Prospective Randomized Study of Advance Directives in Allogeneic Hematopoietic Cell Transplantation Recipients.

Patients undergoing allogeneic hematopoietic cell transplantation (HCT) are at risk for high morbidity and mortality. Advance directives (AD) allow patients to express wishes regarding their care at the end of life, but these are not completed in the majority of patients undergoing HCT, with only 44% of deceased allogeneic HCT recipients at this institution completing an AD in the past decade. Increasing the AD completion rate can improve the quality of care for allogeneic HCT recipients. Our objective was to evaluate whether an alternative AD instrument can increase AD completion rate and patient satisfaction. We conducted a prospective, randomized controlled study of the traditional California AD versus a novel Letter AD, the Stanford What Matters Most Letter, in adult allogeneic HCT recipients. Patients age ≥18 years undergoing first allogeneic HCT at Stanford University were eligible. Prior to HCT conditioning, enrolled patients were assigned at random to complete either the traditional AD or the Letter AD. The primary endpoint was AD completion. The chi-square test was used to compare the AD completion rate between arms. The Wilcoxon rank-sum test was used to compare uncertainty, satisfaction with decision making, and satisfaction with the AD. Of the 212 patients who were eligible, 126 (59.4%) were enrolled and randomized. The mean age was 53.7 years, 57 (45.2%) were female, and 74 (58.7%) were non-Hispanic white. The overall AD completion rate was 71.4% and did not differ between the traditional and Letter AD arms (70.3% versus 72.6%; P = .78). Of those who completed the Letter AD, 66.7%, 42.2%, and 46.7% of patients wished to die gently/naturally, at home, and/or with hospice, respectively. In the traditional AD arm, 60.0% wished to not prolong life if recovery was unlikely. Opinion surveys did not find differences in levels of satisfaction between the traditional AD and Letter AD. Completion rates of AD on this study were high (71.4%) compared with historically reported completion rates and did not significantly differ based on AD version.

The role of palliative care in the management of patients with lung cancer.

Palliative care (PC) is the care of patients and their families with serious illness and is rapidly becoming an important part of the care of cancer patients. Patients with advanced lung cancer are a highly symptomatic population of patients and clearly experience benefits in quality of life and potentially benefits in overall survival when PC is incorporated early on after diagnosis. However, referrals to PC are still reliant on clinical judgment of patient prognosis and symptom burden. Moving forward, improving the integration of PC and lung cancer care will require more efficient real-time screening of patient symptoms, which may be accomplished through the use of patient-reported outcomes.

Therapeutic outcomes in non-small cell lung cancer with BRAF mutations: a single institution, retrospective cohort study.

BACKGROUND: Data describing therapeutic outcomes in patients with non-small cell lung cancers (NSCLC) with BRAF mutations remains limited. METHODS: We conducted a retrospective cohort study of 31 patients with metastatic NSCLC treated at Duke University Hospital who had been identified by next-generation sequencing methods to bear a BRAF mutation in their tumor in order to evaluate clinical response to immunotherapy and chemotherapy. RESULTS: Sixty-five percent of patients identified in this cohort were current or former smokers. Fourteen (45.2%) of patients had a BRAF V600E mutation and 17 (54.8%) had a non-V600E mutation. Median progression-free survival (PFS) in the 23 patients who received first-line chemotherapy was 6.4 months [95% confidence interval (CI), 2.3 to 13.0]. Overall survival (OS) in patients who received first-line chemotherapy showed a median survival of 18 months (95% CI, 7.4 to 28.6). OS comparing patients who had never received immunotherapy at any point was 18.4 months (95% CI, 4.1 to NE) compared to 19.0 months (95% CI, 9.9 to 28.6) in those who had received immunotherapy. We did not find a statistically significant difference in OS in patients with BRAF V600E, BRAF amplification, or non-V600E mutations. There was also no difference in OS in patients treated with targeted BRAF inhibitors compared to those who were not treated with targeted BRAF inhibitors. CONCLUSIONS: We describe therapeutic outcomes for patients with metastatic NSCLC with BRAF mutations treated with either cytotoxic chemotherapy or immunotherapy. Although the sample size is small, the survival curves do not suggest improved clinical activity in this population when treated with immunotherapy.

