Prognostic and predictive significance of nuclear HIF1α expression in locally advanced HNSCC patients treated with chemoradiation with or without nimotuzumab

Background Anti-EGFR-based therapies have limited success in HNSCC patients. Predictive biomarkers are greatly needed to identify the patients likely to be benefited from these targeted therapies. Here, we present the prognostic and predictive association of biomarkers in HPV-negative locally advanced (LA) HNSCC patients.Methods Treatment-naive tumour tissue samples of 404 patients, a subset of randomised Phase 3 trial comparing cisplatin radiation (CRT) versus nimotuzumab plus cisplatin radiation (NCRT) were analysed to evaluate the expression of HIF1α, EGFR and pEGFR by immunohistochemistry and EGFR gene copy change by FISH. Progression-free survival (PFS), locoregional control (LRC) and overall survival (OS) were estimated by Kaplan–Meier method. Hazard ratios were estimated by Cox proportional hazard models.Results Baseline characteristics of the patients were balanced between two treatment groups (CRT vs NCRT) and were representative of the trial cohort. The median follow-up was of 39.13 months. Low HIF1α was associated with better PFS [HR (95% CI) = 0.62 (0.42–0.93)], LRC [HR (95% CI) = 0.56 (0.37–0.86)] and OS [HR (95% CI) = 0.63 (0.43–0.93)] in the CRT group. Multivariable analysis revealed HIF1α as an independent negative prognostic biomarker. For patients with high HIF1α, NCRT significantly improved the outcomes [PFS:HR (95% CI) = 0.55 (0.37–0.82), LRC:HR (95% CI) = 0.55 (0.36–0.85) and OS:HR (95% CI) = 0.54 (0.36–0.81)] compared to CRT. While in patients with low HIF1α, no difference in the clinical outcomes was observed between treatments. Interaction test suggested a predictive value of HIF1α for OS (P = 0.008).Conclusions High HIF1α expression is a predictor of poor clinical response to CRT in HPV-negative LA-HNSCC patients. These patients with high HIF1α significantly benefited with the addition of nimotuzumab to CRT.Clinical trial registration Registered with the Clinical Trial Registry of India (Trial registration identifier—CTRI/2014/09/004980).Subject terms: Tumour biomarkers, Head and neck cancer, Tumour biomarkers, Head and neck cancer, Predictive markers     

Animal Models of Barrett's Esophagus and Esophageal Adenocarcinoma–Past,Present, and Future

Esophageal adenocarcinoma is the fastest rising cancer in the United States. It develops from long‐standing gastroesophageal reflux disease which affects >20% of the general population. It carries a very poor prognosis with 5‐year survival <20%. The disease is known to sequentially progress from reflux esophagitis to a metaplastic precursor, Barrett''s esophagus and then onto dysplasia and esophageal adenocarcinoma. However, only few patients with reflux develop Barrett''s esophagus and only a minority of these turn malignant. The reason for this heterogeneity in clinical progression is unknown. To improve patient management, molecular changes which facilitate disease progression must be identified. Animal models can provide a comprehensive functional and anatomic platform for such a study. Rats and mice have been the most widely studied but disease homology with humans has been questioned. No animal model naturally simulates the inflammation to adenocarcinoma progression as in humans, with all models requiring surgical bypass or destruction of existing antireflux mechanisms. Valuable properties of individual models could be utilized to holistically evaluate disease progression. In this review paper, we critically examined the current animal models of Barrett''s esophagus, their differences and homologies with human disease and how they have shaped our current understanding of Barrett''s carcinogenesis.     

Short-Duration Prednisolone in Children with Nephrotic Syndrome Relapse: A Noninferiority Randomized Controlled Trial

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SGLT2 inhibitors for the treatment of diabetes: a patent review (2013-2018)

Introduction: The sodium-glucose co-transporter 2 (SGLT2) is ascribed to target renal tubular glucose re-absorption, and its inhibition has been proved to induce glucosuria which improves the glycemic index. Accordingly, SGLT2 inhibitors have found to be the promising class of antidiabetic agents for the management of type 2 diabetes mellitus. A large number of SGLT2 inhibitors have developed through structural modification and investigated for their ability to selectivity inhibit SGLT2 transporters with better bioavailability.

Areas covered: This review comprises a summary of patent applications (2013–2018) of SGLT2 inhibitors with focus on chemical structural advancement and therapeutic potentials in the management of diabetes and related disorders.

Expert opinion: SGLT2 inhibitors exert multiple metabolic benefits, including reduced glycated hemoglobin (HbA1c), improved glycemic control (fasting and postprandial), reduced body weight, reduced systolic and diastolic blood pressure and improved HDL cholesterol. Due to the virtue of no interference with insulin action and secretion, their efficacy remains the same even in presence of progressive β cell failure in type 2 diabetes. Additionally, few members of this class have been reported to exhibit cardioprotective, renoprotective, and anticancer activity. However, more study on the long-term outcomes in patients taking SGLT2 inhibitors is warranted.     

Premature Ticagrelor Discontinuation in Secondary Prevention of Atherosclerotic CVD: JACC Review Topic of the Week

Ticagrelor is a cornerstone of modern antithrombotic therapy alongside aspirin in patients with acute coronary syndrome and after percutaneous coronary intervention. Adverse effects such as bleeding and dyspnea have been associated with premature ticagrelor discontinuation, which may limit any potential advantage of ticagrelor over clopidogrel. The randomized trials of ticagrelor captured adverse events, offering the opportunity to more precisely quantify these effects across studies. Therefore, a meta-analysis of 4 randomized clinical trials of ticagrelor conducted between January 2007 and June 2017 was performed to quantify the incidence and causes of premature ticagrelor discontinuation. Among 66,870 patients followed for a median 18 months, premature ticagrelor discontinuation was seen in 25%; bleeding was the most common cause of discontinuation followed by dyspnea. Versus the comparators, the relative risk of dyspnea-related discontinuation during follow-up was 6.4-fold higher, the relative risk of bleeding was 3.2-fold higher, and the relative risk of discontinuation due to any adverse event was 59% higher for patients receiving ticagrelor. Understanding these potential barriers to adherence to ticagrelor is crucial for informed patient-physician decision making and can inform future efforts to improve ticagrelor adherence. This review discusses the incidence, causes, and biological mechanisms of ticagrelor-related adverse effects and offers strategies to improve adherence to ticagrelor.     

