Harshit Garg

A Combined Gene Signature of Hypoxia and Notch Pathway in Human Glioblastoma and Its Prognostic Relevance

Hypoxia is a hallmark of solid tumors including glioblastoma (GBM). Its synergism with Notch signaling promotes progression in different cancers. However, Notch signaling exhibits pleiotropic roles and the existing literature lacks a comprehensive understanding of its perturbations under hypoxia in GBM with respect to all components of the pathway. We identified the key molecular cluster(s) characteristic of the Notch pathway response in hypoxic GBM tumors and gliomaspheres. Expression of Notch and hypoxia genes was evaluated in primary human GBM tissues by q-PCR. Clustering and statistical analyses were applied to identify the combination of hypoxia markers correlated with upregulated Notch pathway components. We found well-segregated tumor—clusters representing high and low HIF-1α/PGK1-expressors which accounted for differential expression of Notch signaling genes. In combination, a five-hypoxia marker set (HIF-1α/PGK1/VEGF/CA9/OPN) was determined as the best predictor for induction of Notch1/Dll1/Hes1/Hes6/Hey1/Hey2. Similar Notch-axis genes were activated in gliomaspheres, but not monolayer cultures, under moderate/severe hypoxia (2%/0.2% O2). Preliminary evidence suggested inverse correlation between patient survival and increased expression of constituents of the hypoxia-Notch gene signature. Together, our findings delineated the Notch-axis maximally associated with hypoxia in resected GBM, which might be prognostically relevant. Its upregulation in hypoxia-exposed gliomaspheres signify them as a better in-vitro model for studying hypoxia-Notch interactions than monolayer cultures.

An update on the role of medical treatment including antioxidant therapy in varicocele

Varicocele-associated male infertility has classically been managed using surgery or assisted reproductive techniques. With increasing evidence of oxidative stress as a pathophysiological factor in varicocele-associated infertility, medical therapy especially antioxidants might become a treatment option with lower risks. We reviewed the existing literature on the role of various medical agents in the management of male infertility attributed to varicoceles. Medical therapy is typically evaluated in three different situations such as (a) comparison of two drugs or one drug with placebo, (b) comparison of drugs versus surgery, and (c) comparison of drugs as adjuvant therapy with surgery versus drug therapy alone. Due to heterogeneity of data and lack of well-conducted studies, there is insufficient data to recommend routine use of medical therapy for men with varicocele-associated infertility and surgery remains the treatment of choice. Pregnancy and live birth rates are usually not reported in most studies and mere improvement in sperm parameters or antioxidant capacity is insufficient to support its routine use. Antioxidant therapy is a potential option due to its theoretical benefit, data from preclinical studies, and lack of major side effects. Adjuvant therapy with antioxidants after surgical repair of varicocele may improve the outcome and is a potential area for further research.

Utility of transient elastography (fibroscan) and impact of bariatric surgery on nonalcoholic fatty liver disease (NAFLD) in morbidly obese patients

BACKGROUND Controlled attenuation parameter (CAP) is a novel, noninvasive technique for assessing hepatic steatosis. However, its role in morbidly obese individuals is unclear. The effect of bariatric surgery on inflammation and fibrosis needs to be explored. OBJECTIVES To assess the utility of CAP for assessment of hepatic steatosis in morbidly obese individuals and evaluate the effect of bariatric surgery on hepatic steatosis and fibrosis. SETTING A tertiary care academic hospital. METHODS Baseline details of anthropometric data, laboratory parameters, FibroScan (XL probe), and liver biopsy were collected. Follow-up liver biopsy was done at 1 year. RESULTS Of the 124 patients screened, 76 patients were included; mean body mass index was 45.2 ± 7.1 kg/m2. FibroScan success rate was 87.9%. The median liver stiffness measurement (LSM) and CAP were 7.0 (5.0-9.5) kPa and 326.5 (301-360.5) dB/m, respectively. On liver histopathology, severe steatosis and nonalcoholic steatohepatitis were present in 5.3% and 15.8%; significant fibrosis (≥stage 2) and cirrhosis in 39.5% and 2.6%, respectively. Area under receiver operator characteristic curve of LSM for prediction of significant fibrosis (F2-4 versus F0-1) and advanced fibrosis (F3-4 versus F0-2) was .65 (95% confidence interval [CI]: .52-.77) and .83 (95% CI: .72-.94), respectively. The area under receiver operator characteristic curve of CAP for differentiating moderate hepatic steatosis (S2-3 versus S0-1) and severe hepatic steatosis (S3 versus S0-2) was .74 (95% CI: .62-.86) and .82 (95% CI: .73-.91), respectively. At 1-year follow-up, 32 patients underwent liver biopsy. In these patients, there was significant improvement in hepatic steatosis (P = .001), lobular inflammation (P = .033), ballooning (P<.001), and fibrosis (P = .003). Nonalcoholic steatohepatitis was resolved in 3 of 4 (75%) patients. LSM and CAP significantly declined. CONCLUSIONS LSM and CAP are feasible and accurate at diagnosing advanced fibrosis and severe hepatic steatosis in morbidly obese individuals. Bariatric surgery is associated with significant improvement in LSM, CAP, steatohepatitis, and fibrosis.

Impact of bariatric surgery on obstructive sleep apnoea–hypopnea syndrome in morbidly obese patients

Background: Obstructive sleep apnea (OSA) is commonly associated with morbid obesity. Weight loss following bariatric surgery results in resolution or improvement of OSA. However, few studies have done objective assessment of the impact of bariatric surgery on OSA. Objective: The aim of this study was to assess the outcome of bariatric surgery on OSA. Setting: The study was conducted in the teaching institution of a tertiary care centre. Methods: Twenty-seven morbidly obese patients seeking bariatric surgery were administered Epworth Sleepiness Scale (ESS) health questionnaire and subjected to overnight polysomnography. Repeat assessment using ESS and polysomnography was done at 3–6 months after surgery. Results: Mean age was 42.4 ± 10.5 years, and majority (77.8%) were female. The mean pre-operative weight and body mass index (BMI) were 126.4 ± 24.9 kg and 48.4 ± 8.2 kg/m2, respectively. Nearly 29.6% patients had symptoms of excessive daytime somnolence based on ESS score and overnight polysomnography detected the presence of OSA in 96.3% patients, of which 51.9% had severe OSA. At mean follow-up of 5.2 ± 2.5 months after surgery, mean weight and BMI decreased to 107.4 ± 24.5 kg and 41.2 ± 8.2 kg/m2, respectively. Mean ESS score and mean apnoea–hypopnea index declined from 8.9 ± 3.2 to 4.03 ± 2.15 (P < 0.001) and from 31.8 ± 20.4 to 20.2 ± 23.1 (P = 0.007), respectively. Number of patients requiring continuous positive airway pressure (CPAP) therapy declined from 15 to 3 and average CPAP requirement came down from 11.3 cm of H2O to 6 cm of H2O. Conclusion: OSA was present in a significant proportion of patients undergoing bariatric surgery. Bariatric surgery resulted in significant improvement in both subjective and objective parameters of OSA.

Comparative study of outcomes following laparoscopic Roux-en-Y gastric bypass and sleeve gastrectomy in morbidly obese patients: A case control study

AIM To compare the impact of laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG) on weight loss and obesity related comorbidities over two year follow-up via case control study design. METHODS Forty patients undergoing LRYGB, who completed their two year follow-up were matched with 40 patients undergoing LSG for age, gender, body mass index and presence of type 2 diabetes mellitus (T2DM). Data of these patients was retrospectively reviewed to compare the outcome in terms of weight loss and improvement in comorbidities, i.e., T2DM, hypertension (HTN), obstructive sleep apnea syndrome (OSAS), hypothyroidism and gastroesophageal reflux disease (GERD). RESULTS Percentage excess weight loss (EWL%) was similar in LRYGB and LSG groups at one year follow-up (70.5% vs 66.5%, P = 0.36) while it was significantly greater for LRYGB group after two years as compared to LSG group (76.5% vs 67.9%, P = 0.04). The complication rate after LRYGB and LSG was similar (10% vs 7.5%, P = 0.99). The median duration of T2DM and mean number of oral hypoglycemic agents were higher in LRYGB group than LSG group (7 years vs 5 years and 2.2 vs 1.8 respectively, P < 0.05). Both LRYGB and LSG had significant but similar improvement in T2DM, HTN, OSAS and hypothyroidism. However, GERD resolved in all patients undergoing LRYGB while it resolved in only 50% cases with LSG. Eight point three percent patients developed new-onset GERD after LSG. CONCLUSION LRYGB has better outcomes in terms of weight loss two years after surgery as compared to LSG. The impact of LRYGB and LSG on T2DM, HTN, OSAS and hypothyroidism is similar. However, LRYGB has significant resolution of GERD as compared to LSG.

Laparoscopic management of recurrent pheochromocytoma: A case report

Recurrence of pheochromocytoma after a total adrenalectomy is uncommon. Such recurrent tumours are mostly managed by the open technique, with very few studies reporting laparoscopic management. We hereby report a case of successful laparoscopic management of a recurrent pheochromocytoma after total adrenalectomy for left adrenal pheochromocytoma.

Secondary mania following cancer chemotherapy with capecitabine

Mania-like states occurring due to neurological, metabolic or toxic conditions, without a primary mood disorder have been reported in scientific literature as secondary mania. A major clinical problem in such situations often stems from the difficulty to understand if the mood disturbance is indeed secondary to an organic cause or a coincidental primary mood disorder. Chemotherapy regimens have been associated with multiple psychiatric complications, including psychosis, mania and anxiety. Capecitabine is implicated to be associated with encephalopathy whose clinical presentation often mimics that of psychosis. However, presentations with mania have not been reported until with the capecitabine and oxaliplatin combination chemotherapy regimen. In this report, we describe a case of secondary mania in a patient suffering from carcinoma colon on treatment with chemotherapy regimen of capecitabine and oxaliplatin.

Impact of concomitant laparoscopic sleeve gastrectomy and hiatal hernia repair on gastro-oesophageal reflux disease in morbidly obese patients

Background: The aim of this study was to analyse the impact of hiatal hernia repair (HHR) on gastro-oesophageal reflux disease (GERD) in morbidly obese patients with hiatus hernia undergoing laparoscopic sleeve gastrectomy (LSG). Materials and Methods: It is a retrospective study involving ten morbidly obese patients with large hiatus hernia diagnosed on pre-operative endoscopy who underwent LSG and simultaneous HHR. The patients were assessed for symptoms of GERD using a Severity symptom score (SS) questionnaire and anti-reflux medications. Results: Of the ten patients, five patients had GERD preoperatively. At the mean follow-up of 11.70 ± 6.07 months after surgery, four patients (80%) showed complete resolution while one patient complained of persistence of symptoms. Endoscopy in this patient revealed resolution of esophagitis indicating that the persistent symptoms were not attributable to reflux. The other five patients without GERD remained free of any symptom attributable to GERD. Thus, in all ten patients, repair of hiatal hernia (HH) during LSG led to either resolution of GERD or prevented any new onset symptom related to GER. Conclusion: In morbidly obese patients with HH with or without GERD undergoing LSG, repair of the hiatus hernia helps in amelioration of GERD and prevents any new onset GER. Thus, the presence of HH should not be considered as a contraindication for LSG.