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.

Osteomacs promote maintenance of murine hematopoiesis through megakaryocyte-induced upregulation of Embigin and CD166.

Maintenance of hematopoietic stem cell (HSC) function in the niche is an orchestrated event. Osteomacs (OM) are key cellular components of the niche. Previously, we documented that osteoblasts, OM, and megakaryocytes interact to promote hematopoiesis. Here, we further characterize OM and identify megakaryocyte-induced mediators that augment the role of OM in the niche. Single-cell mRNA-seq, mass spectrometry, and CyTOF examination of megakaryocyte-stimulated OM suggested that upregulation of CD166 and Embigin on OM augment their hematopoiesis maintenance function. CD166 knockout OM or shRNA-Embigin knockdown OM confirmed that the loss of these molecules significantly reduced the ability of OM to augment the osteoblast-mediated hematopoietic-enhancing activity. Recombinant CD166 and Embigin partially substituted for OM function, characterizing both proteins as critical mediators of OM hematopoietic function. Our data identify Embigin and CD166 as OM-regulated critical components of HSC function in the niche and potential participants in various in vitro manipulations of stem cells.

Real world study of safety and efficacy of lorlatinib as second line and beyond in ALK-rearranged advanced non-small cell lung cancer patients in India - a multicentre chart review study (ROSELAND).

Background: Lorlatinib, an anaplastic lymphoma kinase (ALK)-inhibitor, is approved as frontline as well as subsequent line of therapy in ALK-rearranged advanced non-small cell lung cancer (NSCLC). There is limited literature about safety and efficacy of lorlatinib in Indian patients. Materials and methods: This was a retrospective multicentre study on patients with ALK-rearranged advanced NSCLC received lorlatinib as second line and beyond between May 2017 and December 2021. ALK was tested either by immunohistochemistry or fluorescent in-situ hybridisation. Clinicopathologic features, treatment details, toxicity and outcomes were analysed. Results: A total of 38 patients were enrolled with a median age of 54 years (range: 30-72) and male: female ratio of 20:18. Fifteen (44%) patients had brain metastases at baseline. Lorlatinib use was - second line in 11 (29%), third line in 21 (55%) and fourth line in 4 (11%) of patients, respectively. The best radiologic response to lorlatinib was - complete response in 9 (24%), partial response in 17 (46%), stable disease in 9 (24%) and progressive disease in 2 (5%) of patients, respectively. After a median follow-up of 76.6 months (95% CI: 68.9-100), the median progression-free survival (PFS) of lorlatinib was not reached (95% CI: 24.3-not reached) and median overall survival (OS) of the whole cohort was 93.1 months (95% CI: 62-not reached). Both median PFS (p = 0.48) and median OS (p = 0.74) was similar between second line and later line use of lorlatinib. Thirty-three (87%) patients experienced treatment-related toxicity and six (16%) patients required dose modification. Conclusion: Lorlatinib was highly efficacious in terms of overall response rate, median PFS and median OS in this small real-world cohort of advanced ALK+ve NSCLC with a manageable safety profile.

Evaluation of non-cancer risk owing to groundwater fluoride and iron in a semi-arid region near the Indo-Bangladesh international frontier.

Groundwater quality in Hili, a semi-arid border region at Indo-Bangladesh border, was investigated in the post-monsoon season of 2021, succeeded by assessment of probabilistic health risk arising from fluoride (F-) and iron (Fe) intake, with the hypothesis that groundwater quality of the region was not satisfactory for human consumption and health, considering earlier reports on high groundwater F- and Fe in few of the neighboring districts. All water samples were found to be potable in terms of Ca2+, Mg2+, Cl-, SO42- and NO3-, , but F- and Fe exceeded prescribed safe limits for drinking water in about 48% and 7% samples. Almost all water samples were found to be good for irrigation in terms of sodium adsorption ratio (SAR), soluble sodium percentage (SSP), Kelly's index (KI), %Na and magnesium ratio (MR). The principal component analysis (PCA) identified three major factors influencing groundwater quality, explaining about 71.8% of total variance and indicated that groundwater quality was primarily influenced by geochemical factors. Carbonate and silicate weathering were mainly responsible for dissolution of minerals in groundwater. Non-carcinogenic risk due to cumulative impact of F-and Fe intake was in the order of THIChildren > THIInfant > THIAdult. As per Monte Carlo simulation run with 5000 trials to ascertain the order of probabilistic health risk, the most dominant governing factors behind non-carcinogenic risk caused by F-and Fe intake were their concentration (Ci) followed by ingestion rate (IR), and exposure duration (ED).

