, or early mycosis fungoides. The differential diagnosis of PPD also includes hyperglobulinemic purpura, purpuric clothing dermatitis, stasis pigmentation, scurvy, leukocytoclastic vasculitis, and drug hypersensitivity reactions.1,5 Thus, a complete blood count and peripheral smear are necessary to rule out thrombocytopenia. Coagulation screen, bleeding time, platelet aggregation, and capillary fragility test help to exclude other causes of purpura. Testing for antinuclear antibodies, rheumatoid factor, anti-HBsAg antibody, and anti-hepatitis C virus antibody aids in excluding a rheumatologic or viral etiology. In PPD, laboratory testing is often unremarkable with occasional target-shaped, teardrop erythrocytes, anisocytosis, and hypochromia seen on peripheral blood smear.1 Dermatoscopy, which is a diagnostic technique that renders the corneal layer of skin translucent, may assist in visualization of the distinct pattern of petechiae and purpura.5 Serial biopsies and gene arrangement studies may be necessary to differentiate PPD from mycosis fungoides; a polyclonal T-cell population suggests the former while a monoclonal T-cell population suggests the latter. In many cases, PPD may mimic early mycosis fungoides and is even hypothesized to transform into mycosis fungoides due to their similar etiology of T-cell dyscrasia.7 Widespread involvement of purpuric patches and pruritus lasting longer than a year or atypical pigmented purpuric lesions should prompt further diagnostic measures, including serial biopsies and gene arrangement studies. Clinical picture and history, histology, and gene arrangement studies may aid in the distinction; however, differentiating between the 2 disorders remains a diagnostic limitation as PPD may histologically and/or genetically resemble mycosis fungoides.7,8 Although many cases of PPD are asymptomatic, the cosmetic effects of the persistent rash can cause significant distress to patients and affect quality of life.9 There is currently no proven medical intervention to treat PPD. Treating the underlying condition or removing the offending agent may be beneficial. The mainstay of treatment is symptom management via topical corticosteroids and antihistamines for pruritus. Leg compression and avoiding long periods of standing are recommended to prevent associated venous stasis.1 Psoralen photochemotherapy has been shown to be successful in treating Schamberg disease, pigmented purpuric dermatosis of Gougerot-Blum, and lichen aureus.1 Narrow-band ultraviolet B phototherapy has also demonstrated efficacy in Schamberg disease and Majocchi purpura.10 Griseofulvin, pentoxifylline,

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cyclosporine, and a combination of oral rutoside and ascorbic acid have shown encouraging results in small case studies.1 The patient in the case presented elected to undergo treatment with topical triamcinolone. At 1-month follow-up, the skin discoloration remained and had not significantly improved. ■

4. Sharma L, Gupta S. Clinicoepidemiological study of pigmented purpuric dermatoses. Indian Dermatol Online J. 2012;3(1):17-20. 5. Ozkaya DB, Emiroglu N, Su O, et al. Dermatoscopic findings of pigmented purpuric dermatosis. An Bras Dermatol. 2016;91(5):584-587. 6. Ehsani AH, Ghodsi SZ, Nourmohammad-Pour P, Aghazadeh N, Damavandi MR. Pigmented purpura dermatosis and viral hepatitis: a case-

Anna Poliner, BSA, is a medical student; Talia Noorily, BA, is a medical student; and Christopher Rizk, MD, is a dermatology fellow at Baylor College of Medicine, Houston,Texas.

control study. Australas J Dermatol. 2013;54(3):225-227. 7. Riyaz N, Sasidharanpillai S, Abdul Latheef EN, Davul H, Ashraf F. Pigmented purpuric dermatosis or mycosis fungoides: a diagnostic dilemma. Indian Dermatol Online J. 2016;7(3):183-185.

References

8. Ladrigan MK, Poligone B. The spectrum of pigmented purpuric

1. Sardana K, Sarkar R, Sehgal VN. Pigmented purpuric dermatoses: an over-

dermatosis and mycosis fungoides: atypical T-cell dyscrasia. Cutis. 2014;

view. Int J Dermatol. 2004;43(7):482-488.

94(6):297-300.

2. Kim DH, Seo SH, Ahn HH, Kye YC, Choi JE. Characteristics and

9. Plachouri KM, Florou V, Georgiou S. Therapeutic strategies for pigmented

clinical manifestations of pigmented purpuric dermatosis. Ann Dermatol.

purpuric dermatoses: a systematic literature review [published online May 18,

2015;27(4):404-410.

