IL15RA and SMAD3 Genetic Variants Predict Overall Survival in Metastatic Colorectal Cancer Patients Treated with FOLFIRI Therapy: A New Paradigm

Simple SummaryThere is an increasing scientific interest in the study of the interaction between the immune system and drugs in cancer that can affect the efficacy of an anti-cancer treatment. This study was undertaken to better understand if the genetic characteristic of a cancer patient's immune system can predict the tumor response to the treatment and the duration of survival. The topic was studied on 335 metastatic colorectal cancer patients treated with a first-line chemotherapy (FOLFIRI regimen, irinotecan-5-fluorouracil-leucovorin). The research highlighted two markers, IL15RA-rs7910212 and SMAD3-rs7179840, significantly associated with the patient's survival. When considering IL15RA-rs7910212 and SMAD3-rs7179840 in combination with other two genetic markers previously investigated (NR1I2-rs1054190, VDR-rs7299460), we built up a highly predictive genetic score of survival. The herein identified markers must be further validated, but still represent good candidates to understand how much a patient with a metastatic colorectal cancer can benefit from a chemotherapy with FOLFIRI regimen.A new paradigm in cancer chemotherapy derives from the interaction between chemotherapeutics, including irinotecan and 5-fluorouracil (5-FU), and the immune system. The patient's immune response can modulate chemotherapy effectiveness, and, on the other hand, chemotherapeutic agents can foster tumor cell immunogenicity. On these grounds, the analysis of the cancer patients' immunogenetic characteristics and their effect on survival after chemotherapy represent a new frontier. This study aims to identify genetic determinants in the immuno-related pathways predictive of overall survival (OS) after FOLFIRI (irinotecan, 5-FU, leucovorin) therapy. Two independent cohorts comprising a total of 335 patients with metastatic colorectal cancer (mCRC) homogeneously treated with first-line FOLFIRI were included in the study. The prognostic effect of 192 tagging genetic polymorphisms in 34 immune-related genes was evaluated using the bead array technology. The IL15RA rs7910212-C allele was associated with worse OS in both discovery (HR: 1.57, p = 0.0327, Bootstrap p-value = 0.0280) and replication (HR: 1.71, p = 0.0411) cohorts. Conversely, SMAD3 rs7179840-C allele was associated with better OS in both discovery (HR: 0.65, p = 0.0202, Bootstrap p-value = 0.0203) and replication (HR: 0.61, p = 0.0216) cohorts. A genetic prognostic score was generated integrating IL15RA-rs7910212 and SMAD3-rs7179840 markers with inflammation-related prognostic polymorphisms we previously identified in the same study population (i.e., PXR [NR1I2]-rs1054190, VDR-rs7299460). The calculated genetic score successfully discriminated patients with different survival probabilities (p < 0.0001 log-rank test). These findings provide new insight on the prognostic value of genetic determinants, such as IL15RA and SMAD3 markers, and could offer a new decision tool to improve the clinical management of patients with mCRC receiving FOLFIRI

The Genome Sequence of the Grape Phylloxera Provides Insights into the Evolution, Adaptation, and Invasion Routes of an Iconic Pest

Background: Although native to North America, the invasion of the aphid-like grape phylloxera Daktulosphaira vitifoliae across the globe altered the course of grape cultivation. For the past 150 years, viticulture relied on grafting-resistant North American Vitis species as rootstocks, thereby limiting genetic stocks tolerant to other stressors such as pathogens and climate change. Limited understanding of the insect genetics resulted in successive outbreaks across the globe when rootstocks failed. Here we report the 294-Mb genome of D. vitifoliae as a basic tool to understand host plant manipulation, nutritional endosymbiosis, and enhance global viticulture. Results: Using a combination of genome, RNA, and population resequencing, we found grape phylloxera showed high duplication rates since its common ancestor with aphids, but similarity in most metabolic genes, despite lacking obligate nutritional symbioses and feeding from parenchyma. Similarly, no enrichment occurred in development genes in relation to viviparity. However, phylloxera evolved > 2700 unique genes that resemble putative effectors and are active during feeding. Population sequencing revealed the global invasion began from the upper Mississippi River in North America, spread to Europe and from there to the rest of the world. Conclusions: The grape phylloxera genome reveals genetic architecture relative to the evolution of nutritional endosymbiosis, viviparity, and herbivory. The extraordinary expansion in effector genes also suggests novel adaptations to plant feeding and how insects induce complex plant phenotypes, for instance galls. Finally, our understanding of the origin of this invasive species and its genome provide genetics resources to alleviate rootstock bottlenecks restricting the advancement of viticulture

