Faculty Bibliography

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has affected our lives in a lot of different ways. We have observed a variety of clinical presentations in people infected with SARS-CoV-2 or coronavirus disease 2019 (COVID-19). Here, we present a case of COVID-19 who developed colitis ten days after an initial positive test for SARS-CoV-2.

UNLABELLED:Targeted therapy of ROS1-fusion-driven non-small cell lung cancer (NSCLC) has achieved notable clinical success. Despite this, resistance to therapy inevitably poses a significant challenge. MYC amplification was present in ∼19% of lorlatinib-resistant ROS1-driven NSCLC. We hypothesized that MYC overexpression drives ROS1-TKI resistance. Using complementary approaches in multiple models, including a MYC-amplified patient-derived cell line and xenograft (LUAD-0006), we established that MYC overexpression induces broad ROS1-TKI resistance. Pharmacologic inhibition of ROS1 combined with MYC knockdown were essential to completely suppress LUAD-0006 cell proliferation compared with either treatment alone. We interrogated cellular signaling in ROS1-TKI-resistant LUAD-0006 and discovered significant differential regulation of targets associated with cell cycle, apoptosis, and mitochondrial function. Combinatorial treatment of mitochondrial inhibitors with crizotinib revealed inhibitory synergism, suggesting increased reliance on glutamine metabolism and fatty-acid synthesis in chronic ROS1-TKI treated LUAD-0006 cells. In vitro experiments further revealed that CDK4/6 and BET bromodomain inhibitors effectively mitigate ROS1-TKI resistance in MYC-overexpressing cells. Notably, in vivo studies demonstrate that tumor control may be regained by combining ROS1-TKI and CDK4/6 inhibition. Our results contribute to the broader understanding of ROS1-TKI resistance in NSCLC. IMPLICATIONS:This study functionally characterizes MYC overexpression as a novel form of therapeutic resistance to ROS1 tyrosine kinase inhibitors in non-small cell lung cancer and proposes rational combination treatment strategies.

AIM:Deterioration of patients from COVID-19 is associated with cytokine release syndrome attributed to an elevation in pro-inflammatory cytokines. Vitamin D reduces proinflammatory cytokines, and has the possibility of reducing complications from respiratory tract illnesses. METHOD:This was a retrospective, observational, cohort study of patients with COVID-19 disease within a New York City Health System. Adult patients were included if they tested positive for SARS-CoV-2, and had a serum 25-hydroxy vitamin D level (25(OH)D) within the three previous months prior to their detected SARS-CoV-2 test. Patients were compared and evaluated based upon their 25(OH)D levels. The primary endpoints were hospitalization, need for oxygen support, and 90-day mortality. RESULTS: 0.0002)] from COVID-19. Deficient plasma 25(OH)D levels were not independently associated with 90-day mortality or risk of hospitalization. Hospitalization rates (98%), oxygen support (93%), and mortality rates (49%) were highest in patients who had 25(OH)D levels less than 10 ng/ml when compared to other 25(OH)D levels. CONCLUSION:Serum 25-hydroxy vitamin D levels may affect the need for oxygen support therapy in patients with COVID-19.

Radiation therapy (RT) is a crucial part of cancer care, but previous work suggests that many non-radiation oncologist physicians are uncomfortable referring for RT. To evaluate training and understanding of RT, the authors sent invitations to complete an online questionnaire to all physicians at a community hospital in Bronx, NY, which asked about oncology training and self-rated and objective knowledge of RT. Out of 247 invited participants, 87 responded (35%). Among responders, 19 were attending physicians (22%) and 66 (76%) were residents. Seventy-two percent of respondents reported caring for > 5 cancer patients in the past month, but 54% reported never referring patients for RT. Sixty-nine percent of respondents stated they received no radiation oncology training in medical school, and 36% reported no general oncology training. Approximately half believed themselves to be "somewhat knowledgeable" about RT indications (48%), benefits (53%), and side effects (55%). Objective assessment mean score was 6.2/12 (median 7) for all respondents; Respondents with internal medicine specialization scored higher than others (mean 7.7 vs 3.5; p < 0.01). Scores did not differ between attending and resident physicians, resident post-graduate levels, or receiving oncology training in medical school. The factors most commonly cited as affecting RT referral decisions were type of cancer, patient wishes, family wishes, poor functional status, and life expectancy. Many physicians are unaware of RT effectiveness or indications, which may affect referral patterns. Previous oncology training was not associated with higher knowledge scores.

