Development of the Functional Assessment of Cancer Therapy-Immune Checkpoint Modulator (FACT-ICM): A toxicity subscale to measure quality of life in patients with cancer who are treated with ICMs.

BACKGROUND: Patients with cancer who are treated with immune checkpoint modulators (ICMs) have their health-related quality of life (HRQOL) measured using general patient-reported outcome (PRO) tools. To the authors' knowledge, no instrument has been developed to date specifically for patients treated with ICMs. The objective of the current study was to develop a toxicity subscale PRO instrument for patients treated with ICMs to assess HRQOL. METHODS: Input was collected from a systematic review as well as patients and physicians experienced with ICM treatment. Descriptive thematic analysis was used to evaluate the qualitative data obtained from patient focus groups and interviews, which informed an initial list of items that described ICM side effects and their impact on HRQOL. These inputs informed item generation and/or reduction to develop a toxicity subscale. RESULTS: Focus groups and individual interviews with 37 ICM-treated patients generated an initial list of 176 items. After a first round of item reduction that produced a shortened list of 76 items, 16 physicians who care for patients who are treated with ICMs were surveyed with a list of 49 patient-reported side effects and 11 physicians participated in follow-up interviews. A second round of item reduction was informed by the physician responses to produce a list of 25 items. CONCLUSIONS: To the authors' knowledge, this 25-item list is the first HRQOL-focused toxicity subscale for patients treated with ICMs and was developed in accordance with US Food and Drug Administration guidelines, which prioritize patient input in developing PRO tools. The subscale will be combined with the Functional Assessment of Cancer Therapy-General (FACT-G) to form the FACT-ICM. Prior to recommending the formal use of this PRO instrument, the authors will evaluate its validity and reliability in longitudinal studies involving substantially more patients.

Evidence of small-fiber neuropathy in neurofibromatosis type 1.

INTRODUCTION: Large-fiber neuropathy is rare in neurofibromatosis type 1, but small-fiber neuropathy has not been studied. METHODS: Patients with neurofibromatosis type 1 underwent nerve conduction studies for large-fiber assessment. Small-fiber tests included quantitative thermal thresholds, laser Doppler flare imaging, intraepidermal nerve fiber density, and corneal nerve fiber length. RESULTS: Of the 52 patients enrolled, 31 (60%) were female and the mean age was 33.0 ± 12.3 years. Four (8%) patients had abnormal nerve conduction studies. Small-fiber tests were frequently abnormal: thermal thresholds in 7 (13%); laser Doppler flare imaging in 10 (19%); intraepidermal nerve fiber density in 11 (22%); and corneal nerve fiber length in 27 (52%). The mean corneal nerve fiber length was below normative level (10.1 ± 2.7 mm/mm3 ). DISCUSSION: Small-fiber neuropathy may be common in neurofibromatosis type 1, and should be investigated in symptomatic patients.

Cognitive rehabilitation for executive dysfunction in brain tumor patients: a pilot randomized controlled trial.

PURPOSE: Patients with brain tumors face unique quality of life challenges. Executive dysfunction is common and functionally limiting, with no established treatments as standard care. This pilot study evaluated the efficacy of Goal Management Training (GMT), a behavioral intervention combining mindfulness and strategy training, for improving executive and real-life functioning in this population. METHODS: Twenty-five primary brain tumor survivors were randomized to GMT, an active control (Brain Health Program, BHP), or a wait-list (WAIT) control group. The BHP was a supportive care intervention offering education and activities to promote general brain health, without cognitive strategy training. Participants in GMT and BHP completed eight individual sessions and homework between sessions; those in WAIT received usual care. Assessments at baseline, immediately post-training, and 4-month follow-up used a battery of objective and subjective measures, including functional goal attainment. RESULTS: Adherence (% sessions completed) was high for both GMT (98.9%) and BHP (84.4%). Executive functions improved with GMT but not BHP or WAIT (repeated measures analysis of variance, time-by-group interaction, post-training P = 0.077, follow-up P = 0.046). Both intervention groups reported fewer cognitive concerns at post-training (P = 0.049) and follow-up (P < 0.001). Functional goal attainment was greatest with GMT (post-training P = 0.027, follow-up P = 0.064). CONCLUSIONS: GMT improved executive and real-life functioning in brain tumor survivors, with gains maintained at 4-month follow-up. Clinical implementation of this adaptable program merits consideration for clinically stable patients with cognitive dysfunction. Further development and larger prospective cognitive rehabilitation trials appear warranted.

