Genomic Landscape and Targeted Treatment of Gallbladder Cancer: Results of a First Ongoing Prospective Study.

Background Prognosis of gallbladder cancer (GBC) has not changed in the past 20 years. Comprehensive genomic profiling (CGP) carries potential to determine the actionability for multiple targets, including ERBB2 , ERBB3 , MET , ROSI , FGFR , and PIK3 . This study evaluates the role of CGP and targeted therapies. Methods This is a multicenter, prospective, single-arm study. All consecutive patients of unresectable and/or metastatic GBC of age ≥18 years were enrolled. Hybrid capture-based CGP was performed by Foundation Medicine CDx. All patients received first-line chemotherapy with gemcitabine-cisplatin regimen. Patients with ERBB2/3 amplification received trastuzumab with capecitabine or nab-paclitaxel, and patients with MET amplification were treated with crizotinib. For ERBB2/3 mutations, lapatinib plus capecitabine regimen was used. Results Fifty patients were studied with a median age of 56 years (range 26-83) and a male-to-female ratio of 1:1.6. ERBB2 and ERBB3 amplification was seen in 9 (18%) and 2 (4%) patients, respectively. Four patients with ERBB2 amplification received trastuzumab and/or lapatinib, showed partial response, and maintained response beyond 12 weeks. One patient had mixed response, whereas two patients progressed on trastuzumab and lapatinib. Three patients with ERBB3 mutations showed response to lapatinib-capecitabine. One patient with MET amplification responded to crizotinib for 4 weeks. PIK3 mutations were present in 14% of cases and were independent of ERBB aberrations. Conclusion GBC is enriched in 28% of patients with ERBB2 and ERBB3 amplifications and/or mutations. Responses are seen with lapatinib in concurrent ERBB2 mutation and amplification. ERBB3 mutation showed response to lapatinib. MET and PIK3 are new findings in GBC, which may be targeted.

Discordance between Fluorescence In Situ Hybridization and Immunohistochemistry Analysis of Anaplastic Lymphoma Kinase Rearrangement in Indian Patients with Non-Small Cell Lung Cancer.

Aims This study aims to evaluate the incidence of anaplastic lymphoma kinase (ALK) mutation in nonsmall cell lung cancer (NSCLC) incorporating fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) methods and to look for any discordance. Methods We evaluated 101 samples obtained from an enriched cohort of NSCLCs patients from the Army Hospital Research and Referral, New Delhi, India, between November 2016 and November 2018. IHC was performed using the highly-sensitive D5F3 rabbit monoclonal primary antibody. FISH was performed with dual-color, break-apart probe (ZytoLight SPEC) on formalin-fixed, and paraffin-embedded tissue. Discordance between IHC and FISH for ALK rearrangements was evaluated. Pearson correlation coefficient ( r ) was performed to identify any association of ALK presence (by IHC and FISH) with smoking brain metastasis, programmed death-ligand (PD-L1) expression, pleural effusion, and histopathological subtype. Results A total of 7.92% (8/101) cases tested by IHC and 9.9% (10/101) cases tested by FISH were positive for ALK rearrangement. Of 93 ALK IHC-negative cases, 4 were ALK FISH-positive, whereas of 91 ALK FISH-negative cases, 4 were ALK IHC-positive cases. The correlation analysis demonstrated no or very weak correlation in ALK mutations by IHC or FISH with smoking, brain metastasis, PD-L1 expression, pleural effusion, and histopathological examination, except a weak positive correlation ( r = 0.33) observed between brain metastasis and ALK rearrangement identified by FISH. Conclusions Our study demonstrated a somewhat similar incidence of ALK FISH-positive cases and ALK IHC-positive cases, though the incidence was numerically higher for ALK-FISH method.

Proposed low-density lipoprotein cholesterol goals for secondary prevention and familial hypercholesterolemia in India with focus on PCSK9 inhibitor monoclonal antibodies: Expert consensus statement from Lipid Association of India.

BACKGROUND: Rates of atherosclerotic cardiovascular disease (ASCVD) are strikingly high in India compared to Western countries and are increasing. Moreover, ASCVD events occur at a younger age with only modest hypercholesterolemia, most commonly with low levels of high-density lipoprotein cholesterol. The course of ASCVD also appears to be more fulminant with higher mortality. OBJECTIVE: In light of these issues, the Lipid Association of India (LAI) endeavored to develop revised guidelines with more aggressive low-density lipoprotein cholesterol (LDL-C) goals in secondary prevention and for patients with familial hypercholesterolemia compared to guidelines in the United States and other countries. METHODS: Owing to the paucity of clinical outcomes data in India, it was necessary to place major emphasis on expert opinion as a complement to randomized placebo-controlled data generated mostly in non-Indian cohorts. To facilitate this process, the LAI conducted a series of 19 meetings among 162 lipid specialists in 13 cities throughout India over a period of 11 months before formulating this expert consensus statement. RESULTS: The LAI recommends an LDL-C goal <50 mg/dL in all patients in secondary prevention or very high-risk primary prevention but proposes an optional goal ≤30 mg/dL in category A extreme-risk patients (eg, coronary artery disease + familial hypercholesterolemia) and a recommended goal ≤30 mg/dL in category B extreme-risk patients [coronary artery disease + (1) diabetes and polyvascular disease/≥3 major ASCVD risk factors/end organ damage, or (2) recurrent acute coronary syndrome within 12 months despite LDL-C <50 mg/dL, or (3) homozygous familial hypercholesterolemia]. CONCLUSIONS: More aggressive LDL-C goals are needed for prevention of ASCVD in India, as described in this expert consensus statement. Use of statins and ezetimibe needs to increase in India in combination with improved control of other ASCVD risk factors. Proprotein convertase subtilisin kexin type 9 inhibitors can improve LDL-C goal achievement in patients with refractory hypercholesterolemia.

Improved soil physical properties and cotton root parameters under sub-soiling enhance yield of Cotton-Wheat cropping system.

A field experiment has been conducted in Cotton-Wheat cropping system for three cropping cycles, wherein we evaluated a total of five treatments (Control, Sub-soiling at 1.0 m, Sub-soiling at 1.5 m, Cross sub-soiling at 1.0 m and Cross sub-soiling at 1.5 m) in complete randomized block design to find out the effect of sub-soiling on the physical properties of soil and root parameters of cotton in Indian Punjab, where heavy machinery usage in farm operations is causing soil compaction leading to ill effects. Data elucidated that any level of sub-soiling not only improved soil physical properties by reduction in bulk density but also enhanced steady state infiltration rate as compared to control. Data also revealed that root length, fresh root weight plant-1 and dry root weight plant-1 of cotton exhibited significant differences in sub-soiled plots versus control for initial two years of experimentation but trivial differences existed thereafter. Consequently, both cotton and wheat crop resulted in higher yield owing to above mentioned reasons. The field data set is made publicly available to enable critical or extended analysis.

Information homeostasis as a fundamental principle governing the cell division and death.

To express the genetic information with minimal error is one of the key functions of a cell. Here we propose an information theory based, phenomenological model for the expression of genetic information. Based on the model we propose the concept of 'information homeostasis' which ensures that genetic information is expressed with minimal error. We suggest that together with energy homeostasis, information homeostasis is a fundamental working principle of a biological cell. This model proposes a novel explanation of why a cell divides and why it stops to divide and, thus, provides novel insights into oncogenesis and various neuro-degenerative diseases. Moreover, the model suggests a theoretical framework to understand cell division and death, beyond specific biochemical pathways.