Secondary Fracture Prevention: Consensus Clinical Recommendations from a Multistakeholder Coalition RELEASE DATE: September 20, 2019 PRIOR VERSION: Not applicable DEVELOPER: American Society for Bone and Mineral Research Task Force and Multistakeholder Coalition FUNDING SOURCE: American Society for Bone and Mineral Research and the Center for Medical Technology Policy TARGET POPULATION: Adults 65 years or older with a hip or vertebral fracture. This review will focus on the core recommendations and their application in the practice of hospital medicine.

BACKGROUND:New York City emerged as an epicenter of the coronavirus disease 2019 (COVID-19) pandemic. OBJECTIVE:To describe the clinical characteristics and risk factors associated with mortality in a large patient population in the USA. DESIGN:Retrospective cohort study. PARTICIPANTS:6493 patients who had laboratory-confirmed COVID-19 with clinical outcomes between March 13 and April 17, 2020, who were seen in one of the 8 hospitals and/or over 400 ambulatory practices in the New York City metropolitan area MAIN MEASURES: Clinical characteristics and risk factors associated with in-hospital mortality. KEY RESULTS:(HR 1.80, CI 1.60-2.02), IL-6 greater than 100 pg/mL (HR 1.50, CI 1.12-2.03), D-dimer greater than 2 mcg/mL (HR 1.19, CI 1.02-1.39), and troponin greater than 0.03 ng/mL (HR 1.40, CI 1.23-1.62). Decreased risk of in-hospital mortality was associated with female sex (HR 0.84, CI 0.77-0.90), African American race (HR 0.78 CI 0.65-0.95), and hydroxychloroquine use (HR 0.53, CI 0.41-0.67). CONCLUSIONS:Among patients with COVID-19, older age, male sex, hypotension, tachypnea, hypoxia, impaired renal function, elevated D-dimer, and elevated troponin were associated with increased in-hospital mortality and hydroxychloroquine use was associated with decreased in-hospital mortality.

Alcohol use is a common social and recreational activity in our society. Misuse of alcohol can lead to significant medical comorbidities that can affect essentially every organ system and lead to high health care costs and utilization. Heavy alcohol use across the spectrum from binge drinking and intoxication to chronic alcohol use disorder can lead to high morbidity and mortality both in the long and short term. Recognizing and treating common neurologic, gastrointestinal, and hematological manifestations of excess alcohol intake are essential for those who care for hospitalized patients. Withdrawal is among the most common and dangerous sequela associated with alcohol use disorder.

PURPOSE:ROS1 tyrosine kinase inhibitors (TKI) provide significant benefit in lung adenocarcinoma patients with ROS1 fusions. However, as observed with all targeted therapies, resistance arises. Detecting mechanisms of acquired resistance (AR) is crucial to finding novel therapies and improve patient outcomes. EXPERIMENTAL DESIGN:ROS1 fusions were expressed in HBEC and NIH-3T3 cells either by cDNA overexpression (CD74/ROS1, SLC34A2/ROS1) or CRISPR-Cas9-mediated genomic engineering (EZR/ROS1). We reviewed targeted large-panel sequencing data (using the MSK-IMPACT assay) patients treated with ROS1 TKIs, and genetic alterations hypothesized to confer AR were modeled in these cell lines. RESULTS:in ROS1 fusion-positive cells activated MEK/ERK signaling and conferred resistance to ROS1 TKIs. Combined targeting of ROS1 and MEK inhibited growth of cells expressing both ROS1 fusion and MEK1del. CONCLUSIONS:We demonstrate that downstream activation of the MAPK pathway can mediate of innate acquired resistance to ROS1 TKIs and that patients harboring ROS1 fusion and concurrent downstream MAPK pathway alterations have worse survival. Our findings suggest a treatment strategy to target both aberrations.