Roswell Park Studies Highlight Emerging Treatment Options for Neuroendocrine Tumors

and travelled to the “gut-brain" (the nervous system in our gut), and also to the brain.

If some of the beta amyloid build up in the central nervous system (brain and spinal cord) is originating from the outside the brain (peripheral nervous system), reducing the amount that makes it to the brain, or trapping the protein in the periphery may delay the onset of Alzheimer’s disease. This treatment would begin before any signs of dementia appear in the patient.

The researchers at The Chinese University of Hong Kong injected fluorescently-tagged beta-amyloid into the gut of mice. The proteins moved to the nervous system in our gut. The misfolded proteins were seen a year later in parts of the brain involved in cognitive deficits of Alzheimer’s disease including the hippocampus, the part of our brain that affects our memory. These animals experienced cognitive impairments.

As this study was conducted in mice, it needs verification by looking for post-mortem changes in inflammation in the gut and brain of patients with Alzheimer’s disease.

Development of drug treatments for Alzheimer’s disease has been unsuccessful so we instead need new approaches for preventing AD development. This could be a potential route for preventing the disease by targeting these misfolded proteins in the gut.

Commenting on the study, senior author John A Rudd said:

“This concept is similar to the transport of misfolded proteins from the gut such as those responsible for mad cow disease. If this is the case, a similar process may start in humans many years ahead of the manifestations of the classical hallmarks of AD including memory loss, and so prevention strategies would need to start earlier as well.”

Roswell Park Studies Highlight Emerging Treatment Options for Neuroendocrine Tumors • Study underway with SurVaxM, a cancer vaccine targeting the protein survivin • Nintedanib treatment slowed cancer growth in patients with prior therapy • Treatments add new options to the few currently available for NET patients

Two new studies led by Renuka Iyer, MD, Section Chief for Gastrointestinal Oncology at Roswell Park Comprehensive Cancer Center, highlight possible new treatment options for patients with neuroendocrine tumors (NETs) — a rare and hard-to-treat cancer.

The first publication focuses on a cancer immunotherapy developed by two of her Roswell Park colleagues that has been shown to help patients with brain tumors live longer.

Robert Fenstermaker, MD, Chair of Neurosurgery, and Michael Ciesielski, PhD, Assistant Professor of Neurosurgery, have reported that the novel vaccine they developed, SurVaxM, combined with standard therapy, gave brain tumor patients significantly longer survival rates compared with those who received standard therapy alone.

They stained NET specimens for the molecule the vaccine targets — survivin, a protein often found at high levels in cancerous tumors, where it promotes cancer cell survival through proliferation and metastasis. They found an unusually high level in the specimens, and brought in Dr. Iyer to take it to the next step.

Dr. Iyer and colleagues pursued further studies exploring whether the protein might serve as a prognostic and potentially therapeutic marker in patients with NETs. They have shared those findings in an article in the journal Oncotarget.

The team discovered survivin in 52% of the neuroendocrine samples they studied.

“We saw that the SurVaxM vaccine has the potential to help half our patients with NETs, especially patients with more aggressive tumors and those whose tumors originated in their lungs, for whom options are urgently needed,” Dr. Iyer says.

Dr. Iyer secured funding from the Neuroendocrine Tumor Research Foundation (NETRF) in 2019 for a clinical trial (NCT03879694) of SurVaxM in patients with NETs; that study is open and enrolling new patients.

In pursuit of another novel treatment for this rare cancer, Dr. Iyer also led a team of researchers from Roswell Park, Ohio State University Comprehensive Cancer Center and Memorial Sloan Kettering Cancer Center to study nintedanib (brand names Ofev and Vargatef ), an oral antiangiogenic agent that targets key tumor cell-signaling pathways. Nintedanib inhibits the fibroblast growth factor receptor (FGFR), which is highly expressed in those tumors. For that reason, the team hypothesized, it could be active in patients with NETS.

The findings have been published in Cancer, a journal of the American Cancer Society.

“We found that nintedanib is effective as a treatment option for NET patients and can slow the cancer growth for almost a year. Nintedanib was well tolerated and delayed deterioration in quality of life,” Dr. Iyer says.

The most significant finding of this study was that nintedanib can slow cancer growth even when the patients have had many prior therapies. These results will help inform future trials targeting novel pathways, such as serotonin signaling, especially for nonpancreatic NET patients, for whom options are very limited.

“Both of these published reports are exciting findings as they pave the way for promising new treatment options for NET patients,” adds Dr. Iyer.

