Nivolumab-Induced Thrombotic Thrombocytopenic Purpura in a Patient with Anal Squamous Cell Carcinoma: A Lesson on Hematologic Toxicity from Immunotherapy.

Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening microangiopathic hemolytic anemia characterized by thrombocytopenia, hemolytic anemia, and ischemic organ damage. It is mainly caused by an autoreactive antibody directed at ADAMTS13. Immunotherapy is frequently associated with autoimmune complications in patients with cancer, but only three cases of TTP have been reported, none implicating single treatment with the anti-programmed cell death receptor 1 ligand antibody nivolumab. We present the first identified and reported case of nivolumab-associated TTP in a 51-year-old woman with stage IIIc anal carcinoma who achieved complete response following chemoradiation and received adjuvant nivolumab as part of a randomized clinical trial. Twelve weeks into treatment, she presented with dark urine, progressive fatigue, and headache. TTP diagnosis was based on laboratory evidence of hemolytic anemia, thrombocytopenia, and ADAMTS13 activity of 9% associated with an inhibitor. She was treated with daily plasma exchange and oral prednisone and responded well to treatment, with platelet counts over 100 K/cmm within 4 days. We reviewed and summarized data from all reported cases of TTP associated with cancer immunotherapy. We provide guidance on identification and management of this devastating hematologic complication, focusing on the importance of early recognition, as most patients achieve complete recovery with appropriate treatment. KEY POINTS: Thrombotic thrombocytopenic purpura (TTP) was originally excluded from previous reviews of hematologic immune-related adverse events; however, several cases have been reported in the past 2 years in patients treated with either single agent or combination of cytotoxic T-lymphocyte-associated antigen 4 and the programmed cell death receptor 1 (PD-1) or the PD-1 ligand inhibitors. Although rare, TTP is a life-threatening condition that could be challenging to diagnose, and early recognition is key as delayed treatment is associated with significant increase in mortality. The pathophysiology of immunotherapy-induced TTP is likely related to autoimmune inhibition of ADAMTS13; the addition of prednisone and rituximab to urgent plasmapheresis appears to be effective and should be part of the up-front management for these patients.

Neuromuscular complications of immune checkpoint inhibitor therapy.

Immune checkpoint inhibitor (ICPI) therapy unleashes the body's natural immune system to fight cancer. ICPIs improve overall cancer survival, however, the unbridling of the immune system may induce a variety of immune-related adverse events. Neuromuscular immune complications are rare but they can be severe. Myasthenia gravis and inflammatory neuropathy are the most common neuromuscular adverse events but a variety of others including inflammatory myopathy are reported. The pathophysiologic mechanism of these autoimmune disorders may differ from that of non-ICPI-related immune diseases. Accordingly, while the optimal treatment for ICPI-related neuromuscular disorders generally follows a traditional paradigm, there are important novel considerations in selecting appropriate immunosuppressive therapy. This review presents 2 new cases, a summary of neuromuscular ICPI complications, and an approach to the diagnosis and treatment of these disorders. Muscle Nerve, 2018.

Weekly vs Every-3-Week Carboplatin with Weekly Paclitaxel in Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer: A Retrospective Analysis.

Background: Adding carboplatin to weekly paclitaxel as part of neoadjuvant chemotherapy (NACT) for stage II-III triple negative breast cancer (TNBC) has been shown to significantly increase the pathologic complete response (pCR) rate. Hematologic toxicities associated with every 3-week dosing of carboplatin have led some oncologists to explore weekly dosing as an alternative, but there are little published data comparing the two dosing schedules. Methods: We performed a retrospective analysis of patients who received paclitaxel and carboplatin, usually followed by AC, as initial NACT for TNBC at two academic cancer centers between 2008 and 2018 for whom pathologic results and post-operative follow-up were available. We recorded pCR, defined as ypT0/isN0, treatment delivery and disease-free survival, censored as of the patient's last follow-up visit. Results: A total of 76 patients were identified (median age 49 years). A total of 47 received weekly carboplatin, of whom 83% received at least 11 of 12 planned doses, and 29 received every 3-week carboplatin, of whom 90% received all 4 planned doses. pCR rates were similar, 53% with weekly and 55% with every 3-week carboplatin dosing. At median follow-up of 18 months (range <1-118), 93% of patients who achieved pCR were alive and free from recurrence, compared to 74% of those who did not. Conclusion: pCR rates were similar between patients receiving weekly or every 3-week carboplatin and were similar to those reported in prior trials with carboplatin. These data suggest that providers can choose either weekly or every 3-week carboplatin dosing without compromising the likelihood of achieving pCR.

Experience and Attitudes Regarding Medical Aid in Dying, Act 39, among Vermont Specialty Practices.

Introduction: In 2013, the Vermont legislature passed Act 39: The Patient Choice and Control at End-of-Life Act, which legalized medical aid in dying (MAID) under specific circumstances for terminally ill Vermont residents. In the five years since the law was passed, 52 patients in Vermont have been prescribed medications to hasten death; however, important information regarding the experiences of the patient, caregiver, or physician involved in this process is lacking. Objective: To survey the subspecialty physicians with the greatest contact with these patient populations, to better understand the physicians' attitudes and experiences with Act 39, and to gather more data about the utilization of Act 39 in Vermont. Design: Physicians practicing Hematology/Oncology, Neurology, and/or Palliative Care at the University of Vermont Medical Group and affiliated hospitals in the state of Vermont were invited to participate. Participants were contacted via e-mail to complete blinded surveys, and responses were collected over several months in 2018. Results: The attitudes and practices related to Act 39 were collected from 37 subspecialty physicians in Vermont. Seventy-one percent of the participants supported MAID via Act 39; however, many felt that they could use more information and resources to counsel a patient (51.4%) and complete the paperwork and prescription for life-ending medication (37.4%). Conclusion: This is the first study to collect information regarding physicians' attitudes and experiences regarding Act 39 in Vermont. Most respondents supported Act 39, but there is a need and desire for more physician education and resources regarding patient counseling and paperwork.

N-Terminal pro-B-type natriuretic peptide and stroke risk across a spectrum of cerebrovascular disease: The REasons for Geographic and Racial Differences in Stroke cohort.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP), a commonly used clinical marker of cardiac function, is associated with the presence of stroke symptoms and is a strong risk factor for future atrial fibrillation, stroke, and all-cause mortality. Few data are available on the association between NT-proBNP levels and stroke recurrence. OBJECTIVE: We studied the relationship between NT-proBNP and risk of future ischemic stroke across the continuum of preexisting cerebrovascular conditions: asymptomatic, prior stroke symptoms, prior transient ischemic attack (TIA), and prior stroke. METHODS: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort enrolled 30,239 black and white Americans aged 45 years and older from 2003 to 2007. With 5.4 years follow-up, baseline NT-proBNP was measured in 892 participants who developed ischemic stroke and a 4328-person cohort random sample. Hazard ratios of stroke by baseline NT-proBNP were calculated in groups based on the presence of prebaseline cerebrovascular conditions. RESULTS: In the fully adjusted model, elevated NT-proBNP was associated with stroke risk in participants without a preexisting cerebrovascular condition (hazard ratio [HR], 2.32; 95% confidence interval [CI], 1.84-2.94) and in participants with a history of stroke symptoms (HR, 1.67; 95% CI, 1.01-2.78) or transient ischemic attack (HR, 2.66; 95% CI, 1.00-7.04) but not among those with prior stroke (HR, 1.26; 95% CI, 0.71-2.21). CONCLUSIONS: These findings support the potential for NT-proBNP testing to identify people who are at highest risk for future stroke.