'IHPBA-APHPBA clinical practice guidelines': international Delphi consensus recommendations for gallbladder cancer.

BACKGROUND: The Delphi consensus study was carried out under the auspices of the International and Asia-Pacific Hepato-Pancreato-Biliary Associations (IHPBA-APHPBA) to develop practice guidelines for management of gallbladder cancer (GBC) globally. METHOD: GBC experts from 17 countries, spanning 6 continents, participated in a hybrid four-round Delphi consensus development process. The methodology involved email, online consultations, and in-person discussions. Sixty eight clinical questions (CQs) covering various domains related to GBC, were administered to the experts. A consensus recommendation was accepted only when endorsed by more than 75% of the participating experts. RESULTS: Out of the sixty experts invited initially to participate in the consensus process 45 (75%) responded to the invitation. The consensus was achieved in 92.6% (63/68) of the CQs. Consensus covers epidemiological aspects of GBC, early, incidental and advanced GBC management, definitions for radical GBC resections, the extent of liver resection, lymph node dissection, and definitions of borderline resectable and locally advanced GBC. CONCLUSIONS: This is the first international Delphi consensus on GBC. These recommendations provide uniform terminology and practical clinical guidelines on the current management of GBC. Unresolved contentious issues like borderline resectable/locally advanced GBC need to be addressed by future clinical studies.

Effects of a Plant-Based High-Protein Diet on Fatigue in Breast Cancer Patients Undergoing Adjuvant Chemotherapy - a Randomized Controlled Trial.

BACKGROUND: Breast cancer patients undergoing chemotherapy (CT) experience fatigue and other side-effects. Studies exploring interventions with a plant-based, high-protein diet on fatigue and body composition are lacking. The effects of these interventions on fatigue, body mass index (BMI), and body composition were evaluated. METHOD: Newly diagnosed breast cancer patients who were scheduled for adjuvant CT (n = 103) were randomly assigned to the intervention or control group. Study outcomes included fatigue using fatigue symptom inventory and body composition using bioelectric impedance analyzer done at the start of CT, 3rd CT, and 3 weeks after CT. Linear mixed models were used to compare groups over time. RESULTS: Fatigue decreased from 57% to 28% in the intervention group and increased from 65% to 78% in the control group (p < 0.001). BMI decreased by 0.7 ± 0.8 kg/m2 in the intervention group, while the decrease was 0.4 ± 1.3 kg/m2 in the control group (p = 0.015). Fat mass decreased in the intervention group (p < 0.001) and muscle mass improved in the intervention group and decreased in the control group (p < 0.05). CONCLUSIONS: A plant-based, high-protein diet during CT resulted in positive changes in fatigue, BMI and body composition.

The clinical utility and safety of short-course immune checkpoint inhibitors in multiple tumours-A real-world multicentric study from India.

The real-world data on short course of immune checkpoint inhibitor (ICI) use are sparse and merit exploration. A multicentric observational study on the safety and efficacy of ICI in oncology patients between August 2014 and October 2020 involves 1011 patients across 13 centers in India. The median age was 59 (min 16-max 98) years with male preponderance (77.9%). The predominant cohort received short-course ICI therapy; the median number of cycles was 5 (95% confidence interval [CI] 1-27), and the median duration of therapy was 3 (95% CI 0.5-13) months. ICIs were used commonly in the second and third line setting in our study (66.4%, n = 671). Objective response rate (complete or partial response) was documented in 254 (25.1%) of the patients, 202 (20.0%) had stable disease, and 374 (37.0%) had progressive disease. The clinical benefit rate was present in 456 (45.1%). Among the patients whom ICI was stopped (n = 906), the most common reason for cessation of ICI was disease progression (616, 68.0%) followed by logistic reasons like financial constraints (234, 25.82%). With a median follow-up of 14.1 (95% CI 12.9-15.3) months, there were 616 events of progression and 443 events of death, and the median progression free survival and overall survival were 6.4 (95% CI 5.5-7.3) and 13.6 (95% CI 11.6-15.7) months, respectively, in the overall cohort. Among the immune-related adverse events, autoimmune pneumonitis (29, 3.8%) and thyroiditis (24, 2.4%) were common. Real-world multicentric Indian data predominantly with short-course ICI therapy have comparable efficacy/safety to international literature with standard ICI therapy.

Efficacy of scaffold-mediated localized chemotherapy in cancer: A systematic review of current research.

