Practical Consensus Guidelines for the Use of S-1 in GI Malignancies.

Purvish M ParikhS-1 (5-fluorouracil prodrug [tegafur] in combination with 5-chloro-2,4-dihydroxypyridine [CDHP] and potassium oxonate [OXO]) was first approved in 1999. In order to make it easy for community oncologists, we decided to put together this expert consensus guideline for its use in gastrointestinal (GI) malignancies. A total of 15 subject matter experts used modified Delphi method to discuss, analyze, and vote on key aspects regarding practical approach to use of S-1 in GI cancers, a process involving 6 months of work. The consensus guidelines specify how S-1 use can be optimized in patients with colorectal, gastric, and pancreatic tumors. The voting for the 17 key points resulted in a majority consensus for all the statements (approval ranging from 13/15 [87%] to 15/15 [100%]). S-1 is a combination of three drugs (tegafur, CDHP, and OXO) specifically designed to reduce toxicity and enhance efficacy; clinical data and meta-analysis confirm both factors; and it is recommended as standard of care for GI cancers. S-1 is approved and one of the standards of care for all lines of therapy in colorectal cancer and pancreatic cancers. S-1 with oxaliplatin is the standard of care for gastric cancers.

Interaction of physico-chemical parameters with Shannon-Weaver Diversity Index based on phytoplankton diversity in coastal water of Diu, India.

Phytoplankton acts as carbon sinks due to photosynthetic efficacy and their diversity is expressed by SWDI (Shannon-Weaver Diversity Index), which depends on water quality parameters. The coastal water of Diu was studied for three seasons, and the relationship between different parameters and SWDI was established. Subsequently, an attempt was made to build up a prediction model of SWDI based on multilayer perceptron Artificial neural network (ANN) using the R programme. Analysis shows interrelationship between the water quality parameters and phytoplankton diversity is same in linear principal component analysis (PCA) and neural network model. Variations of different parameters depend on seasonal changes. The ANN model shows that ammonia and phosphate are key parameters that influence the SWDI of phytoplankton. Seasonal variation in SWDI is related to variation in water quality parameters, as explained by both ANN and PCA. Hence, the ANN model can be an important tool for coastal environmental interaction study.

Role of immunotherapy in metastatic EGFRm NSCLC: Is it relevant?

EGFR-TKIs have changed the landscape of metastatic NSCLC treatment with a significant improvement in survival of EGFRm patients compared to wild-type EGFR. Even with the newer third generation EGFR TKIs like, Osimertinib, which has proven efficacy against the resistance mutation of EGFRm T790M, progression eventually occurs. There are limited treatment options for patients with metastatic EGFRm NSCLC with other acquired resistance. Therefore, novel therapeutic combination strategies are being researched to overcome potential resistance to EGFR-TKI-targeted therapy. The ICIs targeting the programmed cell death-1 pathway in patients with EGFRm NSCLC were greatly anticipated based on preclinical studies showing increased PD-L1 expression. In clinical settings, this increased expression did not translate into a survival benefit. Treatment with ICIs failed to positively affect EGFRm patients because of multiple reasons: nonsynonymous tumor mutational burden, lower PD-L1 expression in tumors, and cancer cells utilizing alternate immune escape mechanisms. The NCCN guidelines currently do not recommend immunotherapy in patients with metastatic EGFRm NSCLC. Recently, a subgroup analysis in the IMpower150 study provided a signal for overall survival of atezolizumab with bevacizumab plus chemotherapy in EGFRm-TKI progressed patients. Based on these encouraging findings, several combinations of ICIs and EGFR-TKIs are being evaluated in TKI-failed EGFRm patients. These regimens might provide a favorable therapeutic effect by combining higher response rates of TKIs and durable disease control of ICIs. However, further research is warranted to understand the exact underlying molecular and cellular mechanisms responsible for the clinical benefits. In this article, we explored the TKI failed metastatic EGFRm NSCLC, reviewed the available clinical data of ICI use in metastatic EGFRm NSCLC, and discussed its emerging role as a combination regimen in this patient population.

Patterns of epidermal growth factor receptor testing across 111 tertiary care centers in India: Result of a questionnaire-based survey.