2018]. J Dermatol Treat. https://doi.org/10.1080/09546634.2018.1473553

3. Gönül M, Çakmak SK, Özcan N, Oğuz ID, Gül Ü, Biyikli Z. Clinical and

10. Fathy H, Abdelgaber S. Treatment of pigmented purpuric dermatoses

laboratory findings of pigmented purpuric dermatoses. Ann Dermatol. 2014;

with narrow-band UVB: a report of six cases. J Eur Acad Dermatol Venereol.

26(5):610-614.

2011;25(5):603-606.

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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY 2019 37

LEGAL ADVISOR CASE

Fired for Refusing a Flu Shot

BY ANN W. LATNER, JD

Ms F hated winter. It wasn’t because of the cold, or the icy roads, or the increase in patients in the hospital where the 42-year-old nurse practitioner worked. It wasn’t due to the early afternoon sunsets or the fact that she both arrived and left work in darkness. What she most hated about winter was influenza. She wasn’t concerned about getting the flu — she hadn’t had it since she was a teenager — but this was the season when flu shots were being pushed, and she did not want one. Until two years ago, this hadn’t been a problem. Ms F had spent the early part of her career working with a physician in a small practice.Whether Ms F had or hadn’t gotten her flu shot was never questioned, and no one ever pushed her to get one. In fact, Ms F had not had a flu shot in decades. She was not against them in other people – she certainly understood their value and their ability to save lives. But she herself felt very strongly about what she put into her body. Ms F was a vegetarian who ate a whole-foodbased diet, eschewing processed foods and added sugar, fats, and chemicals. She exercised daily and treated her body as a temple, avoiding alcohol and

A nurse practitioner sues her former employer after being fired for refusing to get a flu shot. The Civil Rights Act of 1964 protects employees against discrimination on a number of traits, including religion.

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drugs. Her holistic lifestyle was very important to her, as was keeping her body as chemical-free as possible. Two years ago, she left the small medical practice and took a job in the gastroenterology department of her local hospital.The first October that she was there, she noticed how the hospital went into full flu-shot mode.“Have you had your flu shot yet?” read signs all over the break room and around the hospital. Human Resources arranged to have free flu shots made available to all employees, and even gave employees time off to get theirs. Hospital employees cheerfully walked around proudly displaying their “I got my flu shot!” stickers. Ms F kept her head down and went about her business. But this most recent September, the hospital instituted a new policy requiring all staff to get the flu shot. Staff members who had religious Continues on page 40

Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

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LEGAL ADVISOR

An individual with a religious objection to a workplace policy can request a reasonable accommodation. When another several weeks had passed and Ms F had neither been vaccinated nor brought in a letter explaining a religious objection, she was called to the Human Resources department. There she was asked specifically what religious belief precluded her getting the flu shot. “I live a holistic lifestyle,” replied Ms F. “I treat my body as though it were holy, and I avoid unnecessary chemicals, including food additives, alcohol, or drugs. I strongly believe the flu shot is unnecessary for me.” “That’s not a religion,” said the Human Resources manager. “You have 2 weeks to either bring in a letter from your religious leader or to get the flu shot. Otherwise, I’m sorry, but you will be terminated from your position.” After 2 weeks passed without Ms F doing either, she was called into a meeting in the Human Resources department again and was officially terminated. She left the hospital angry that she was being precluded from treating her own body the way she wanted to without having to lose her job. Ms F consulted an attorney and sued the hospital in federal court for religious discrimination under the Civil Rights Act. In response, the hospital filed a motion to dismiss the case, arguing that it should be dismissed on its face because Ms F never identified a sincerely held belief that fit the definition of a religion.The court agreed and dismissed the case, holding that a healthy, holistic lifestyle is not a religion, and that since Ms F’s objection to the flu shot was not religious, it was not protected by the Civil Rights Act.