OBJECTIVE: To assess the efficacy of scaffold-mediated localized chemotherapy in cancer. METHODS: Databases including PubMed, Cochrane Library, and SCOPUS were searched for articles reporting the use of scaffold-mediated localized drug delivery in cancer. Essential data including scaffold fabrication material and methods, drug dosage and release duration and its effect on the cancer cells were extracted. RESULTS: 15 articles out of 60 screened, fulfilled the eligibility criteria. Among the 15 studies, 5 studies included only cell lines and 2 studies were on mouse models, while 8 studies involved a combination of cell lines and mouse models. Scaffold materials included both synthetic polymers such as poly-lactide, polycaprolactone and natural materials including d-periosteum and human micro-fragmented adipose tissueA wide number of other variables included the fabrication procedure, drugs used, and the methods used to assess the effects on cancer. As a result, it was not possible to make any direct comparison of the efficacy of the therapeutic strategy used in each of these studies. CONCLUSION: Irrespective of the many variables, a common consensus in all the included studies was that scaffold mediated localized drug delivery effectively reduced cancer cell viability by increasing drug bioavailability to the target tissue, while its localized effect reduced the risk of systemic toxicity.

Is toombak a risk factor for oral leukoplakia and oral squamous cell carcinoma ? A systematic review.

INTRODUCTION: Toombak is a form of smokeless tobacco that is not well known in Western Society but is widely used by the Sudanese population and many others in the sub-Sahara region. However, unlike other smokeless tobacco products, information on the carcinogenic potential of toombak is scarce. The present review explored any potential epidemiological association between the use of toombak and oral leukoplakia and oral squamous cell carcinoma (OSCC). METHODS: Databases including the Web of Science, SCOPUS, EMBASE and PubMed were searched for literature on the potential association between toombak and oral leukoplakia and OSCC. The search also included grey literature. The search period extended from 1990 to 2018. Following data mining, the study selection was conducted by two reviewers independently. RESULTS: Eight studies that satisfied the inclusion criteria were included. Based on these results, there was a threefoldto sevenfold increased risk of developing the oral leukoplakia and oral squamous cell carcinoma among toombak users compared with non-users. CONCLUSION: Based on the results of the systematic review, there is a strong epidemiological evidence to suggest toombak to be a major risk factor for both oral leukoplakia and OSCC. Further studies are necessary to evaluate the molecular pathway of toombak-induced oral carcinogenesis.

Ganglioglioma in children and young adults: single institution experience and review of the literature.

BACKGROUND: Ganglioglioma (GG) is a rare mixed glial-neuronal neoplasm accounting for 0.5-5% of all pediatric central nervous system (CNS) tumors. Rarity of this tumor has precluded defining robust treatment guidelines. This retrospective study evaluates the prognostic factors and outcomes of this rare neoplasm. PATIENTS AND METHODS: Retrospective analysis of 55 patients with GG was conducted to describe clinical findings, and outcomes. Kaplan-Meier survival and Cox-regression analyses were performed to assess the overall survival (OS) and progression-free survival (PFS). RESULTS: The mean age at diagnosis was 11.8 years (range 1-21 years) with a median follow-up period of 9.5 years. 53 patients (92.7%) had low grade GG and 2 patients had anaplastic GG. 25 patients had tumor progression, whose median PFS was 12 years. Six patients with low grade GG progressed to a higher grade, with median survival of 9.1 month after transformation. The 5 and 10 year PFS were 65 and 57%, respectively. The 5 and 10 year OS was 96 and 86% respectively. 8 of the 19 (42%) samples tested demonstrated positivity for the BRAF V600E mutation. Multivariate Cox regression analyses showed location and extent of resection were significant factors for PFS and presence of metastatsis attained significance for OS. CONCLUSION: This is the one of the largest retrospective study of pediatric GG. Identifying clinical variables, which could stratify these tumors into low- and high-risk groups might help to profile a risk-based therapeutic strategy. Collaborative multiinstitutional prospective studies are warranted to delineate treatment consensus and investigate prognostic factors.

Stiripentol efficacy and safety in Dravet syndrome: a 12-year observational study.

AIM: To assess long-term safety and efficacy of stiripentol as an antiepileptic medication for people with Dravet syndrome. METHOD: A prospective, observational open-label study (2003-2015) of the efficacy and long-term safety of stiripentol in patients with Dravet syndrome and ongoing seizures. Frequency of generalized tonic-clonic seizures, focal seizures, status epilepticus, and adverse events were recorded. RESULTS: Forty-one patients started stiripentol, with median age at enrolment 5 years 7 months (range 11mo-22y) and median duration of treatment 37 months (range 2-141mo). Twenty out of 41 patients had greater than or equal to 50% long-term reduction in frequency of generalized tonic-clonic seizures. Frequency of focal seizures was decreased by greater than or equal to 50% in 11 out of 23 patients over the long-term. Frequency of status epilepticus was decreased by 50% or more in 11 out of 26 patients. The most common adverse events were anorexia, weight loss, sedation, and behavioural changes. One patient had worsening of absence and myoclonic seizures. Another developed recurrent pancreatitis on concurrent valproate. INTERPRETATION: Stiripentol improves long-term seizure frequency in approximately 50% of patients with Dravet syndrome, when used as part of unrestricted polytherapy. Long-term use appears safe. In more than 40% of patients, episodes of status epilepticus markedly decrease after stiripentol initiation. What this paper adds Frequency of status epilepticus is reduced in 40% of patients with Dravet syndrome after stiripentol initiation. Stiripentol is effective for generalized tonic-clonic and focal seizures. Stiripentol can be safely used with a range of antiepileptic drugs.