Bevacizumab in Recurrent High-Grade Gliomas: A Canadian Retrospective Study.

BACKGROUND: Bevacizumab has been used in recurrent glioblastoma (rGBM) since 2010 in Canada. Given its cost, potential toxicities, and unclear efficacy, further studies are required to better define suitable candidates for therapy. METHODS: A single-center retrospective review of patients started on bevacizumab for rGBM from 2012 to 2015 was performed. Patient demographics, tumor characteristics, treatment regimen, and dates of clinical progression and death were collected. Overall survival (OS) and progression-free survival (PFS) were used as clinical outcomes and estimates. Radiological response was assessed using modified Response Assessment in Neuro-Oncology criteria. RESULTS: A total of 80 patients were included. There were 67 reported deaths, and the median OS was 9.2 months (95% confidence interval [CI 95%]=7.0-10.1 months), with a 12-month OS of 31% (CI 95%=21.9-43.5%). Some 79 patients were included for analysis of clinical progression, among whom 61 had documented clinical progression. The median clinical PFS was 4.6 months (CI 95%=3.8-6.4 months), and the 6-month clinical PFS was 39% (CI 95%=29.0-52.9%). Addition of chemotherapy did not improve clinical outcomes. A total of 68 patients were included for radiological progression analysis, with 58 radiological progressions. The median radiological PFS was 5.8 months (CI 95%=4.2-6.7 months), and the 6-month radiological PFS was 46% (CI 95%=35.6-60.0%). CONCLUSIONS: This is the first reported Canadian experience with bevacizumab for rGBM. Our clinical outcomes are consistent with published data from multicenter phase II and III trials on bevacizumab in rGBM. More research is required to determine which subtype(s) of patients with rGBM could benefit from bevacizumab upon recurrence.

Management and Outcomes in the Oldest-Old Population with Glioblastoma.

OBJECTIVES: Glioblastoma is a lethal disease in the elderly population. We aimed to evaluate disease and treatment outcomes in the oldest-old patients. METHODS: Patients >80 years old with histologically confirmed glioblastoma treated between 2004 and 2009 were identified. We included patients managed with best supportive care (BSC), temozolomide (TMZ) alone, radiotherapy (RT) alone, or concomitantly with TMZ (CRT). Survival outcomes were analyzed using the Kaplan-Meier method. RESULTS: Ultimately, 48 patients were analyzed. Median age and Eastern Cooperative Oncology Group (ECOG) Performance Status were 82 years and 2, respectively. The median Age-Adjusted Charlson Index (AAC) was 6. Gross total and subtotal resections were performed in 16.7% and 18.8% of patients, respectively. Biopsy followed by RT alone was the treatment modality for 23/48 (47.9%), while 17/48 (35.4%) received surgery followed by RT alone or CRT. A total of 8 (16.7%) were managed with BSC after biopsy. Median overall survival (OS) and progression-free survival (PFS) were 4.1 (95% confidence interval [95% CI] 3.3-4.9) and 2.7 (95% CI 1.5-3.9) months, respectively. Improved median OS was observed in those treated with surgical resection followed by RT alone or CRT (7.1 months), compared to biopsy followed by RT alone (4.2 months) or BSC (2.0 months; p=0.002). Surgical resection, age≤85, and AAC<6 were associated with better OS (p=0.032, p=0.031, and p=0.02, respectively). Cause of death was neurological progression in 56% of cases. RT was well-tolerated. CONCLUSIONS: PFS and OS outcomes remain poor in the oldest-old patients (>80 years old). Younger age, lower AAC, surgical resection, and adjuvant treatment were associated with improved OS.

Neutrophil-lymphocyte ratio dynamics during concurrent chemo-radiotherapy for glioblastoma is an independent predictor for overall survival.