La qualité des soins, les guides de pratique et les modalités d’organisation

Laflamme Brigitte, Fervers Béatrice, Couture Félix, Minvielle Étienne. La qualité des soins, les guides de pratique et les modalités d’organisation. In: Santé, Société et Solidarité, n°1, 2010. Le cancer au quotidien. pp. 77-86

Transcranial functional ultrasound imaging of the brain using microbubble-enhanced ultrasensitive Doppler

International audienc

Perceptions and intentions toward medical assistance in dying among Canadian medical students

Abstract Background Medical assistance in dying (MAID) was legalized in Canada in 2016. As of July 2017, approximately 2149 patients have accessed MAID. There remains no national-level data on the perspectives of future physicians about MAID or its changing legal status. We provide evidence from a national survey of Canadian medical students about their opinions, intentions, and concerns about MAID. Methods From October 2016 to July 2017, we distributed an anonymous online survey to all students at 15 of Canada’s 17 medical schools. The survey collected data on respondent socio-demographic characteristics, features of their medical education, intentions for medical practice, and perspectives on MAID. We analyzed responses using univariate descriptive and stepwise multivariate logistic regression. Results In 1210 completed surveys, 71% of respondents reported being willing to provide MAID under a legal framework that permits it. Non-religious respondents reported greater willingness to participate in MAID than respondents of any religious affiliation (p < 0.001). Frequency of religious attendance was inversely associated with willingness to provide MAID (p < 0.001). Medical students born in Québec were more willing to provide MAID than respondents from other provinces (OR 2.21; p < 0.001). Age, sex, socioeconomic status, year of medical study, previous academic major, and rural/urban city of birth were not associated with willingness to provide MAID. Conclusion As the current class of medical students becomes the first cohort of new physicians to enter Canada’s changing medical and legal landscape around MAID, our findings inform the public debate by examining attributes associated with support or opposition to the practice

Improved Progression-Free Survival in Irinotecan-Treated Metastatic Colorectal Cancer Patients Carrying the HNF1A Coding Variant p.I27L

Hepatocyte nuclear factor 1-alpha (HNF1A) is a liver-enriched transcription factor that plays a key role in many aspects of hepatic functions including detoxification processes. We examined whether HNF1A polymorphisms are associated with clinical outcomes in two independent cohorts combining 417 European ancestry patients with metastatic colorectal cancer (mCRC) treated with irinotecan-based chemotherapy. The intronic rs2244608A&gt;G marker was predictive of an improved progression-free survival with a trend in the Canadian cohort and reaching significance in the Italian cohort, with hazard ratios (HR) of 0.74 and 0.72, P = 0.076 and 0.038, respectively. A strong association between rs2244608A&gt;G and improved PFS was found in the combined analysis of both cohorts (HR = 0.72; P = 0.002). Consistent with an altered HNF1A function, mCRC carriers of the rs2244608G minor allele displayed enhanced drug exposure by 45% (P = 0.032) compared to non-carriers. In Caucasians, rs2244608A&gt;G is in strong linkage with the coding variant rs1169288c.79A&gt;C (HNF1A p.I27L). In healthy donors, we observed an altered hepatic (ABCC1, P = 0.009, ABCC2, P = 0.048 and CYP3A5, P = 0.001; n = 89) and intestinal (TOP1, P = 0.004; n = 75) gene expression associated with the rs1169288C allele. In addition, the rs1169288C polymorphism could significantly increase the ABCC1 promoter activity by 27% (P = 0.008) and 15% (P = 0.041) in the human kidney HEK293 and the human liver HepG2 cell lines, respectively. Our findings suggest that the HNF1A rs2244608, or the tightly linked functional coding variant p.I27L, might be a potential prognostic marker with irinotecan-based regimens