Neurocritical Care Challenges in the Time of COVID-19

James E. Szalados, MD, JD, MBA, FCCM, FCCP, FNCS. Attorney-at-Law and Consulting Attorney / NeuroLaw Board-Certified Neurointensivist and Fellow of the Neurocritical Care Society Medical Director, Neurocritical Care, Rochester Regional Health System

Critical care medicine (CCM), or ‘intensive care medicine’ is a medical subspecialty which focusses on the care of patients with acute life-threatening illnesses, such as overwhelming infections with sepsis, severe trauma, or major surgery. The hallmark of critical illness is the failure, or impending failure, of one or more organ systems (multiple organ dysfunction or ‘MODS’) which requires life support through advanced diagnostic, monitoring, and therapeutic technologies. The Intensive Care Unit (ICU) is where a multi-disciplinary team of physicians, advanced practice providers, pharmacists, nurses and therapists bring their knowledge, training, and experience together to treat these highly complex patients. Neurocritical care, also sometimes referred to as ‘neurointensive care’ is a further sub-subspecialty of CCM which focuses on the critical care of injuries and diseases which affect the nervous system (patients requiring neurocritical care often have co-existing MODS) requiring, for example, mechanical ventilation, cardiovascular support, renal replacement therapy, and sepsis management. The Neurocritical Care Society is the international organization which represents neurointensivists.

COVID-19 (Coronavirus 2019) is a transmissible coronavirus mostly known for causing acute and life-threatening respiratory failure, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is now a global pandemic. Although much has been learned about COVID-19 since it was first detected in Wuhan, China, the knowledge base is limited; even today there is more anecdote than science regarding COVID-19. Nonetheless, a key hallmark of COVID-19 infection, in some but not all patients, is an explosive systemic inflammation response which results in a hemostatic derangement somewhat similar to other pro-thrombotic states, such as disseminated intravascular coagulation (DIC), or consumption coagulopathy, that results in microcirculatory and macrocirculatory venous and arterial thrombosis, with wide-ranging organ dysfunction including pneumonitis, thrombosis such as pulmonary embolism, severe encephalopathy, polyneuropathy, and acute ischemic stroke (AIS). Therefore, although patients with COVID can first present with respiratory symptoms, atypical gastrointestinal, or cardiac symptoms, sometimes the first sign of COVID-19 infection is a stroke.

The COVID-19 virus binds to angiotensin-converting enzyme 2 (ACE2) receptors on brain endothelial and other smooth muscle cells. Since Angiotensin II is a pro-inflammatory mediator and vasoconstrictor, the occupation of ACE2 receptors by COVID-19 promotes activation of the ACE1/ angiotensin II axis to cause vasoconstriction, cerebral ischemia, and strokes. Data suggests that the (1) Incidence of acute ischemic stroke in patients with COVID-19 ranges from 0.9% to 2.7%; (2) severity of stroke is at least moderate (NIHSS score 19), with a high prevalence (40.9%) of large vessel occlusion; and (3) mortality rate is high (38.0%). Stroke patients presenting with COVID-19 also have elevated levels of antiphospholipid antibodies (aPL), which may further promote hypercoagulability. The structure of the viral membrane is also pro-inflammatory in itself causing a diffuse "endotheliitis". Hypothetically then, in my opinion, the mechanism by which the COVID-19 virus attacks the ACE2 receptor, and therefore the microcirculation, may in part, explain why COVID is so much more severe, and potentially lethal, in patients with pre-existing microangiopathy (microcirculatory disease) such as diabetic and hypertensive vascular disease.

When COVID-19 binds to the endothelial cells lining the blood vessels (including the lung, heart, and the brain) the resulting inflammatory response can also cause a vasculitis (inflammation of the blood vessels) that not only can cause rashes, stroke and encephalopathy, but also extensive cerebral small-vessel ischemic lesions resembling cerebral vasculitis in

a characteristic combined imaging pattern of ischemia, and hemorrhage. In some cases, these lesions are implicated in necrotizing encephalitis. Thus, COVID patients receiving thrombolytic ‘clot busters’ or anticoagulation for AIS management or prophylaxis may be at increased risk of intracerebral hemorrhages.

In the experience of the Neurocritical Care Unit (NCCU) at Rochester General Hospital (RGH), the complexity of acute ischemic stroke (AIS) and COVID-19 has presented numerous complex CCM management challenges; to a large extent, these challenges mirror those reported by other NCCUs across the U.S. It can also only be speculated that at least some patients with COVID-19-related neurocritical care emergencies did not ever timely reach the healthcare system.

Evaluation and Management Challenges in the Care of the Neurocritical Care Patient with COVID-19:

The key principles in the management of acute brain injury are: (1) time is brain; and, (2) prevention of secondary brain injury, where possible. Patients with acute hypoxemia, or sepsis, often present confused and delirious; in such cases careful assessment is needed to determine that the patient does not have an AIS-in evolution or a malignant encephalopathy. Basic elements of interventional medicine, such as historytaking or informed consent to treatment, are made much more complex when families and caregivers cannot be at the bedside. In any emergency scenario however, the protection of first responders and the care team is a priority. Testing for COVID-19, once available, helped optimize the safety of the team and other patients. Since COVID-19 is transmitted primarily via aerosolized secretions, a secure airway through early intubation not only minimized the risk of secondary brain injury from aspiration or hypoxemia, but also reasonably minimized the risk of viral transmission during transport, imaging, intervention, and early post-stroke care. For example, many patient with COVID and AIS required multiple CT imaging studies, mechanical thrombectomy by neurointerventionalists, and even neurosurgical interventions. Once in the NCCU, providers, nurses, and therapists were responsible for, at least, hourly patient assessments and bedside interventions such as monitoring interventions, neurological examinations, and ventilator adjustments; complicated by full isolation precautions. Experience at the RGH NCCU also corroborates that the intense brain vasculitis may have precipitated brain

hemorrhage after revascularization in COVID-19 infected patients who presented with AIS. In some cases, patients with AIS and other acute neurological injuries required advanced intervention at RGH via Extracorporeal Membrane Oxygenation (ECMO) to provide oxygen and remove carbon dioxide directly through a cardiac-bypass-like system that bypassed lungs acutely injured by the SARS-CoV-2 acute respiratory distress syndrome (ARDS).