Delayed onset of neurosarcoidosis after concurrent ipilimumab/nivolumab therapy.

BACKGROUND: Immune checkpoint inhibitors have transformed the treatment landscape for many cancers, including metastatic melanoma, but have also opened the door for a diverse variety of immune-related adverse effects. CASE PRESENTATION: We describe the first reported case of presumed neurosarcoidosis as an immune-related adverse effect that developed nearly a year after discontinuation of treatment with combination ipilimumab and nivolumab for recurrent metastatic melanoma. The patient was noted to develop clinical signs consistent with systemic sarcoidosis shortly after the initiation of treatment and underwent a biopsy of hilar lymphadenopathy that confirmed sarcoidosis and after which immunotherapy was discontinued. His melanoma remained stable on surveillance imaging for the next year after which time he developed neurological symptoms and was found to have MRI brain abnormalities without evidence of intracranial metastatic disease, consistent with probable neurosarcoidosis given biopsy-proven systemic sarcoidosis and lack of evidence of CNS infection or malignancy. He underwent treatment with high dose steroids, followed by infliximab, and then methotrexate with both clinical and radiographic improvement within 4 months of starting treatment. CONCLUSIONS: Immune-related adverse effects often occur within 3-6 months of receiving immune checkpoint inhibitor therapy, with some reports of late toxicity. This report highlights a case of probable neurosarcoidosis nearly a year after discontinuation of immune checkpoint therapy. The potential for durable responses after discontinuation of therapy also likely underscores a potential for late toxicity. In patients presenting with new or unexplained symptoms after checkpoint inhibitor therapy, the index of suspicion for an immune-related adverse effect should remain high, irrespective of timing.

NF-κB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer.

Although oncogene-targeted therapy often elicits profound initial tumor responses in patients, responses are generally incomplete because some tumor cells survive initial therapy as residual disease that enables eventual acquired resistance. The mechanisms underlying tumor cell adaptation and survival during initial therapy are incompletely understood. Here, through the study of EGFR mutant lung adenocarcinoma, we show that NF-κB signaling is rapidly engaged upon initial EGFR inhibitor treatment to promote tumor cell survival and residual disease. EGFR oncogene inhibition induced an EGFR-TRAF2-RIP1-IKK complex that stimulated an NF-κB-mediated transcriptional survival program. The direct NF-κB inhibitor PBS-1086 suppressed this adaptive survival program and increased the magnitude and duration of initial EGFR inhibitor response in multiple NSCLC models, including a patient-derived xenograft. These findings unveil NF-κB activation as a critical adaptive survival mechanism engaged by EGFR oncogene inhibition and provide rationale for EGFR and NF-κB co-inhibition to eliminate residual disease and enhance patient responses.

Rubicon controls endosome maturation as a Rab7 effector.

The activation and recruitment of the small GTPase Rab7 to early endosome is a critical step for early to late endosome maturation, a process that requires the class III phosphatidylinositol 3-kinase (PI3KC3) and GTPase regulators. However, the molecular mechanism underlying Rab7 activation and endosome maturation is still poorly defined. Here we report that Rubicon, a component of the PI3KC3 complex, prevents endosome maturation through differential interactions with Rab7 and UVRAG. UVRAG activates PI3KC3 and C-VPS/HOPS, a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on Rab7. We demonstrate that Rubicon sequesters UVRAG from C-VPS/HOPS. Active GTP-bound Rab7 competes for Rubicon binding and releases UVRAG to associate with C-VPS/HOPS, which in turn promotes further loading of Rab7 with GTP. This feed-forward loop ensures rapid amplification of GTP-bound Rab7 and consequent stimulation of endosome maturation. Hence, Rubicon serves as a previously unknown Rab7 effector to ensure the proper progression of the endocytic pathway.