TNFSF4 (OX40L) expression and survival in locally advanced and metastatic melanoma.

Immunotherapy with checkpoint inhibitors revolutionized melanoma treatment in both the adjuvant and metastatic setting, yet not all metastatic patients respond, and metastatic disease still often recurs among immunotherapy-treated patients with locally advanced disease. TNFSF4 is a co-stimulatory checkpoint protein expressed by several types of immune and non-immune cells, and was shown in the past to enhance the anti-neoplastic activity of T cells. Here, we assessed its expression in melanoma and its association with outcome in locally advanced and metastatic disease. We used publicly available data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), and RNA sequencing data from anti-PD1-treated patients at Sheba medical center. TNFSF4 mRNA is expressed in melanoma cell lines and melanoma samples, including those with low lymphocytic infiltrates, and is not associated with the ulceration status of the primary tumor. Low expression of TNFSF4 mRNA is associated with worse prognosis in all melanoma patients and in the cohorts of stage III and stage IIIc-IV patients. Low expression of TNFSF4 mRNAs is also associated with worse prognosis in the subgroup of patients with low lymphocytic infiltrates, suggesting that tumoral TNFSF4 is associated with outcome. TNFSF4 expression was not correlated with the expression of other known checkpoint mRNAs. Last, metastatic patients with TNFSF4 mRNA expression within the lowest quartile have significantly worse outcome on anti-PD1 treatment, and a significantly lower response rate to these agents. Our current work points to TNFSF4 expression in melanoma as a potential determinant of prognosis, and warrants further translational and clinical research.

Exercise systolic blood pressure variability is associated with increased risk for new-onset hypertension among normotensive adults.

Both resting blood pressure (BP) variability and exercise BP previously showed association with incident hypertension. The aim of the present study was to examine whether visit-to-visit variability in exercise systolic blood pressure (SBP) can predict the risk for new-onset hypertension among normotensive adults. We investigated 6546 normotensive men and women who were annually screened in a tertiary medical center and completed treadmill exercise tests at each visit. Based on the initial three baseline annual visits, long-term intervisit variability of exercise SBP among the three tests was measured using standard deviation (SD) and coefficient of variation for each participant. The rate of newly diagnosed hypertension was measured in different variability levels during 6 ± 3 years of follow-up. Multivariate analysis adjusted for various clinical factors, including resting BP, showed that each 5 mm Hg rise in the SD of exercise SBP resulted in a significant 5% increase in the risk for the development of future hypertension (P = .015). Subjects in the upper exercise SBP SD variability tertile had a 28% (P = .007) increased risk for hypertension during follow-up, as compared with those in the lowest tertile. Similar results were achieved for the assessment of coefficient of variation of exercise SBP. In conclusion, visit-to-visit variability in exercise SBP can predict the development of future hypertension among normotensive individuals.

Exercise blood pressure and the risk for future hypertension among normotensive middle-aged adults.

BACKGROUND: The aim of the present study was to examine whether exercise blood pressure can be used to predict the development of hypertension in normotensive middle-aged adults. METHODS AND RESULTS: We investigated 7082 normotensive subjects who were annually screened in a tertiary medical center and completed maximal treadmill exercise tests at each visit. After the initial 3 years, subjects were divided into approximate quartiles according to their average exercise systolic and diastolic blood pressure responses (≤158; 158 to 170; 170 to 183; ≥183 mm Hg for systolic blood pressure and ≤73; 73 to 77; 77 to 82; ≥82 mm Hg for diastolic blood pressure). Mean age of the study population was 48 ± 9 years and 73% were men. Average baseline resting blood pressure was 120/77 ± 12/7 mm Hg. During a follow-up of 5 ± 3 years, 1036 (14.6%) subjects developed hypertension. The cumulative probability of new-onset hypertension at 5 years was significantly increased with increasing quartiles of exercise systolic blood pressure (5%, 9%, 17%, and 35%, respectively; P<0.001), with a similar association shown for diastolic blood pressure. After adjustment for baseline resting blood pressure and clinical parameters, each 5-mm Hg increments in exercise either systolic or diastolic blood pressures were independently associated with respective 11% (P<0.001) and 30% (P<0.001) increased risk for the development of hypertension. CONCLUSIONS: In normotensive middle-aged individuals, blood pressure response to exercise is associated with future development of hypertension.

