Oncogenetic pedigrees: Relation between design and ability to predict mutation.

We consider the risk of a disease caused by the presence within the genome of one deleterious mutation or two interacting mutations. For an individual, the probability of being mutated/doubly mutated can be estimated by knowing the phenotype of the other members in the family pedigree. We study the performance of this process as a function of the size, the shape of the family tree and the parameters of the model. We carry out simulations using the parameters pertaining to breast/ovarian cancer in BRCA-mutated families.

Benefits of using corneal topography to choose subjective refraction technique in keratoconus (RE-CON): a prospective comparative crossover clinical study.

PURPOSE: In prospective no-masking, comparative, crossover monocenter clinical trial, we aimed to evaluate whether the optimal subjective refraction technique varies with the keratoconus topography and to identify relevant topographic criteria. METHOD: This study included 72 keratoconus eyes with impaired visual acuity. Each eye tested three methods of refraction (Jackson cylinder, astigmatism dial, stenopeic slit), resulting in three eyeglass lenses. Patients were assigned to the group corresponding to the eyeglass lens offering the best visual acuity. Five topographical characteristics were collected via the Pentacam: mean keratometry (Km), maximum keratometry (Kmax), distance from corneal center to Kmax (dKmax), Belin/Ambrosio Display (BAD_D), and index of surface variance (ISV). RESULTS: Forty-six eyes were included in the dial group (64.8%), 23 eyes in the cylinder group (32.4%), and only 2 eyes in the slit group (2.8%); thus, we only compared dial and cylinder groups. The main analysis retrieved a significant probability to choose dial technic for BAD_D (p = 0.024); when BAD_D is > 9.71 (ROC threshold), the positive predictive value (PPV) = 89.5%, and for ISV, p = 0.012; when ISV is > 77, PPV = 89.1%. The sub-analysis of patients with different visual acuities between cylinder and dial confirmed these results with slightly different thresholds: the probability to choose dial technic was for BAD_D, p = 0.03; when BAD_D is > 7.55, PPV = 90%, and for ISV, p = 0.0084; when ISV is > 71, PPV = 88.5%. CONCLUSION: Refraction method is linked to topographic indices ISV and BAD_D. A BAD_D > 7.55 indicates the dial method. In addition to keratoconus screening and diagnosis, this study suggests a new application of the topographer to select a suitable refraction method for eyeglass prescription. TRIAL REGISTRATION: Study registered on the ClinicalTrials.gov database under n°: NCT04174209.

Multicenter randomized phase II study comparing docetaxel plus curcumin versus docetaxel plus placebo in first-line treatment of metastatic castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) patients have a poor prognosis, and curcumin is known to have antineoplastic properties. On the basis of previous phase I and phase II studies, we investigated whether the association of curcumin with docetaxel could improve prognosis among mCRPC patients. METHODS: A total of 50 mCRPC patients (included from June 2014 to July 2016) treated with docetaxel in association with oral curcumin (6 g/d for 7 days every 3 weeks) versus placebo were included in this double-blind, randomized, phase II study. The primary endpoint was to evaluate the time to progression. Among the secondary endpoints, compliance, overall survival, prostate-specific antigen (PSA) response, safety, curcumin absorption, and quality of life were investigated. An interim analysis was planned in the modified intention-to-treat population with data at 6 months (22 patients per arm). RESULTS: Despite good compliance and a verified absorption of curcumin, no difference was shown for our primary endpoint: progression-free survival (PFS) between the placebo and curcumin groups was, respectively, 5.3 months versus 3.7 months, p = 0.75. Similarly, no difference was observed for the secondary objectives: PSA response rate (p = 0.88), overall survival (p = 0.50), and quality of life (p = 0.49 and p = 0.47). CONCLUSION: Even though our previous studies and data in the literature seemed to support an association between curcumin and cancer therapies in order to improve patient outcome and prognosis, the results from this interim analysis clearly showed that adding curcumin to mCRPC patients' treatment strategies was not efficacious. The study was discontinued on the grounds of futility.

Continuous Wound Infiltration With Ropivacaine After Mastectomy: A Randomized Controlled Trial.

BACKGROUND: To evaluate the efficacy of continuous wound infiltration with ropivacaine to reduce acute postoperative pain in patients undergoing mastectomy for carcinoma of the breast. MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled trial was conducted. One hundred fifty patients were randomly assigned to receive continuous ropivacaine (0.2%) (group A, n = 74) or saline solution (0.9%) (group B, n = 76) at 10 mL/h for 48 h through a multilumen catheter placed during the surgical procedure. