The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The ...aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I–III colon cancer.
An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I–III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance.
Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0·97 for colon tumour; r=0·97 for invasive margin; p<0·0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 8% patients with a high Immunoscore vs 65 (19%) patients with an intermediate Immunoscore vs 51 (32%) patients with a low Immunoscore; hazard ratio HR for high vs low Immunoscore 0·20, 95% CI 0·10–0·38; p<0·0001). The findings were confirmed in the two validation sets (n=1981). In the stratified Cox multivariable analysis, the Immunoscore association with time to recurrence was independent of patient age, sex, T stage, N stage, microsatellite instability, and existing prognostic factors (p<0·0001). Of 1434 patients with stage II cancer, the difference in risk of recurrence at 5 years was significant (HR for high vs low Immunoscore 0·33, 95% CI 0·21–0·52; p<0·0001), including in Cox multivariable analysis (p<0·0001). Immunoscore had the highest relative contribution to the risk of all clinical parameters, including the American Joint Committee on Cancer and Union for International Cancer Control TNM classification system.
The Immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer. These results support the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer.
French National Institute of Health and Medical Research, the LabEx Immuno-oncology, the Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants and the Society for Immunotherapy of Cancer.
Genome-Wide Association Studies (GWAS) have identified Fibroblast growth factor receptor 2 (FGFR2) as a candidate gene for breast cancer with single nucleotide polymorphisms (SNPs) located in intron ...2 region as the susceptibility loci strongly associated with the risk. However, replicate studies have often failed to extrapolate the association to diverse ethnic regions. This hints towards the existing heterogeneity among different populations, arising due to differential linkage disequilibrium (LD) structures and frequencies of SNPs within the associated regions of the genome. It is therefore important to revisit the previously linked candidates in varied population groups to unravel the extent of heterogeneity. In an attempt to investigate the role of FGFR2 polymorphisms in susceptibility to the risk of breast cancer among North Indian women, we genotyped rs2981582, rs1219648, rs2981578 and rs7895676 polymorphisms in 368 breast cancer patients and 484 healthy controls by Polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP) assay. We observed a statistically significant association with breast cancer risk for all the four genetic variants (P<0.05). In per-allele model for rs2981582, rs1219648, rs7895676 and in dominant model for rs2981578, association remained significant after bonferroni correction (P<0.0125). On performing stratified analysis, significant correlations with various clinicopathological as well as environmental and lifestyle characteristics were observed. It was evident that rs1219648 and rs2981578 interacted with exogenous hormone use and advanced clinical stage III (after Bonferroni correction, P<0.000694), respectively. Furthermore, combined analysis on these four loci revealed that compared to women with 0-1 risk loci, those with 2-4 risk loci had increased risk (OR = 1.645, 95%CI = 1.152-2.347, P = 0.006). In haplotype analysis, for rs2981578, rs2981582 and rs1219648, risk haplotype (GTG) was associated with a significantly increased risk compared to the common (ACA) haplotype (OR = 1.365, 95% CI = 1.086-1.717, P = 0.008). Our results suggest that intron 2 SNPs of FGFR2 may contribute to genetic susceptibility of breast cancer in North India population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The present study includes a systematic analysis of sediment contamination by heavy metals of the River Ghaghara flowing through the Uttar Pradesh and Bihar in Indian Territory. To estimate the ...geochemical environment of the river, seven heavy metals, namely Co, Cu, Cr, Ni, Cd, Zn, and Pb were examined from the freshly deposited river bed sediment. All the sediment samples were collected on a seasonal basis for the assessment of fluctuation in 2014–2015 and after preparation samples were analyzed using standard procedure. Result showed that heavy metal concentration ranged between 11.37 and 18.42 mg/kg for Co, 2.76 and 11.74 mg/kg for Cu, 61.25 and 87.68 mg/kg for Cr, 15.29 and 25.59 mg/kg for Ni, 0.21 and 0.28 mg/kg for Cd, 13.26 and 17.59 mg/kg for Zn, 10.71 and 14.26 mg/kg for Pb in different season. Metal contamination factor indicates the anthropogenic input in the river sediment was in the range of (0.62–0.97) for Co, (0.04–0.26) for Cu, (0.68–0.97) for Cr, (0.22–0.38) for Ni, (0.70–0.93) for Cd, (0.14–0.19) for Zn, and (0.54–0.71) for Pb. The highest contamination degree of the sediment was noticed as 4.01 at Ayodhya and lowest as 3.16 at Katerniaghat. Geo-accumulation index was noted between (0 and 1) which showed that sediment was uncontaminated to moderately contaminated and may have adverse affects on freshwater ecology of the river. Pollution load index (PLI) was found highest at Chhapra which was 0.45 and lowest at Katerniaghat which was 0.35 and it indicates that the river sediment has a low level of contamination. Significant high correlation was observed between Co, Cu, and Zn, it suggests same source of contamination input is mainly due to human settlement and agriculture activity. Positive correlation between Zn, Co, Cu, Cr, and Ni indicated a natural origin of these elements in the river sediment. Cluster analysis suggests grouping of similar polluted sites. The strong similarity between Co, Zn, Pb, Ni, Cu, and Cd showed relationship of these metals come from the same origin, which is possibly from natural and anthropogenic input which was also confirmed by correlation analysis. Using the various pollution indicators it was found that the river bed sediment is less contaminated by toxic metals during the study but the sediment quality may degrade in the near future due to increasing anthropogenic inputs in the river basin, hence proper management strategies are required to control the direct dumping of wastewater in the river.