Elevated neutrophil-lymphocyte ratio (NLR) may predict worse outcomes in cancer, including glioblastoma (GBM). This study assessed whether change in NLR during focal radiotherapy and concomitant temozolomide (RT-TMZ) provides further prognostic information. This was a retrospective review of patients treated with RT-TMZ for histologically confirmed GBM from January 2004 to September 2010. Variables assessed included age, ECOG performance status (PS), dexamethasone use and extent of surgery. Hematological results were collected at baseline, during and 4 weeks post RT-TMZ. Kaplan-Meier method was used to calculate overall survival (OS). Multivariable analysis (MVA) assessed for joint effect of covariates on OS and Pearson Correlation Coefficients assessed for association between dexamethasone dose and NLR change. With a median age of 55 (range 18-70), 369 patients were included. Median follow up was 15.1 month (range 1.6-134.6). The OS was 66.1% (95% CI 61.2-70.6) and 31.4 (95% CI 26.8-36.1) at 1 and 2 years, respectively. On univariate analysis, both decrease in NLR post RT-TMZ (HR 0.641, p < 0.0001) and baseline NLR < 7.5 (HR 0.628, p < 0.0001) were associated with longer OS. On MVA decrease in NLR (HR 0.727, 95% CI 0.578-0.915), age (HR 1.025, 95% CI 1.012-1.038), baseline neutrophil (<8) (HR 0.689, 95% CI 0.532-0.891), total TMZ cycles (HR 0.89, 95% CI 0.867-0.913) and PS (HR 0.476, 95% CI 0.332-0.683) were independent predictors of OS. These findings suggest that a decrease in NLR during RT-TMZ, accounting for known prognostic factors, is an independent prognostic factor for survival in GBM.

Guillain-Barré Syndrome following a series of novel therapies adapting the gold-standard in the era of immune priming.

Over the past two decades, there has been a fundamental shift away from traditional cytotoxic chemotherapy towards the identification, and subsequent suppression of specific oncogenes. Immunotherapy and targeted therapy prime the immune system, potentially leading to deleterious side effects. The following case of Guillain-Barré Syndrome (GBS) emphasizes the importance of considering every agent when iatrogenic toxicity is suspected. We underline the possibility of immune priming by checkpoint inhibitors. An optimal understanding of the pathogenesis and toxicity of targeted therapy is key in an era where the prognosis of melanoma is revolutionized by the use of novel agents. Our case emphasizes the importance of considering every agent in the context of toxicity induced by combined novel therapies.

Searching for autoimmune encephalitis: Beware of normal CSF.

OBJECTIVE: To determine the prevalence of cerebrospinal fluid (CSF) markers associated with inflammation (i.e., elevated white blood cell count, protein concentration, and CSF-specific oligoclonal bands) in patients with early active autoimmune encephalitis (AE). METHODS: CSF characteristics, including WBC count, protein concentration, and oligoclonal banding, were analyzed in patients diagnosed with AE at two tertiary care centers. RESULTS: Ninety-five patients were included in the study. CSF white blood cell counts and protein levels were within normal limits for 27% (CI95%: 19-37) of patients with AE. When results of oligoclonal banding were added, 14% (CI95%: 6-16) of patients with AE had "normal" CSF. The median CSF white blood cell count was 8 cells/mm3 (range: 0-544) and the median CSF protein concentration was 0.42 g/L (range: 0.15-3.92). CONCLUSIONS: White blood cell counts and protein levels were within normal limits in the CSF of a substantial proportion of patients with early active AE. Inclusion of CSF oligoclonal banding identified a higher proportion of patients with an inflammatory CSF profile, especially when CSF was sampled early in the disease process.

Pilomotor seizures marked by infraslow activity and acetazolamide responsiveness.

A patient with pilomotor seizures post anti-LGI1 limbic encephalitis, refractory to immunotherapy and anti-epileptic drugs, was investigated with electroencephalography and magnetoencephalography. Seizures occurred daily (14.9 ± 4.9/day), with catamenial exacerbation, inducible by hyperventilation. Anterior temporal ictal onsets were heralded (by ~15 sec) by high amplitude ipsilateral electromagnetic infraslow activity. The catamenial/ventilatory sensitivity and the infraslow activity (reflecting glial depolarization) suggested an ionic, CO 2/pH-related glioneuronal mechanism. Furosemide decreased seizure frequency by ~33%. Acetazolamide led to immediate seizure freedom, but lost efficacy with daily treatment. A cycling acetazolamide regimen (2 days on, 4 days off) plus low-dose topiramate maintained >95% reduction (0.5 ± 0.9/day) in seizures.