Stress-buffering effect of social support on immunity and infectious risk during chemotherapy for breast cancer

Objective: This study investigated the stress-buffering effect of social support on immune function and infectious risk in women with breast cancer, during and after chemotherapy. Method: Data were collected from 50 women with breast cancer before and after their chemotherapy, as well as three months later. Stress was measured by daily hassles related to cancer and social support by marital status (MS) and perceived support from friends (Ps-fr). Blood was collected to measure innate immune markers (i.e., T cells, NK cells and neutrophils). Infections were evaluated using a semi-structured interview. Moderation, mediation and moderated mediation models were computed to test the hypotheses. Results: Higher stress at baseline was found to significantly predict a higher occurrence of infections during chemotherapy, but not three months later. The relationship between stress and infections was not significantly explained by any of the immune markers. The interaction between stress and social support was tested using MS alone and combined with Ps-fr. A protective effect of social support on the deleterious effect of stress on infectious risk was found. Single patients reporting lower Ps-fr showed the strongest association between stress and infections, while the weakest association was found in patients in a committed relationship with a higher level of Ps-fr. Conclusions: Women experiencing more stress before the beginning of chemotherapy would appear to be at a higher risk of developing infections during their treatment. Results of this study also suggest that this effect could be buffered by the presence of a romantic partner and by higher Ps-fr

Insomnia, immunity, and infections in cancer patients : results from a longitudinal study

Background: Insomnia is very common in cancer patients receiving chemotherapy. Poor sleep is associated with immune alterations but the actual impact on health resulting from such immune changes has rarely been studied. The aim of this study was to evaluate, in women treated with chemotherapy for breast or gynecological cancer, the relationships between insomnia, immunity, and the occurrence of infections. Method: Fifty-two patients were assessed before chemotherapy (Time [T]1), on 4 occasions during the first 2 cycles of chemotherapy (i.e., on immunosuppression and recovery weeks; T2–T5), at posttreatment (T6), and at 3-month (T7) and 6-month (T8) follow-ups. A clinical interview was administered to assess insomnia (Insomnia Interview Schedule) and the occurrence of infections. Patients were categorized into 1 of these 3 subgroups on the basis of the insomnia interview at T1: good sleepers (GS), insomnia symptoms (SX), and insomnia syndrome (SYN). Finally, blood samples were collected at each time point (T1–T8) to measure several immune parameters (e.g., neutrophils, lymphocytes). Results: Mixed-model analyses of covariance revealed that SYN patients at T1 had significantly lower counts of some blood cells after chemotherapy (T6) as compared to GS (i.e., total white blood cells and neutrophils) and as compared to GS and SX patients (i.e., total lymphocytes, CD3+ and CD4+ cells). At T8, SYN patients at T1 showed significantly lower lymphocytes, CD3+ and CD4+ counts as compared to SX patients. Finally, SYN patients at T1 were at a significantly higher risk of reporting infectious episodes at T5 as compared to SX patients. Conclusions: Although replication is warranted, these results suggest that prechemotherapy insomnia may potentiate the vulnerability to show immune alterations and develop infections due to chemotherapy during the cancer care trajectory. Overall, they further emphasize the need to provide effective treatments for sleep difficulties in patients undergoing chemotherapy

IL15RA and SMAD3 Genetic Variants Predict Overall Survival in Metastatic Colorectal Cancer Patients Treated with FOLFIRI Therapy: A New Paradigm

A new paradigm in cancer chemotherapy derives from the interaction between chemotherapeutics, including irinotecan and 5-fluorouracil (5-FU), and the immune system. The patient’s immune response can modulate chemotherapy effectiveness, and, on the other hand, chemotherapeutic agents can foster tumor cell immunogenicity. On these grounds, the analysis of the cancer patients’ immunogenetic characteristics and their effect on survival after chemotherapy represent a new frontier. This study aims to identify genetic determinants in the immuno-related pathways predictive of overall survival (OS) after FOLFIRI (irinotecan, 5-FU, leucovorin) therapy. Two independent cohorts comprising a total of 335 patients with metastatic colorectal cancer (mCRC) homogeneously treated with first-line FOLFIRI were included in the study. The prognostic effect of 192 tagging genetic polymorphisms in 34 immune-related genes was evaluated using the bead array technology. The IL15RA rs7910212-C allele was associated with worse OS in both discovery (HR: 1.57, p = 0.0327, Bootstrap p-value = 0.0280) and replication (HR: 1.71, p = 0.0411) cohorts. Conversely, SMAD3 rs7179840-C allele was associated with better OS in both discovery (HR: 0.65, p = 0.0202, Bootstrap p-value = 0.0203) and replication (HR: 0.61, p = 0.0216) cohorts. A genetic prognostic score was generated integrating IL15RA-rs7910212 and SMAD3-rs7179840 markers with inflammation-related prognostic polymorphisms we previously identified in the same study population (i.e., PXR [NR1I2]-rs1054190, VDR-rs7299460). The calculated genetic score successfully discriminated patients with different survival probabilities (p &lt; 0.0001 log-rank test). These findings provide new insight on the prognostic value of genetic determinants, such as IL15RA and SMAD3 markers, and could offer a new decision tool to improve the clinical management of patients with mCRC receiving FOLFIRI

Germline Polymorphisms in the Nuclear Receptors PXR and VDR as Novel Prognostic Markers in Metastatic Colorectal Cancer Patients Treated With FOLFIRI

Nuclear receptors act as mediators of cancer-related inflammation and gene expression. They have a regulatory effect on genes encoding proteins related to drug adsorption, distribution, metabolism, and excretion. The aim of the present study was to highlight novel prognostic markers among polymorphisms in genes encoding for nuclear receptor proteins and inflammation-related cytokines in patients treated with a FOLFIRI regimen. This study included two independent cohorts comprising a total of 337 mCRC patients homogeneously treated with first-line FOLFIRI. Genotyping of 246 haplotype-tagging polymorphisms in 22 genes was performed using bead array technology. The NR1I2 (PXR)-rs1054190 and VDR-rs7299460 polymorphisms were significantly associated with patient overall survival (OS). A detrimental effect of the NR1I2 rs1054190-TT genotype on OS was observed in both the discovery and replication cohorts (HR = 6.84, P = 0.0021, q-value = 0.1278 and HR = 3.56, P = 0.0414, respectively). Patients harboring the NR1I2 rs1054190-TT genotype had a median OS of 9 months vs. 21 months in patients with C-allele (P < 0.0001 log-rank test). VDR rs7299460-T was consistently associated with a longer OS in both cohorts (discovery: HR = 0.61, P = 0.0075, q-value = 0.1535; replication: HR = 0.57, P = 0.0477). Patients with the VDR rs7299460-T allele had a median OS of 23 months compared to 18 months in those with the CC genotype (P = 0.0489, log-rank test). The NR1I2-rs1054190 polymorphism also had an effect on the duration of progression-free survival, consistent with the effect observed on OS. Two novel prognostic markers for mCRC treated with FOLFIRI were described and, if validated by prospective trials, have a potential application in the management of these patients