BACKGROUND: We conducted a survey of 111 medical oncologists across India to understand the current pattern of epidermal growth factor receptor (EGFR) mutation testing at their respective centers. METHODS: Medical oncologists from 111 institutes across India were interviewed face to face using a structured questionnaire. They were divided into two groups - Group 1 with in-house EGFR testing and Group 2 who send samples to central/commercial laboratories outside their institutions. Answers of the two groups were analyzed to see the prevailing patterns of EGFR testing and differences between the two groups if any. RESULTS: Ninety-five percent (105/111) of medical oncologists recommended testing for EGFR mutations in patients with adenocarcinoma histology and 40% (44/111) recommended EGFR testing in squamous cell histology. The average time duration to get EGFR test results was 10 days in Group 1 centers versus 18 days in Group 2 centers. Ninety-six percent (106/111) of the medical oncologists from Group 1 centers requested for factoring additional sample for biomarker testing compared to 69% (77/111) of the oncologists from Group 2 centers. Sixty-nine percent (77/111) of medical oncologists in Group 1 centers would prefer to wait for the test results before initiating treatment compared to 46% (51/111) in Group 2. EGFR tyrosine-kinase inhibitors were used in only approximately 60% of patients with diagnosed EGFR mutation in the first line. For patients in whom chemotherapy was initiated while waiting for test results, 50% (56/111) of medical oncologists would prefer to complete 4-6 cycles before switching to targeted therapy. At the time of progression, rebiopsy was possible in approximately 25% of the patients. CONCLUSIONS: Turnaround time for molecular testing should improve so that eligible patients can benefit from targeted therapies in the first line. There is a need to increase the awareness among pulmonologists, oncologists, and interventional radiologists regarding the importance of adequate samples required for molecular tests.

A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer.

BACKGROUND: We conducted a phase 2b, randomised, double-blind, placebo-controlled screening trial to evaluate the addition of the multikinase inhibitor sorafenib (antiproliferative/antiangiogenic) to first-line paclitaxel for human epidermal growth factor receptor 2 (HER2)-negative locally recurrent/metastatic breast cancer. METHODS: Patients were randomised to paclitaxel (90mg/m(2), weekly, intravenously, 3 weeks on/1 week off) plus sorafenib (400mg, orally, twice daily) or placebo. The primary endpoint was progression-free survival (PFS). A sample size of 220 patients was planned with relative risk ≤ 0.82 (1-sided α=0.14) after 120 events supporting a treatment effect. FINDINGS: Patients were randomised in India (n=170), the United States (n=52) and Brazil (n=15). Median PFS was 6.9 months for sorafenib versus 5.6 months for placebo (hazard ratio (HR)=0.788; 95% confidence interval (CI), 0.558-1.112; P=0.1715 [1-sided P=0.0857]). The addition of sorafenib increased time to progression (median, 8.1 versus 5.6 months; HR=0.674; 95% CI 0.465-0.975; P=0.0343) and improved overall response (67% versus 54%; P=0.0468). Overall survival did not statistically differ (median, 16.8 versus 17.4 months; HR=1.022; 95% CI 0.715-1.461; P=0.904). Grade 3/4 toxicities (sorafenib versus placebo) included hand-foot skin reaction (31% versus 3%), neutropenia (13% versus 7%) and anaemia (11% versus 6%). Two treatment-related deaths occurred (malaria and liver dysfunction) in the sorafenib arm. INTERPRETATION: The addition of sorafenib to paclitaxel improved disease control but did not significantly improve PFS to support a phase 3 trial of similar design. Toxicity of the combination was manageable with dose reductions.

Physiological differentiation among nine-spined stickleback populations: effects of copper exposure.

Nine-spined stickleback (Pungitius pungitius) exhibit a very wide geographical distribution and are increasingly used in ecological and evolutionary research. While pronounced morphological and behavioural differentiation among local populations has been shown, physiological differentiation, especially with respect to stress responses, has not been investigated. However, this would be of interest since the increased use of sticklebacks as ecotoxicological sentinel species presumes a uniform response of used populations to stressors. Metabolic rates of nine-spined sticklebacks from five populations residing in similar latitude across Fennoscandia (Baltic Sea, White Sea, two Finnish and one Russian pond) were compared under controlled conditions, and the effects of exposure to increasing copper concentrations (0-7.1micromoll(-1)) on resting metabolic rate, condition factor and survival were tested. While sticklebacks from the two Finnish pond populations consisting of 'giant' fish were the largest, body condition index was highest in the Baltic population. Weight-corrected resting metabolic rates were also significantly different between populations with the highest rate in the Baltic (89.6+/-18.3, n=12) and the lowest in the White Sea and the Russian pond populations (62.2+/-10.3, n=10 and 56.5+/-10.3nmol O(2) min(-1)g(-1), n=12, respectively). Allometric metabolic rate - weight analysis revealed a metabolic scaling exponent of 0.986, significantly higher than a generally accepted exponent for fish (0.88), suggesting an elevated resting metabolic rate for the two 'giant' stickleback populations. Copper exposure caused an overall increase in metabolic rate of 3.1nmol O(2) min(-1)g(-1)/1micromoll(-1) increase in copper. However, the copper-induced changes in metabolic rate differed significantly among populations, with the least increase in the Baltic and the highest increases in the two Finnish pond populations. Survival of fish following copper exposure was significantly lower for Baltic and one Finnish pond population (mean time to death: 32 days), compared to the White Sea and the other Finnish and Russian pond populations (mean time to death: 68 days). The results demonstrate significant physiological differences in metabolic rate and stress response among local populations, and suggest that caution has to be exercised and pilot studies have to be carried out when different wild populations of a single species are used for ecotoxicological monitoring.