Legal Background

Title VII of the Civil Rights Act of 1964 protects employees against discrimination on a number of traits, including religion. The protection works similarly to the Americans With Disabilities Act; it states that someone with a religious objection to a workplace policy can request reasonable accommodation for his or her beliefs or practices. Typical accommodations would be flexible scheduling to avoid someone having to work on their religion’s holy day or exceptions to company dress code to allow for religious head coverings.The hospital in question actually had an accommodation in place for those with religious objections that would allow them to wear a mask during flu season. However, all of these accommodations are based on a sincerely held religious belief. In this case, although the court noted that Ms F clearly had a sincere and strongly held belief, it was not based on religion and thus not protected by Title VII. Protecting Yourself

It is important to note that courts have recognized nontraditional religious beliefs under certain circumstances. For example, the Third Circuit has recognized nontraditional “religious” beliefs if the beliefs address “fundamental and ultimate questions having to do with deep and imponderable matters,” if there are signs of a ‘belief-system,’ or if the belief occupies a place in the person’s life parallel to that filled by God in a traditionally religious person.” On another note, an employee can generally get a medical exemption (rather than a religious one) from a vaccine if that person can prove (via a physician) that they have an allergy to the immunization or some other reason why it would be dangerous to his or her health. However, that exemption is entirely different from an objection based on religious principles. If you have an objection to the flu shot for either medical or religious reasons, be sure you know what your employer’s policy is, particularly before you accept the job. ■ Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, NY.

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“I went with the tasting menu.”

issues precluding the flu shot were required to bring in a letter from their religious leader, and those who were granted a religious exemption would be required to wear a mask when dealing with patients during flu season. Again, signs went up in the break room, and staff was on hand to give flu shots to employees. Ms F cared for her patients and avoided the break room. After a few weeks, her manager asked whether she had gotten the flu shot yet. Ms F replied that she had not, nor did she intend to. Her manager reiterated the new policy requiring all employees to get the shot or bring in proof of a religious preclusion. “They are going to fire anyone who doesn’t either get the shot or bring in proof of a religious exemption,” warned her manager.

Conference Roundup 2018 SABCS

MASTECTOMY OFTEN CHOSEN OVER BREASTCONSERVING SURGERY Although use of neoadjuvant systemic therapy increased the number of young women with breast cancer eligible for breast-conserving surgery (BCS), nearly half still chose to undergo mastectomy despite response, according to theYoung Women’s Breast Cancer Study presented at the 2018 San Antonio Breast Cancer Symposium. According to the researchers,“these data highlight that surgical decision making among young women with breast cancer is often driven by factors beyond extent of disease and clinical response to therapy.” The study enrolled 1302 women aged 40 or younger with breast cancer. The researchers were looking at response to neoadjuvant therapy, patient eligibility for BCS before and after neoadjuvant therapy, and chosen surgical treatment. Of the enrolled women, 62% had unilateral stage I to III breast cancer and 40% received neoadjuvant therapy. The median age of these women was 36 years. Prior to neoadjuvant therapy, 27% were eligible for BCS, 15% were considered to be borderline, and 53% were ineligible. Among the patients who were ineligible or borderline, 38% became eligible for BCS after undergoing neoadjuvant therapy. Four patients who were eligible prior to therapy become ineligible after treatment. Among patients eligible for BCS after therapy, about half (49%) attempted BCS and 93% were successful. The other half

(51%) of women chose to undergo mastectomy.Among the reasons given for undergoing mastectomy, the most common was patient preference (46%), followed by BRCA or TP53 mutation (37%), family history (4%), or unknown reasons (13%). Overall, 24% of patients achieved pathologic complete response. Of those with complete response, 64% underwent mastectomy, but only 44% of the mastectomies were performed for anatomic indications.

CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY IN BREAST CANCER Many breast cancer survivors experience chemotherapy-induced peripheral neuropathy (CIPN), characterized by potentially debilitating pain, numbness, and tingling. CIPN can be measured by subjectively analyzing patient reported outcomes or by objectively performing quantitative sensory testing. However, little is known about how closely these 2 measurements correlate.A recent study presented at the San Antonio Breast Cancer Symposium evaluated how closely objective measurements of CIPN match what is experienced by the patient. The study utilized baseline patient information from 2 ongoing clinical trials of breast cancer survivors who experienced moderate to severe CIPN after chemotherapy completion for at least 3 months. Subjective, patient-reported pain was evaluated using the Neuropathic Pain Scale (NPS) and Functional Assessment of Cancer Therapy-Gynecologic Oncology

Group/Neurotoxicity subscale (FACT/ GOG-Ntx). Quantitative sensory testing was measured using Vin Frey’s filaments tactile threshold and by a biothesiometer measurement of vibration. The 2 types of data were then tested for correlation. The researchers noted a moderate correlation between patient-reported numbness using the FACT/GOG-Ntx scale and the quantitative assessment. In other words, patient-reported numbness or tingling in hands and feet was associated with an objectively measured decrease in patient tactile and vibration perception. However, patient-reported numbness using the NPS scale was positively correlated with an objectively measured decrease in tactile but not vibration perception. This suggests that the 2 subjective patientreported scales correlate differently with objective measurements of CIPN. The

San Antonio Breast Cancer Symposium San Antonio, Texas

Peripheral neuropathy is characterized by pain, numbness, and tingling.

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Conference Roundup authors concluded, “As CIPN presents a diverse range of symptoms, better quantifying the subjective and objective measures of CIPN can help incorporate these tools in observational and intervention trials.”

MASSAGE FOR CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY Massage was found to alleviate chemotherapy-induced peripheral neuropathy (CIPN) in patients with breast cancer undergoing adjuvant paclitaxel, according to a study presented at the 2018 San Antonio Breast Cancer Symposium. CIPN can be a debilitating adverse effect of chemotherapy treatment, one whose alleviation using pharmacologic approaches may also have its own major side effects. The study authors turned to massage as a multidisciplinary approach to managing CIPN. The study was conducted at the Dr Abdurrahman Yurtaslan Ankara Training and Research Hospital in Turkey between July 2017 and June 2018, and included 37 patients with breast cancer who had no previous diagnosis of CIPN and who had received the first cycle of adjuvant paclitaxel. Eighteen patients were assigned to an intervention group that received 12 classical massage sessions on the days of chemotherapy treatment, encompassing a 20-minute foot massage and a 10-minute

The intervention group received both foot and hand massage sessions.

hand massage. Nineteen patients were assigned to a control group that received only routine care. Subjective patient assessment tools including the Self-Leeds Assessment of Neuropathic Symptoms and Sign (S-LANSS) were used to assess CIPN. Electromyography (EMG) was used as an objective CIPN measurement. The subjective S-LANSS scores of the patients who received the massage were significantly lower than the scores of the control group. Additionally, based on EMG, the muscle action potential of the ulnar nerve and posterior tibial nerve were significantly higher in the treatment group than the control group at week 12. Based on these results, incorporating classical massage into the overall care regimen of patients with breast cancer receiving adjuvant paclitaxel may prevent CIPN in these patients.

INCREASED BREAST CANCER RISK FOR AFRICAN AMERICAN VETERANS Women veterans may be at increased risk for breast cancer due to unique service-related exposures, such as burn pits, depleted uranium, and posttraumatic stress disorder (PTSD). However, results from a recent pilot study presented at the San Antonio Breast Cancer Symposium suggested the alternative possibility of an innate or genetic risk, particularly among female African American veterans, who have been traditionally underrepresented in breast cancer research. The study included a total of 99 female veterans, average age 54, recruited at Veteran Affairs Medical Centers in Bronx, New York, and Washington, DC, between 2015 and 2018. The majority of participants were African American (60%), with 13% Hispanic, 14% nonHispanic white, and 13% categorized as other.The study authors calculated 5-year and lifetime risks of developing invasive breast cancer using the Gail Breast Cancer Risk Assessment tool (BCRAT).

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Among all patients, 35% were considered high risk with a 5-year BCRAT greater than 1.66%, 51% of whom were African American, 14% Hispanic, and 17% other. Overall, 22% of patients had prior breast biopsies and 57% had a family history of breast cancer. In comparison, among African American female veterans alone, 33% had prior breast biopsies and 94% had a family history of breast cancer. Encompassing all the study participants, 29% had PTSD, 31% of whom had a high risk of breast cancer. “To our knowledge, this is the only study with 60% African American women veterans. High participation rates among African Americans in this pilot study have uncovered the potential for further inquiry into this population,” wrote the authors.

METASTATIC vs EARLY STAGE HR+/HER2- BREAST CANCER MUTATIONS IDENTIFIED Use of whole exome sequencing of metastatic breast cancers has identified 11 driver gene alterations and 4 mutational processes enriched in hormone receptor-positive/ HER2-negative metastatic breast cancers. Fabrice Andre, of the Institut Gustave Roussy in France, who presented the results of the study at the 2018 San Antonio Breast Cancer Symposium, wrote that this additional information may help identify new candidate targets and stratify patients eligible for innovative therapies. The research included patients with metastatic breast cancer and available biopsy as part of several precision medicine trials (SAFIR01, SAFIR02, PERMED, MOSCATO, SHIVA). The researchers performed sequencing on 387 patients with HR-positive/HER2-negative breast cancer, 186 patients with triple-negative breast cancer, and 32 patients with HER2overexpressing breast cancers. Among these patients, 24 driver genes were significantly mutated. In the patients with HR-positive/HER2-negative

disease, 11 genes were found to be more frequently mutated in the metastatic setting compared with early-stage disease. These mutations included TP53 (29%), KMT2C (13%), NCOR1 (8%), NF1 (7%), RB1 (4%), C16orf3 (2%), FRG1 (6%), ESR1 (21%), RIC8A (4%), AKT1 (7%), and PLSCR5 (2%). No gene alterations were enriched in patients with metastatic HER2-overexpressing or triple-negative disease. The majority of patients (73%) with HR-positive/HER2-negative metastatic disease had an actionable alteration compared with only 55% of patients with early-stage disease (P < .01). The researchers also assessed mutational signatures to understand which mutational processes could drive cancer progression and found that in metastatic HR-positive/ HER2-negative disease there was an increase in APOBEC, S3 (HRD), S10 (POLE-associated signature), and S17 signatures compared with early-stage disease.

PREGNANCY AND QUALITY OF LIFE IN WOMEN WITH BREAST CANCER Quality of life in patients with breast cancer diagnosed during pregnancy is lower than that of nonpregnant patients with breast cancer, according to a study presented at the 2018 San Antonio Breast Cancer Symposium. The study evaluated quality of life of 21 pregnant women with breast cancer diagnosed between 2000-2016, using the EORTC QLQ-C30, the EORTC QLQBR 45, and the EORTC SHQ-22 questionnaires. Breast cancer was diagnosed in 16 of the patients during their pregnancy at a mean of 21.14 weeks and in 5 patients during the first year following delivery. All patients underwent surgery and chemotherapy, with 10 patients receiving hormonal therapy and 12 radiation therapy. There were no significant differences between pregnant patients and a reference breast cancer population at a follow-up

Pregnant patients in the study reported more clinically relevant financial difficulties.

period of 5.2 years using the EORTC QLQ-C30 questionnaire. However, pregnant patients reported more clinically relevant financial difficulties. According to a disease-specific questionnaire (EORTC BC 45), pregnant patients with breast cancer had significantly lower scores for body image, upset by hair loss, side effects of the systemic therapy, and future perspective. Approximately 40% of patients had decreased libido, 37% had impaired sexual activity, and 25% reported feeling less feminine because of the disease. “Despite the small number of patients, the results indicate that [pregnant breast cancer] patients are a vulnerable group, especially regarding outer appearance,” wrote the authors. They also noted the EORTC QLQ BR 45 questionnaire was more effective at assessing quality of life of these patients than the EORTC QLQ 30 questionnaire, suggesting the importance of using disease-specific questionnaires to appropriately assess quality of life in specific populations.

WORSE CLINICAL OUT COMES IN BLACK WOMEN WITH BREAST CANCER Black women with hormone receptorpositive, HER2-negative, node-negative breast cancer had worse clinical outcomes compared with white women in the phase 3 TAILORx trial, despite having

similar recurrence scores and receiving comparable systemic therapy.The results were presented at the 2018 San Antonio Breast Cancer Symposium. The preplanned analysis included 9719 participants from the TAILORx trial.The relationship between clinical outcomes and race (determined using either selfidentified race or genetically determined ancestry) and ethnicity were evaluated. Broken down by race, the trial included 8189 white women (84%), 693 black women (7%), 405 Asian women (4%), and 432 women categorized as other/ unknown race (4%). Broken down by ethnicity, the trial included 7635 nonHispanic women (79%), 889 Hispanic women (9%), and 1195 women whose ethnicity was labeled as unknown (12%). Black patients with breast cancer had the same median recurrence risk as white patients (recurrence score distribution; 17 vs 17). Similarly, Hispanic patients had the same median recurrence risk as non-Hispanic patients (17 vs 17). Black women with breast cancer had worse invasive disease-free survival (hazard ratio [HR] = 1.33; P = .005), distant relapse-free interval (HR = 1.21; P = .28), relapse-free interval (HR = 1.39; P = .02), and overall survival (HR = 1.52; P = .005) compared with white patients with breast cancer. “Careful attention to monitoring adherence to endocrine therapy for all races and ethnicities is necessary,” said the study presenter Kathy Albain, MD, Huizenga Family Endowed Chair in Oncology Research and professor of medicine at Loyola University Chicago Stritch School of Medicine and director of the Breast and Thoracic Oncology Programs at the Cardinal Bernardin Cancer Center of Loyola Medicine in Maywood, Illinois. “These findings add to emerging evidence that biologic basis with or without other factors may contribute to racial outcomes disparities in hormone receptor-positive breast cancer.” ■

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