Most breast cancers express androgen receptors (AR). This prospective imaging sub-study explored imaging AR with 18 F-fluoro-5α-dihydrotestosterone (FDHT)-PET in patients with metastatic breast cancer (MBC) receiving selective AR modulation (SARM) therapy (GTx-024).Methods: 11 post-menopausal women with estrogen receptor positive MBC underwent FDHT-PET/CT at baseline, 6, and 12 weeks after starting SARM therapy. Abnormal tumor FDHT uptake was quantified using maximum SUV (SUVmax). AR status was determined from tumor biopsy specimens. FDHT-SUVmax percent change between scans was calculated. Best overall response was categorized as clinical benefit (CB: non-progressive disease [PD]), or PD using RECIST 1.1).Results: Median baseline FDHT-SUVmax was 4.1 (range 1.4-5.9) for AR+ tumors versus 2.3 (range 1.5-3.2) for AR-tumors (p=0.22). Quantitative AR expression and baseline FDHT uptake were weakly correlated (Pearson rho=0.39, p=0.30). Seven participants with CB at 12 weeks tended to have larger declines in FDHT uptake compared to those with PD at both 6 (median decline, range: -26.8%, -42.9 to -14.1% vs. -3.7%, -31% to +29%, respectively, p=0.11) and 12 weeks (median decline, range: -35.7%, -69.5 to -7.7% vs. -20.1%, -26.6% to +56.5%, respectively, p=0.17) after starting GTx-024. Conclusion:This hypothesis-generating data suggests that FDHT-PET/CT is worth further study as an imaging biomarker for evaluating response of MBC to SARM therapy and reiterates the feasibility of including molecular imaging in multidisciplinary therapeutic trials.

IMPORTANCE De novo bullous pemphigoid (BP) is a rare immune-mediated adverse event from immune checkpoint inhibitors (ICIs) that can necessitate permanent discontinuation of the anticancer therapy, but the risk factors for developing this toxic effect are unknown.OBJECTIVE To compare potential risk factors for BP in patients treated with ICIs who did and did not develop BP. DESIGN, SETTING, AND PARTICIPANTSThis cohort and nested propensity score-matched case-control study was conducted at the Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Massachusetts General Hospital. All patients at these facilities with de novo BP after ICI treatment were compared with all patients on the cancer registry who were treated with ICIs between October 1, 2014, and December 31, 2020. Patients with incomplete or blinded data regarding the ICI agent or total cycles were excluded. EXPOSURESIn the cohort, assessed potential risk factors included age at ICI introduction, sex, ICI molecular target, and cancer type, which were then used as matching variables. In the propensity score-matched case-control analysis, risk factors assessed included sex, race and ethnicity, cancer stage, metastasis sites, idiopathic BP comorbidities, pre-ICI vaccination, radiation history, body mass index, and derived neutrophil-to-lymphocyte ratio. MAIN OUTCOMES AND MEASURESDiagnosis of BP at any point after ICI treatment, confirmed by direct immunofluorescence, indirect immunofluorescence, autoantibody serologies, or diagnostic consensus among study board-certified dermatologists. Odds ratios (ORs) and 95% CIs were calculated for all risk factors. In the secondary analysis, best overall responses to ICIs between cases and controls were compared by Fisher exact test. RESULTS Among 5636 patients treated with ICIs at Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Massachusetts General Hospital during the study period, 35 (0.6%; median [IQR] age, 72.8 [13.4] years; 71.4% [25] male patients) developed BP. In a multivariate logistic regression model that assessed 2955 patients with complete data in the cancer registry, age 70 years or older (OR, 2.32; 95% CI, 1.19-4.59; P = .01), having melanoma (OR, 3.21; 95% CI, 1.51-6.58; P < .003), and having nonmelanoma skin cancer (OR, 8.32; 95% CI, 2.81-21.13; P < .001) were significantly associated with developing BP. In the nested 1:2 case-control comparison of all 35 cases to 70 propensity score-matched controls, a complete or partial response on initial restaging imaging was a risk factor for BP development (OR, 3.37; 95% CI, 1.35-9.30; P = .01). Bullous pemphigoid cases also more frequently exhibited overall tumor response to ICIs than matched controls (29 of 35 [82.9%] vs 43 of 70 [61.4%]; P = .03). CONCLUSIONS AND RELEVANCEIn this cohort study, age 70 years or older and skin cancer were associated with increased risk of developing ICI-associated BP. Given the association of BP with improved initial and best overall tumor responses, early identification and toxic effect-directed treat...