Practice Patterns and Survival in Patients with Resected Pancreatic Ductal Adenocarcinomas (PDAC) - Results from the Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP) Study.

BACKGROUND: There is limited data from India with regard to presentation, practice patterns and survivals in resected pancreatic ductal adenocarcinomas (PDACs). METHODS: The Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP) included data from 8 major academic institutions across India and presents the outcomes in upfront resected PDACs from January 2015 to June 2019. RESULTS: Of 288 patients, R0 resection was achieved in 81% and adjuvant therapy was administered in 75% of patients. With a median follow-up of 42 months (95% CI: 39-45), median DFS for the entire cohort was 39 months (95% CI: 25.4-52.5), and median overall survival (OS) was 45 months (95% CI: 32.3-57.7). A separate analysis was done in which patients were divided into 3 groups: (a) those with stage I and absent PNI (SI&PNI-), (b) those with either stage II/III OR presence of PNI (SII/III/PNI+), and (c) those with stage II/III AND presence of PNI (SII/III&PNI+). The DFS was significantly lesser in patients with SII/III&PNI+ (median 25, 95% CI: 14.1-35.9 months), compared to SII/III/PNI + (median 40, 95% CI: 24-55 months) and SI&PNI- (median, not reached) (p = 0.036)). CONCLUSIONS: The MIPPAP study shows that resectable PDACs in India have survivals at par with previously published data. Adjuvant therapy was administered in 75% patients. Adjuvant radiotherapy does not seem to add to survival after R0 resection.

First results of fast visible imaging diagnostic in Aditya-U tokamak.

A Fast Visible Imaging Diagnostic (FVID) system, measuring the visible light emission spectrum (400-1000 nm) from tokamak plasma, has been installed on the Aditya-U tokamak to monitor the two-dimensional dynamics of the poloidal cross section of the plasma. In this work, we present the design and installation of the FVID system on the Aditya-U tokamak. The evolution of plasma and plasma-wall interactions is described. The signature of the runaway electron beam in visible imaging and its correlation with other diagnostics is presented. The estimation of the electron cyclotron resonance layer position during pre-ionization is also discussed in this work.

Efficacy of cyclin-dependent kinase 4/6 inhibitors in patients with metastatic hormone positive breast cancer: a single institutional study from India.

Purpose: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have shown marked benefit in the treatment of hormone positive metastatic breast cancer (HR+ MBC). There are limited real-world studies with palbociclib and ribociclib. Here we report our experience with CDK4/6 inhibitors in these groups of patients. Material and methods: Patients with HR+ MBC who have received either palbociclib or ribociclib during the course of their treatment from January 2017 to January 2022 were included in the study. The baseline demographic features, treatment details and toxicity were recorded. Patients who received at least 1 month of therapy were included in the survival analysis. Results: A total of 144 patients received CDK4/6 inhibitors during the time period. The median age of the population was 53 (30-80) years. Ninety-eight (71.4%) patients presented with de novo metastatic disease. The most common site of metastasis was to the skeleton (74.2%). Most patients (75%) received palbociclib as their therapy. At a median follow-up of 20.2 months, the median progression free survival (PFS) of the whole population was 16.5 (95% confidence interval (95% CI): 11.6-25.5) months and the median overall survival (OS) was 29.7 (95% CI: 21.7-44.6) months. The presence of liver metastases, low progesterone receptor positivity (Allred score < 6) and prior systemic treatment were poor prognostic factors for both PFS and OS in multivariate analysis. Drug was discontinued for only 2.1% of the patient population. Conclusions: Use of CDK4/6 inhibitors has led to improvement in PFS and OS in patients with HR+ MBC and it is well tolerated. The presence of liver metastases and low progesterone receptor positivity (Allred score < 6) and prior treatment are poor prognostic factors.