Budd-Chiari syndrome in very young adult patients with polycythemia vera: report of case series with good outcome with direct thrombin inhibitor treatment.

Polycythemia vera is a Philadelphia chromosome-negative myeloproliferative disorder with incidence of 1% under the age of 25. The Budd-Chiari syndrome (BCS) is a well known complication of polycythemia vera even in children, and characterized by occlusion of hepatic outflow. A computerized archive search of medical records at Sheba Medical Center of the past three decades of patients with polycythemia vera and BCS under the age of 25 years was performed. A work-up for JAK2 V617F mutation and thrombophilia was done. Medical charts and imaging tests were carefully reviewed. Three patients under the age of 22 were finally recruited. Two of those were found in life-threatening condition and improved clinically following treatment with bivalirudin, a direct thrombin inhibitor. It is conceivable that bivalirudin contributed to a favorable outcome of those patients in comparison to historical outcome previously reported. In conclusion, polycythemia vera in the young is not a mild disease since BCS, which is one of its complication, can be fatal even in those age group unrelated to the presence of hereditary thrombophilia. Once BCS occurs, we would suggest giving a trial with bivalirudin before an invasive procedure is planned.

Eosinophilia among returning travelers: a practical approach.

Eosinophilia is not uncommon among returning travelers; however, the optimal diagnostic and therapeutic approach in travelers, as opposed to immigrants and refugees, is not clearly established. This was a retrospective case series. All returning travelers from developing countries presenting at the post-travel clinic with eosinophilia (>or= 500 cells/mcl) during 1994-2006 were evaluated. Data were compared with other referrals to the post-travel clinic and with a random sample of a pre-travel clinic. Of the 955 returning travelers evaluated during the study period, 82 (8.6%) had eosinophilia, and 44 (4.4%) were diagnosed with schistosomiasis. Another 38 (4.2%) cases presented with non-schistosomal eosinophilia (NSE), among whom a definite parasitologic diagnosis was achieved in only 23.7%. However, an empiric course of albendazole led to a clinical improvement in 90% of NSE cases. Helminthic disease probably accounts for the majority of cases of post-travel eosinophilia. Empiric albendazole therapy should be offered to undiagnosed NSE patients.

Lipoid pneumonia: a preventable complication.

BACKGROUND: Lipoid pneumonia is a pneumonitis resulting from the aspiration of lipids, and is commonly associated with the use of mineral oil as a laxative. LP is relatively unfamiliar to clinicians and is probably underdiagnosed. OBJECTIVES: To increase physicians' awareness of LP, its diagnosis and prevention. METHODS: We present two illustrative cases of LP and review the literature. RESULTS: Two cases of LP were diagnosed within half a year in an internal medicine ward. Both cases were elderly patients, and LP was associated with the use of mineral oil as a laxative agent. Computerized tomography revealed bilateral low attenuation infiltrates, associated with a "crazy paving" pattern in one case. Sudan Black staining was diagnostic in both cases--in one on a transbronchial biopsy specimen, and in the other on sputum cytologic examination. Both patients suffered from neurologic diseases and were at risk of aspiration. In both cases clinical symptoms and signs continued for several months prior to diagnosis but resolved after the mineral oil was discontinued. CONCLUSIONS: LP often occurs in elderly patients who are at risk of aspiration. The condition may be underdiagnosed. Since in most cases mineral oil cathartics are the causative agent, an effort at primary prevention is indicated. It is suggested that the licensing of mineral oil for internal use be changed.