Predictors of long-term survival in patients with gallbladder cancer

The aim of this study was to examine the predictors of long-term survival (>24 months) in patients with gall bladder cancer. A retrospective review of 117 cases of gall bladder cancer resected between 1989 and 2000. The resections included 80 simple cholecystectomies and 37 extended procedures. Patients with survival >24 months (n=44) were compared with those having survival <24 months (n=73) for 17 prognostic factors. Overall median survival was 16 months with a 5-year survival of 27%. T status (P=.000) and adjuvant chemoradiotherapy (P=.001) were independent predictors of long-term survival. Survival advantage was seen in T3N+ve disease (P=.007) with extended procedures. Complete (R0) resection was attained in 30 patients with a 5-year survival advantage of 30% as compared with incomplete (R1) resection (P=.0002). Adjuvant chemoradiotherapy improved survival in simple cholecystectomy group (P=.0008) but no advantage was seen after extended procedures. Stage III (P=.001) and node-positive disease (P=.0005) had significant benefit with adjuvant therapy. Poor differentiation and vascular invasion were associated with poor long-term survival. R0 resection was associated with prolonged survival. Extended procedures improved survival in patients with T3N+ve disease. Addition of chemoradiotherapy made significant improvement in long-term survival in stage III and node-positive lesions and in patients undergoing simple cholecystectomy. R0 resection predicted long-term survival in gall bladder cancer. T3 N+ve disease had better survival after extended procedures. Adjuvant chemoradiotherapy improved survival in stage III and node-positive disease. Poor differentiation and vascular invasion were adverse predictors of survival.     

Porphyrin dimers as photosensitizers in photodynamic therapy

Porphyrin dimers 9 with either linkages and possible isomers bis[1-[6,7-bis[2-(methoxycarbonyl)ethyl]-1,3,5,8-tetramethyl-2- vinylporphin-4-yl]ethyl] ether (10) bis[1-[6,7-bis[2-(methoxycarbonyl)ethyl]-1,3,5,8-tetramethyl-4- vinylporphin-2-yl]ethyl] ether (11), and 1-[6,7-bis[2-(methoxycarbonyl)ethyl]-1,3,5,8-tetramethyl-2-vinylporph in- 4-yl]ethyl 1-[6,7-bis[2-(methoxycarbonyl)ethyl]-1,3,5,8-tetramethyl-4-vinylporph in- 2-yl]ethyl ether (12) were synthesized from the corresponding (1-hydroxyethyl)vinyldeuteroporphyrin IX dimethyl esters (Hvd). The pure Hvd isomers 2-(1-hydroxyethyl)-4-vinyldeuteroporphyrin IX dimethyl ester (7) and 4-(1-hydroxyethyl)-2-vinyldeuteroporphyrin IX dimethyl ester (8) were obtained from 2-acetyl-4-(1-hydroxyethyl) deuteroporphyrin IX dimethyl ester (3) and 4-acetyl-2-(1-hydroxyethyl)deuteroporphyrin IX dimethyl ester (4). Porphyrins 3 and 4 were prepared either by partial reduction of 2,4-diacetyldeuteroporphyrin IX dimethyl ester (2) or by oxidation of hematoporphyrin IX dimethyl ester (1) by using tetra-n-propylammonium perruthenate (Prn4N)(RuO4) with N-methylmorpholine N-oxide as an oxidizing agent. The in vivo photosensitizing ability and therapeutic ratios of dimers 9-12 were compared with that of Photofrin II in the SMT-F tumor growing subcutaneously in DBA/2 Ha mice. These dimers were found to have better tumoricidal activity than Photofrin II with reduced skin phototoxicity.     

Warfarin or Low-Molecular-Weight Heparin Therapy does not Prolong Pig-To-Primate Cardiac Xenograft Function

Microvascular thrombosis is a prominent feature in cardiac delayed xenograft rejection (DXR). We investigated the impact of warfarin or low-molecular-weight heparin (LMWH) anti-coagulation on xenograft function using a heterotopic pig-to-primate model. Donor hearts were from CD46 transgenic pigs and baboon immunosuppression included tacrolimus, sirolimus, anti-CD20 and TPC, an alpha-galactosyl-polyethylene glycol conjugate. Three groups of animals were studied. Group 1 (n = 9) was treated with warfarin, Group 2 (n = 13) with LMWH and Group 3, received no anti-coagulant drugs. The median duration of xenograft function was 20 days (range 3-62 days), 18 days (range 5-109 days) and 15 days (range 4-53 days) in Groups 1 to 3 respectively. Anti-coagulation achieved the targeted international normalized prothrombin ratio (INR) and anti-factor Xa levels consistent with effective in vivo therapy yet, no significant impact on median xenograft function was observed. At rejection, a similar histology of thrombosis and ischemia was apparent in each group and the levels of fibrin deposition and platelet thrombi in rejected tissue was the same. Anti-coagulation with warfarin or LMWH did not have a significant impact on the onset of DXR and microvascular thrombosis. However, a role for specific anti-coagulant strategies to achieve long-term xenograft function cannot be excluded.