Physical Insights into Vacancy-Based Memtransistors: Toward Power Efficiency, Reliable Operation, and Scalability.

Memtransistors that combine the properties of transistor and memristor hold significant promise for in-memory computing. While superior data storage capability is achieved in memtransistors through gate voltage-induced conductance modulation, the lateral device configuration would not only result in high write bias, which compromises the power efficiency, but also suffers from unsuccessful memory reset that leads to reliability concerns. To circumvent such performance limitations, an advanced physics-based model is required to uncover the dynamic resistive switching behavior and deduce the key driving parameters for the switching process. This work demonstrates a self-consistent physics-based model which incorporates the often-overlooked effects of lattice temperature, vacancy dynamics, and channel electrostatics to accurately solve the interaction between gate potential, ions, and carriers on the memristive switching mechanism. The completed model is carefully calibrated with an ambipolar WSe2 memtransistor and hence enables the investigation of the carrier polarity effect (electrons vs holes) on vacancy transport. Nevertheless, the validity of the model can be extended to different materials by a simple material-dependent parameter modification. Building upon the existing understanding of Schottky barrier height modulation, our study reveals three key insights─leveraging threshold voltage shifts to lower write bias; optimizing lattice temperature distribution and read bias polarity to achieve successful memory state recovery; engineering contact work function to overcome the detrimental parasitic current flow in short channel ambipolar memtransistors. Therefore, understanding the significant correlation between the switching mechanisms, different material systems, and device structures allows performance optimization of operating modes and device designs for future memtransistors-based computing systems.

Host preference of bluetongue virus vectors, Culicoides species associated with livestock in West Bengal, India: Potential relevance on bluetongue epidemiology.

Determination of host choice of Culicoides species (Diptera: Ceratopogonidae), the vectors of bluetongue virus (BTV), is pivotal to ascertain the role of each species in the transmission of pathogens, pest management and enumeration of disease prediction models. Host preference of livestock associated Culicoides midges was investigated in West Bengal, India with four replicates of a 3 × 3 Latin square design during August and September 2021. Adult Culicoides were mouth aspirated from three BTV hosts viz., cattle, sheep and goats. Mouth aspirating was validated by the sweep net collections. The host-baited collections recorded seven Culicoides species; with the highest landing rate on cattle (n = 5,667; 92.9%) followed by sheep (n = 365; 6.0%) and goat (n = 67; 1.1%). Based on the Jacob's selectivity index, all midge species, except for Culicoides fulvus Sen & Das Gupta, encountered, preferred cattle over other mammalian hosts. Culicoides oxystoma Kieffer, the subgenus Trithecoides Wirth & Hubert and Culicoides actoni Smith, predominated on the ventral region (belly/flank) of the cattle. However, Culicoides peregrinus Kieffer and C. actoni were observed to be prevalent in the leg region of sheep. A significantly higher percentage of female (99.9%) with only 0.3% of male were trapped in aspiration based animal baited collections. On the other hand sweep net and light trap catch comprises of 50.7%, 89.7% female and 49.2%, 10.2% male respectively. Surprisingly, DNA based blood meal analysis revealed human blood from the midges trapped in UV-LED light traps. Supplying the first evidence that Culicoides similis Carter, Ingram & Macfie, C. fulvus and Culicoides palpifer Das Gupta & Ghosh, feed on humans.

Management of human epidermal growth factor receptor 2-negative metastatic breast cancer: Role of poly adenosine diphosphate (ADP-ribose) polymerase inhibitors.