Atypical Neuropsychiatric Presentation in a Patient Expecting Liver Transplantation.

Patients presenting with acute or chronic hepatopathy can develop altered mental status with psychomotor slowing, most commonly indicating encephalopathy. We present the case of a 56-year-old patient who developed subacute atypical neuropsychiatric symptoms including cognitive and behavioural disorganization, manic-like state, and lateralized parkinsonian syndrome. The sequence of events, complete work-up, and detailed neuropsychiatric examination were not compatible with hepatic encephalopathy or delirium; therefore we extended our differential diagnosis and suggested the pathophysiological process described below.

A critical balance: managing coagulation in patients with glioma.

Cancer-associated thrombosis, including both arterial and venous thromboembolism (VTE), is a significant source of morbidity and mortality in patients with glioma. This risk is highest in the immediate postoperative period and is increased by chemotherapy, radiation, and corticosteroids. Systemic anticoagulation with low molecular weight heparin is the treatment of choice in both the therapeutic and prophylactic settings. However, these patients are also at risk of intracranial hemorrhage, a potentially catastrophic complication of anticoagulation, and this risk must be carefully balanced against the risk of VTE. In this review we outline the incidence, pathophysiology and management of thrombosis in patients with glioma, with a focus on clinical considerations including perioperative management, chemotherapy-induced thrombocytopenia, and end-of-life management.

Eosinophilic Fasciitis and Acute Encephalopathy Toxicity from Pembrolizumab Treatment of a Patient with Metastatic Melanoma.

Anti-PD-1 inhibitors have significant activity in metastatic melanoma. Responses often occur early and may be sustained. The optimal duration of treatment with these agents is unknown. Here, we report the case of a 51-year-old woman treated with pembrolizumab, as part of the Keynote-001 trial, as first-line treatment for metastatic disease. She experienced a complete response after 13.8 months of treatment with no adverse events. One month after the last drug infusion and 18 months from starting treatment, the patient presented with eosinophilic fasciitis. She then developed acute confusion and weakness, thought to be due to intracranial vasculitis. High-dose steroids were initiated with resolution of the fasciitis. Aspirin was commenced for presumed vasculitis with resolution of the neurologic symptoms. To our knowledge, there are no previous reports of eosinophilic fasciitis or cerebral vasculitis due to anti-PD-1 agents. This case demonstrates that toxicity may occur in association with pembrolizumab treatment after a prolonged period of treatment without toxicity. Future trials should explore the optimal duration of treatment with pembrolizumab.

Subacute CNS Demyelination after Treatment with Nivolumab for Melanoma.

Immunotherapy with monoclonal antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1) has improved the survival of patients with metastatic melanoma. These agents carry a certain risk of adverse immune-related events. We present a patient with widely metastatic melanoma who was initially treated with ipilimumab and subsequently with nivolumab. After four infusions of nivolumab, he developed subacute multifocal central nervous system (CNS) demyelination. Nivolumab was discontinued and, despite immunosuppressive therapy, the largest lesion progressed significantly, whereas another lesion showed radiographic improvement. After further progression, the patient succumbed to his CNS lesions 4 months later. Autopsy revealed extensive demyelination, a mild multifocal T-cell-rich perivascular lymphoid infiltrate, abundant macrophages, and necrosis. There was no metastatic melanoma in the brain. CNS demyelination has not been described in association with nivolumab. We hypothesize that the combination therapy of ipilimumab and subsequent nivolumab accounted for the severity of the demyelinating process in this patient. This case, with comprehensive clinical, molecular, and neuropathologic characterization, illustrates the need for awareness of these potential CNS complications with the use of multiple checkpoint inhibitors.

Seizure management in patients with gliomas.

Seizures represent a major cause of morbidity in patients diagnosed with brain tumors. Seizures in patients with gliomas are disruptive, impact on quality of life; autonomy; the capacity to operate motor vehicles and opportunities for work. The management of seizures in patients with brain tumors is complex and ideally managed in a multidisciplinary fashion. In addition to antiepileptic drugs, surgery, chemotherapy and radiotherapy have potential roles in the management of a glioma patient with intractable epilepsy. The successful management of seizures in patients with brain tumors is possible, it provides considerable benefits in terms of quality of life and should remain a central goal in patient management.