Electron-positron pair plasmas represent a unique state of matter, whereby there exists an intrinsic and complete symmetry between negatively charged (matter) and positively charged (antimatter) ...particles. These plasmas play a fundamental role in the dynamics of ultra-massive astrophysical objects and are believed to be associated with the emission of ultra-bright gamma-ray bursts. Despite extensive theoretical modelling, our knowledge of this state of matter is still speculative, owing to the extreme difficulty in recreating neutral matter-antimatter plasmas in the laboratory. Here we show that, by using a compact laser-driven setup, ion-free electron-positron plasmas with unique characteristics can be produced. Their charge neutrality (same amount of matter and antimatter), high-density and small divergence finally open up the possibility of studying electron-positron plasmas in controlled laboratory experiments.
Free space optical (FSO) communication systems are gaining high popularity from the last decade due to its various advantages such as no license spectrum, low-cost implementation etc. In this work, ...160 Gbps data is transmitted over 8 km FSO link by adopting alternate mark inversion (AMI), wavelength division multiplexing (WDM) and polarization division multiplexing (PDM) schemes. The results are reported in terms of
factor, bit error rate, signal to noise ratio, total received power and eye diagrams.
Salt stress is one of the major abiotic stresses limiting crop growth and productivity. This work investigated the potential of five ST isolates of Trichoderma harzianum (Th-13, Th-14, Th-19, Th-33 ...and Th-50) applied through seed biopriming in reducing the detrimental effects of salinity stress on wheat (Triticum aestivum L.). Growth, physiological and biochemical parameters were studied to characterize salt tolerance. One factor was treatments (T1, T2, T3, T4, T5 and T6) and second factor was four levels of salt stress viz., 0, 2, 4 and 6 dsm-1. In germination test, most of the isolates (Th-14, Th-19 and Th-13) were effective in improving germination percentage and reducing RPG during salinity stress. Seedlings raised from ST Trichoderma isolates had significantly higher root and shoot lengths, CC and MSI than control at all stress levels. The treatments Th-14, Th-19 and Th-13 showed lower accumulation of MDA content whereas proline content and phenolics were higher in treated plants under both nonsaline and saline conditions. Highest MDA content was observed in control at salt stress level of 6 dSm-1. It is concluded that seed biopriming with different salinity tolerant isolates of Trichoderma reduced severity of the effects of salinity though the amelioration was better in Th-14 under present experimental material and conditions.
The tropomyosin receptor kinase (TRK) pathway controls appetite, balance, and pain sensitivity. While these functions are reflected in the on-target adverse events (AEs) observed with TRK inhibition, ...these AEs remain under-recognized, and pain upon drug withdrawal has not previously been reported. As TRK inhibitors are approved by multiple regulatory agencies for TRK or ROS1 fusion-positive cancers, characterizing these AEs and corresponding management strategies is crucial.
Patients with advanced or unresectable solid tumors treated with a TRK inhibitor were retrospectively identified in a search of clinical databases. Among these patients, the frequency, severity, duration, and management outcomes of AEs including weight gain, dizziness or ataxia, and withdrawal pain were characterized.
Ninety-six patients with 15 unique cancer histologies treated with a TRK inhibitor were identified. Weight gain was observed in 53% 95% confidence interval (CI), 43%–62% of patients and increased with time on TRK inhibition. Pharmacologic intervention, most commonly with glucagon-like peptide 1 analogs or metformin, appeared to result in stabilization or loss of weight. Dizziness, with or without ataxia, was observed in 41% (95% CI, 31%–51%) of patients with a median time to onset of 2 weeks (range, 3 days to 16 months). TRK inhibitor dose reduction was the most effective intervention for dizziness. Pain upon temporary or permanent TRK inhibitor discontinuation was observed in 35% (95% CI, 24%–46%) of patients; this was more common with longer TRK inhibitor use. TRK inhibitor reinitiation was the most effective intervention for withdrawal pain.
TRK inhibition-related AEs including weight gain, dizziness, and withdrawal pain occur in a substantial proportion of patients receiving TRK inhibitors. This safety profile is unique relative to other anticancer therapies and warrants careful monitoring. These on-target toxicities are manageable with pharmacologic intervention and dose modification.
•TRK inhibitors have a unique on-target side-effect profile.•Weight gain, dizziness/ataxia, and paresthesias should be monitored on therapy.•In addition, withdrawal pain can occur in patients who temporarily or permanently discontinue treatment.•These side-effects are manageable with pharmacologic intervention and/or dose modification.
Background No data exist for the long-term outcome of metastatic colorectal cancer (mCRC) from the Southern part of Asia. The primary objective of the study is to evaluate the survival outcome of ...mCRC from an Indian tertiary care center. The study also aims to highlight the treatment pattern practiced and the unique clinico-pathologic characteristics. Methods This is a single-center retrospective observational study done at a large referral tertiary care center in North India. All patients with synchronous or metachronous mCRC who received at least one dose of chemotherapy for metastatic disease, registered between 2003 to 2017 were included. Primary outcome measures were overall survival and progression-free survival and prognostic factors of overall survival. Descriptive analysis was done for the clinicopathological characteristics and treatment patterns. Kaplan Meier method for overall survival and progression-free survival. Cox regression analysis was performed for the determination of the prognostic factors for overall survival. Result Out of 377 eligible patients, 256 patients (68%) had de novo metastatic disease and the remaining 121 (32%) progressed to metastatic disease after initial treatment. The cohort was young (median age, 46 years) with the most common primary site being the rectum. A higher proportion of signet (9%) and mucinous histology (24%). The three common sites of metastasis were the liver, peritoneum, and lung. In the first line, most patients received oxaliplatin-based chemotherapy (70%). Only 12.5% of patients received biologicals in the first-line setting. The median follow-up and median overall survival of study cohort were 17 months and 18.5 months. The factors associated with poor outcome for overall survival on multivariate analysis were ECOG performance status of > 1, high CEA, low albumin, and the number of lines of chemotherapy received (< 2). Conclusion The outcome of mCRC is inferior to the published literature. We found a relatively higher proportion of patients with the following characteristics; younger, rectum as primary tumor location, the signet, and mucinous histology, higher incidence of peritoneum involvement. The routine use of targeted therapies is limited. Government schemes (inclusion of targeted therapies in the Ayushman scheme), NGO assistance, and availability of generic low-cost targeted drugs may increase the availability. Keywords: Metastatic, Colorectal cancer, Real life experience, India
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The purpose of this study was to evaluate the prognostic value of Immunoscore in patients with stage III colon cancer (CC) and to analyze its association with the effect of chemotherapy on time to ...recurrence (TTR).
An international study led by the Society for Immunotherapy of Cancer evaluated the predefined consensus Immunoscore in 763 patients with American Joint Committee on Cancer/Union for International Cancer Control TNM stage III CC from cohort 1 (Canada/United States) and cohort 2 (Europe/Asia). CD3+ and cytotoxic CD8+ T lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The primary end point was TTR. Secondary end points were overall survival (OS), disease-free survival (DFS), prognosis in microsatellite stable (MSS) status, and predictive value of efficacy of chemotherapy.
Patients with a high Immunoscore presented with the lowest risk of recurrence, in both cohorts. Recurrence-free rates at 3 years were 56.9% (95% CI, 50.3% to 64.4%), 65.9% (95% CI, 60.8% to 71.4%), and 76.4% (95% CI, 69.3% to 84.3%) in patients with low, intermediate, and high immunoscores, respectively (hazard ratio HR; high
low, 0.48; 95% CI, 0.32 to 0.71;
= .0003). Patients with high Immunoscore showed significant association with prolonged TTR, OS, and DFS (all
< .001). In Cox multivariable analysis stratified by participating center, Immunoscore association with TTR was independent (HR high
low, 0.41; 95% CI, 0.25 to 0.67;
.0003) of patient's sex, T stage, N stage, sidedness, and microsatellite instability status. Significant association of a high Immunoscore with prolonged TTR was also found among MSS patients (HR high
low, 0.36; 95% CI, 0.21 to 0.62;
.0003). Immunoscore had the strongest contribution χ2 proportion for influencing survival (TTR and OS). Chemotherapy was significantly associated with survival in the high-Immunoscore group for both low-risk (HR chemotherapy
no chemotherapy, 0.42; 95% CI, 0.25 to 0.71;
= .0011) and high-risk (HR chemotherapy
no chemotherapy, 0.5; 95% CI, 0.33 to 0.77;
= .0015) patients, in contrast to the low-Immunoscore group (
> .12).
This study shows that a high Immunoscore significantly associated with prolonged survival in stage III CC. Our findings suggest that patients with a high Immunoscore will benefit the most from chemotherapy in terms of recurrence risk.
PDF