HR+HER2- breast cancers with growth factor receptor-mediated EMT have a poor prognosis and lapatinib downregulates EMT in MCF-7 cells.

Despite an overall good prognosis, a significant proportion of patients with hormone receptor positive human epidermal growth factor receptor 2 negative breast cancers develop distant metastases. The metastatic potential of epithelial cells is known to be regulated by tumor-stromal interaction and mediated by epithelial-to-mesenchymal transition. Hormone receptor positive human epidermal growth factor receptor 2 negative tumors were used to estimate markers of epithelial-to-mesenchymal transition, and the luminal breast cancer cell line MCF-7 was used to examine the interactions between integrins and growth factor receptors in causation of epithelial-to-mesenchymal transition. A total of 140 primary tumors were sub-divided into groups enriched for the markers of epithelial-to-mesenchymal transition (snail family transcriptional repressor 2 and integrin ß6) versus those with low levels. Within the epithelial-to-mesenchymal transition+ tumors, there was a positive correlation between the transcripts of integrin ß6 and growth factor receptors-human epidermal growth factor receptor 2 and epidermal growth factor receptor. In tumors enriched for epithelial-to-mesenchymal transition markers, patients with tumors with the highest quartile of growth factor receptor transcripts had a shorter disease-free survival compared to patients with low growth factor receptor expression by Kaplan-Meier analysis (log rank, p = 0.03). Epithelial-to-mesenchymal transition was induced in MCF-7 cells by treatment with transforming growth factor beta 1 and confirmed by upregulation of SNAI1 and SNAI2 transcripts, increase of vimentin and integrin ß6 protein, and repression of E-cadherin. Treatment of these cells with the dual-specificity tyrosine-kinase inhibitor lapatinib led to downregulation of epithelial-to-mesenchymal transition as indicated by lower levels of SNAI1 and SNAI2 transcripts, integrin αvß6, and matrix metalloproteinase 9 protein. The results suggest that synergistic interactions between growth factor receptors and integrin ß6 could mediate epithelial-to-mesenchymal transition and migration in a subset of luminal breast cancers and lapatinib might be effective in disrupting this interaction.

Maturation of cortical circuits requires Semaphorin 7A.

Abnormal cortical circuits underlie some cognitive and psychiatric disorders, yet the molecular signals that generate normal cortical networks remain poorly understood. Semaphorin 7A (Sema7A) is an atypical member of the semaphorin family that is GPI-linked, expressed principally postnatally, and enriched in sensory cortex. Significantly, SEMA7A is deleted in individuals with 15q24 microdeletion syndrome, characterized by developmental delay, autism, and sensory perceptual deficits. We studied the role that Sema7A plays in establishing functional cortical circuitry in mouse somatosensory barrel cortex. We found that Sema7A is expressed in spiny stellate cells and GABAergic interneurons and that its absence disrupts barrel cytoarchitecture, reduces asymmetrical orientation of spiny stellate cell dendrites, and functionally impairs thalamocortically evoked synaptic responses, with reduced feed-forward GABAergic inhibition. These data identify Sema7A as a regulator of thalamocortical and local circuit development in layer 4 and provide a molecular handle that can be used to explore the coordinated generation of excitatory and inhibitory cortical circuits.

Effects of Yoga in Managing Fatigue in Breast Cancer Patients: A Randomized Controlled Trial.

BACKGROUND: Cancer-related fatigue is widely prevalent in cancer patients and affects quality of life in advanced cancer patients. Fatigue is caused due to both psychologic distress and physiological sequel following cancer progression and its treatment. In this study, we evaluate the effects of yogic intervention in managing fatigue in metastatic breast cancer patients. METHODS: Ninety-one patients with metastatic breast cancer were randomized to receive integrated yoga program (n = 46) or supportive therapy and education (n = 45) over a 3-month period. Assessments such as perceived stress, fatigue symptom inventory, diurnal salivary cortisol, and natural killer cell counts were carried out before and after intervention. Analysis was done using an intention-to-treat approach. Postmeasures for the above outcomes were assessed using ANCOVA with respective baseline measure as a covariate. RESULTS: The results suggest that yoga reduces perceived stress (P = 0.001), fatigue frequency (P < 0.001), fatigue severity (P < 0.001), interference (P < 0.001), and diurnal variation (P < 0.001) when compared to supportive therapy. There was a positive correlation of change in fatigue severity with 9 a.m. salivary cortisol levels. CONCLUSION: The results suggest that yoga reduces fatigue in advanced breast cancer patients.