Human epidermal growth factor receptor 2 (HER2)-negative subset is the most heterogeneous group of metastatic breast cancers (MBCs) as it includes both hormone receptor (HR)-positive and HR-negative breast cancer (or TNBC), which have different therapies and treatment challenges. Though endocrine therapy (ET) remains the treatment backbone in HR-positive HER2-negative cases, about 40% of the patients show intrinsic or acquired resistance to ET due to multiple mechanisms. Combining different therapies such as ET and other targeted therapies with or without chemotherapy fails to give continued benefit, unlike cyclin-dependent kinase (CDK) 4/6 inhibitors that have shown a great benefit. TNBC has conventionally been treated ineffectively with systemic chemotherapy. Recently, poly (ADP-ribose) polymerase inhibitors (PARPi) have emerged for HER2-negative breast cancer (BC) patients, including TNBC. Olaparib and talazoparib have recently been approved in germline BRCA-mutated (gBRCAm) HER2-negative MBC. Additionally, ongoing trials of PARPi in combination with various therapies are expected to provide more and better treatment options for gBRCAm HER2-negative breast cancer.

Survival outcomes with 12 weeks of adjuvant or neoadjuvant trastuzumab in breast cancer.

Background: There is limited access to 1 year of adjuvant trastuzumab in resource-constrained settings. Most randomized studies have failed to prove non-inferiority of shorter durations of adjuvant trastuzumab compared to 1 year However, shorter durations are often used when 1 year is not financially viable. We report the outcomes with 12 weeks of trastuzumab administered as part of curative-intent treatment. Methods: This is a retrospective analysis of patients treated at Tata Memorial Centre, Mumbai, a tertiary care cancer center in India. Patients with human epidermal growth factor receptor (HER2)-positive early or locally advanced breast cancer who received 12 weeks of adjuvant or neoadjuvant trastuzumab with paclitaxel and four cycles of an anthracycline-based regimen in either sequence, through a patient assistance program between January 2011 and December 2012, were analyzed for disease-free survival (DFS), overall survival (OS), and toxicity. Results: A total of 102 patients were analyzed with a data cutoff in September 2019. The median follow-up was 72 months (range 6-90 months), the median age was 46 (24-65) years, 51 (50%) were postmenopausal, 37 (36%) were hormone receptor-positive, and 61 (60%) had stage-III disease. There were 37 DFS events and 26 had OS events. The 5-year DFS was 66% (95% Confidence Interval [CI] 56-75%) and the OS was 76% (95% CI 67-85%), respectively. Cardiac dysfunction developed in 11 (10.7%) patients. Conclusion: The use of neoadjuvant or adjuvant 12-week trastuzumab-paclitaxel in sequence with four anthracycline-based regimens resulted in acceptable long-term outcomes in a group of patients, most of whom had advanced-stage nonmetastatic breast cancer.

First-line Rucaparib Plus Bevacizumab Maintenance Completed One-Year in Germline BRCA1-Mutated Advanced Ovarian Cancer.

The present case study showed the novel approach of Rucaparib and Bevacizumab as first-line maintenance therapy in germline BRCA 1 mutated advanced high-grade serous carcinoma of the ovary. A 56-year-old female with high-grade serous carcinoma of the ovary (ECOG PS1) was treated with carboplatin and paclitaxel in combination with Bevacizumab (CPB), followed by interval debulking surgery. Since the patient was germline BRCA 1 positive, after completion of adjuvant chemotherapy, she was kept on Rucaparib along with Bevacizumab. The patient achieved a complete response and has been leading a disease-free life for the past one year with maintenance therapy of Rucaparib + Bevacizumab, though the patient did experience a few adverse events, including one episode of grade 3 anaemia, occasional grade 3 asthenia, and grade 2 diarrhoea (CTCAE V-4) which was managed by gradual dose reduction of Rucaparib from 600 mg twice daily dose to 300mg twice daily dose. With dose alteration of rucaparib along with bevacizumab as maintenance, the patient continues to tolerate rucaparib and stay relapse-free from disease.

Early Experience with Dabrafenib-Trametinib Combination in Patients with BRAF-Mutated Malignant Melanoma-A Single-Center Experience.

Background Combination of dabrafenib-trametinib is one of the standard treatments in patients with BRAF-mutated advanced malignant melanoma (MM). Real-world data on the usage of this combination is scarce, especially from India. Here, we are reporting our early experience with the usage of this combination therapy. Materials and Methods This is a single institutional data assessment of patients with BRAF-mutated MM registered and treated with BRAF-MEK inhibitors in our hospital. Clinico-pathological features and treatment details were reviewed for all patients. Results A total of seven patients with BRAF-mutated MM treated with this combination therapy with a median age of 66.5 years (range: 49-72 years) and a male:female ratio of 3:4. Six (85.7%) patients had metastatic disease at presentation. In total, 80% of our patient population had two or less than two sites of metastasis at presentation. The initial response rate of the study population was 71%. The drug was well tolerated with fever being the most common side effect which was seen in two (28.5%) of the patients. Conclusion Combination of dabrafenib-trametinib is effective in patients with BRAF-mutated MM with good tolerability. Further studies are required to look for improvement in outcome in this group of patients.

Multidisciplinary management of ovarian germ cell tumours-a single institutional study from India.

BACKGROUND: Ovarian germ cell tumours constitute a heterogeneous group of neoplasm with malignant potential being seen in 5% of cases. There is limited data on treatment outcomes of patients with malignant ovarian germ cell tumours (MOGCT). Here, we present our hospital audit of patients with MOGCT. MATERIAL AND METHODS: This is a retrospective data review of patients with MOGCT treated between May 2011 and December 2019. Patients were treated with staging laparotomy and adjuvant chemotherapy, wherever applicable. Surveillance was allowed for those at low risk for recurrence. Clinicopathologic features and treatment details were recorded, and survival analysis was performed. RESULTS: Sixty-five patients with a median age of 25 years (range: 11-52 years) were treated during the study period. The most common histology was immature teratoma in 35.3% of cases. International Federation of Gynecology and Obstetrics stage IC was the most common stage of presentation (47%). Surveillance was advised for 12.3% of cases. Systemic therapy was given in 51 (78%) patients. At a median follow-up of 46 months (range: 1-109 months), the median progression-free survival (PFS) was not reached. Five-year PFS was 79.3% (95% CI: 65.8-88). The most common toxicity was febrile neutropenia (22%) among those who received systemic therapy. CONCLUSION: Immature teratoma was the most common histology in our series. The majority presented in the early stage. MOGCT is a highly curable disease with surgery and systemic therapy.

Clinicopathological characteristics, prognostic factors and treatment outcomes of seminomatous germ cell tumours from a tertiary cancer centre in eastern India.

Background: . Seminomatous germ cell tumour (SGCT) is a rare but curable malignancy of young adults. The literature on management and outcome of SGCT is scarce from India. We report the demography and treatment outcome of SGCT at our centre. Methods: . We did a retrospective analysis of patients with SGCT treated from March 2011 to December 2018. Patients were staged appropriately with imaging, and pre- and postoperative tumour markers. High inguinal orchiectomy was performed in all with a testicular primary and received subsequent stage-adjusted adjuvant treatment. Patients were monitored for metabolic syndrome during follow-up after completion of treatment. Results: . We treated 85 patients with a median age of 37 (range 20-68) years. The primary site of the tumour was the testis in 80 (94%) and mediastinum in 5 (6%) patients. Cryptorchidism was present in 20 (25%) patients and testicular violation was present in 11 (14%) patients. Stage of the disease was I in 61, II in 13 and III in 6 patients. Adjuvant treatment in stage I disease was single-agent carbo-platin (area under the curve ×7) in 38 (62%), surveillance in 20 (33%) and radiotherapy in 3 (5%) patients. Five patients in the surveillance group relapsed. The 7-year mean (SD) relapse-free survival and overall survival were 83.1% (8%) and 98.7% (1.3%), respectively. Thirty-one patients (n = 52, 60%) had features of metabolic syndrome. Conclusions: . SGCTs have a high cure rate. Long-term follow-up is essential for monitoring toxic effects. Early diagnosis, avoidance of testicular violation and multidisciplinary management are the key features for better long-term outcome in SGCT.

Midbrain infarction in inherited protein S deficiency: a rare association.

Inherited thrombophilic disorders are well-established predisposing factors for venous thromboembolism, but their role in arterial ischaemic stroke is uncertain. The exact mechanism of arterial thrombosis in thrombophilias remains elusive. Herein, we report a case of a 30-year-old woman who was admitted to our facility with sudden-onset right-sided ptosis and ophthalmoplegia. Detailed clinical features, neuroimaging and laboratory evaluation clinched the diagnosis of ischaemic stroke in midbrain due to microvascular obstruction associated with isolated protein S deficiency. She was treated with oral anticoagulant (warfarin) and physiotherapy; without any improvement of her symptoms at 2 months of follow-up. A high index of clinical suspicion is needed in any case of young ischaemic stroke in absence of common cardiac and vascular risk factors, to recognise the presence of inherited thrombophilia.

COVID-19 and the Paris Agreement target: A CGE analysis of alternative economic recovery scenarios for India.

In this paper the Covid-19 pandemic has been analysed from sustainability and climate change perspectives with the help of a recursive dynamic CGE model for India. The Covid-19 could have major long term impacts on GDP, household income, inequality, CO2 emissions, and carbon prices. Significant slowdown in labour intensive informal sectors such as construction and services, as well as in energy intensive and capital goods sectors, leads to adverse impacts on household income and inequality. Our analysis further suggests that climate policy consistent with the Paris Agreement target can complement the economic recovery process. Specifically, recycling of carbon tax revenues to investments could stimulate growth and employment, reduce inequality, and reduce carbon emissions, compared to a scenario without climate policy. Therefore, the need of the hour is to formulate and implement climate friendly recovery strategies.

Outcome of COVID-19 in Solid Organ Malignancies: Experience From a Tertiary Cancer Center in Eastern India.

PURPOSE: The COVID-19 pandemic has imposed a unique challenge to oncology patients. Outcome data on COVID-19 in patients with cancer from the Indian subcontinent are scarce in the literature. We aimed to evaluate the outcome of patients with COVID-19 on active systemic anticancer therapy. MATERIALS AND METHODS: This is a retrospective study of patients with solid organ malignancies undergoing systemic therapy with a diagnosis of COVID-19 between March 2020 and February 2021. COVID-19 was diagnosed if a reverse transcriptase polymerase chain reaction assay from oropharyngeal or nasopharyngeal swab was positive for severe acute respiratory syndrome coronavirus 2. The objectives were to evaluate the outcome of COVID-19 and factors predicting the outcome. RESULTS: A total of 145 patients were included with a median age of 58 years (range, 20-81 years). Treatment was curative in 60 (42%) patients. Of all symptomatic cases (n = 88, 61%), 50 had mild, 27 had moderate and 19 had severe COVID-19-related symptoms as per WHO criteria. Fifty (34%) patients required hospitalization with a median duration of hospital stay of 12 days (range, 4-25 days); five patients required intensive care unit admission. The rest were treated with home isolation and did not require further hospitalization. Twenty-two (15%) patients died, and the risk of death was significantly associated with severity of symptoms (odds ratio, 91.3; 95% CI, 9.1 to 919.5, P = .0001) but not with any other clinical factors. Drug holiday was given to 63 (44%) patients with a median duration of 25 days (range, 7-88 days). The median duration to reverse transcriptase polymerase chain reaction-negative was 16 days (range, 7-62 days). CONCLUSION: COVD-19-related death rate was 15% among patients with solid organ malignancies. The severity of the symptoms was related to mortality. The majority of patients with mild symptoms were treated at home isolation.