Background Given the challenges associated with timely delivery of monoclonal antibody (mAb) therapy to outpatients with Covid-19 who are most likely to benefit, it is critical to understand the effectiveness of such therapy outside the context of clinical trials. Methods Case-control study of 1257 adult outpatients with Covid-19, ≥ 65 years of age or with BMI ≥ 35, who were entered into a lottery for mAb therapy. Results Patients who were called to be offered mAb therapy had a statistically significant, 44% reduction in the odds of hospitalization within 30 days of a positive SARS-CoV-2 test compared with those who were not called (OR 0.56, 95% CI [0.36, 0.89], P=.01). Patients who actually received bamlanivimab had a statistically significant, 68% reduction in the odds of hospitalization compared with those who did not receive bamlanivimab (OR 0.32, 95% CI [0.11, 0.93], P=0.04). There was no statistically significant difference in the odds of death between patients who were called and patients who were not called (OR 1.79, 95% CI [0.52, 6.17], P=0.35), but there was a statistically significant difference in the odds of death between patients who received bamlanivimab and those who did not (OR 0.03, 95% CI [0, 0.25), P&lt;0.01). Conclusions This study supports the effectiveness of bamlanivimab in reducing Covid-19 related hospitalizations in patients ≥ 65 or with BMI ≥ 35 and suggests a mortality benefit.

We present a case report of simultaneous pulmonary emboli and paradoxical embolism to the cerebellum causing a stroke and severe ischemia to the left leg. This patient had risk factors for thromboembolic events that included autoimmune disease, cancer, and recent pelvic surgery. The presence of a perforate foramen ovale was suspected on his initial presentation and confirmed with echocardiography. For acute leg ischemia, this patient underwent emergent left common femoral embolectomy. The potential benefit of immediate anticoagulation had to be weighed against the risk of hemorrhagic transformation of his cerebellar stroke with possible compression of the fourth ventricle. In the end, full anticoagulation was delayed with interval placement of a retrievable inferior vena cava filter. This case illustrates the challenges faced in treating a patient with multiple paradoxical emboli. (J Vasc Surg 2015;-:1-3.) CASE REPORTConsent was obtained from the patient to publish this case report along with the images. The patient is a 57-year-old man who presented to the emergency department with a 12-hour history of vertigo, nausea, left leg weakness, and shortness of breath at rest. He was unable to get out of bed as lifting his head off the pillow led to a sensation that "everything was spinning." He also complained of escalating pain followed by numbness and weakness in his left foot. In addition, his shortness of breath was unusual for him as he normally walked about a mile a day for exercise.Pertinent past medical history included Wegener granulomatosis, transitional cell bladder cancer, hypertension, and venous thromboembolism. He completed a 12-month course of systemic anticoagulation after a pulmonary embolus developed 5 years ago. At that time, the patient was evaluated for a possible hypercoagulable syndrome and none was found. The patient had undergone a radical cystoprostatectomy with neobladder creation for bladder cancer about 2 months before this current presentation.On physical examination, the patient was noted to have nystagmus with head movement. He had significant dysmetria. Speech was slurred but otherwise intact. There was no facial droop. His left lower extremity was white and insensate below the knee. There was minimal plantar flexion, and the left foot was paralyzed. There was no pulse in the left leg. A Doppler signal was present in the left femoral artery. Neurovascular examination findings of the right lower extremity were unremarkable.Pertinent diagnostic imaging included computed tomography (CT) of the head, showing an acute right cerebellar infarct (Fig 1); CT angiography of the chest, showing bilateral pulmonary emboli (Fig 2); and CT of the abdomen and pelvis (done as part of the workup for nausea), showing an acute cutoff at the left common femoral artery.At this point, the patient was diagnosed with a cerebellar stroke, pulmonary emboli, and critical ischemia of the left lower extremity. He was taken emergently to the operating room, where a left common femoral artery embolectomy was perform...

Background: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine (NE) skin cancer caused by severe UV-induced mutations or expression of Merkel cell polyomavirus (MCPyV) large and small T antigens (LT and ST). Despite deep genetic differences between MCPyV-positive and -negative subtypes, current clinical diagnostic markers are indistinguishable and the expression profile of MCC tumors is unexplored. Methods: Here we leveraged bulk and single-cell RNA sequencing of patient-derived tumor biopsies and cell lines to explore the underlying expressional environment of MCC. Results: Strikingly, MCC samples could be separated into expressional subtypes that were independent of MCPyV-status. Instead, we observed an inverse correlation between a NE gene signature and Hippo pathway transcription factors Yes1-associated transcriptional regulator (YAP1) and WW domain containing transcriptional regulator (WWTR1). This inverse correlation was broadly present at the transcript and protein levels in the tumor biopsies as well as in established and patient-derived cell lines. Mechanistically, expression of YAP1 or WWTR1 in a MCPyV-positive MCC cell line induced cell-cycle arrest at least in part through TEADdependent transcriptional repression of MCPyV LT. Conclusion: These findings identify a previously unrecognized heterogeneity in NE gene expression within MCC and support a model of YAP1/WWTR1 silencing as essential for the development of MCPyV-positive MCC.