Potential Moral Distress in the Care of the Neurocritical Care Patient with COVID-19:

In healthcare, moral distress can be described as a discordant emotional response which arises from situations where there is a mismatch between the fundamental beliefs and commitments of medical professionals and the plan of action as limited or prescribed by policies or procedures. Left unaddressed, moral distress can lead to post-traumatic stress and burnout. Specific to COVID-19, moral distress has been attributed, for example, to the (1) overwhelming numbers of patients who urgently need care; (2) availability of testing and treatment options; (3) potential triage and rationing decisions associated with scarce clinical resources, (4) lack of access to personal protective equipment (PPE); (5) high risks for disease transmission and the risks to providers’ families at home; (6) amplification of health inequities and disparities; and, (6) social deprivation and isolation of critically-ill and often dying patients.

Fortunately, high-level planning within the Rochester CCM community, with the support of the many regional hospital administrations, was proactive in making PPE immediately available to all hospital staff; and we developed policies, procedures, and guidelines to facilitate clinical decision-making and support front-line providers. The Rochester health community was largely prepared, learning much from Downstate, and thus, clinical resources did not need to be rationed. However, isolation frequently resulted in social deprivation of patients and families; which resulted in end-of-life decision-making and end-of-life care occurring in isolation rooms often devoid of family - but not care-team, presence and support.

Conclusions:

COVID-19 presented an enormous clinical challenge and strain on the Rochester medical infrastructure; one that was managed through the dedication of multidisciplinary teams of healthcare providers. One important, and often overlooked, lesson from the COVID-19 pandemic is that the first manifestation of infection may not be pulmonary, but rather neurologic. Once again, patients with acute hypoxemia, or sepsis, often arrive confused and delirious; in such cases a careful assessment is needed to determine that the patient does not have an AIS-in evolution or a malignant encephalopathy; in these critically-ill patients, the co-existence of multiple organ dysfunctions can enormously complicate their evaluation and management; compounded by accompanying biohazard environment. Much has been learned; but challenges remain, and as always, we will ‘press on’.

Nothing in the world can take the place of persistence. Talent will not; nothing is more common than unsuccessful men with talent. Genius will not; unrewarded genius is almost a proverb. Education will not; the world is full of educated derelicts. Persistence and determination alone are omnipotent. The slogan “Press On” has solved and always will solve the problems of the human race.

J. Calvin Coolidge

REFERENCES i CDC. Coronavirus (COVID-19). Online at: https://www.cdc.gov/coronavirus/2019-ncov/index. html.

ii Panigada, M, Bottino, N, Tagliabue, P, et al. Hypercoagulability of COVID‐19 patients in intensive care unit: A report of thromboelastography findings and other parameters of hemostasis.

J Thromb Haemost. 2020; 18: 1738– 1742. https://doi.org/10.1111/jth.14850. iii

Hess DC, Eldahshan W, Rutkowski E. COVID-19-Related Stroke. Transl Stroke Res. 2020;11(3):322-325. doi:10.1007/s12975-020-00818-9.

iv Tan YK, Goh C, Leow AST, et al. COVID-19 and ischemic stroke: a systematic review and metasummary of the literature [published online ahead of print, 2020 Jul 13]. J Thromb Thrombolysis. 2020;1-9. doi:10.1007/s11239-020-02228-y.

v Hanafi R, Roger PA, Perin B, et al. COVID-19 Neurologic Complication with CNS Vasculitis-Like Pattern [published online ahead of print, 2020 Jun 18]. AJNR Am J Neuroradiol. 2020;10.3174/ajnr.A6651. doi:10.3174/ajnr.A6651

vi Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B. COVID-19-associated Acute

Hemorrhagic Necrotizing Encephalopathy: CT and MRI Features [published online ahead of print, 2020 Mar 31]. Radiology. 2020;201187. doi:10.1148/radiol.2020201187

vii Morley G, Grady C, McCarthy J, Ulrich CM. Covid-19: Ethical Challenges for Nurses. Hastings

Cent Rep. 2020;50(3):35-39. doi:10.1002/hast.1110.

vii Sara Berg. 4 ways COVID-19 is causing moral distress among physicians. June 18, 2020. Online at: https://www.ama-assn.org/practice-management/physician-health/4-ways-covid-19-causingmoral-distress-among-physicians.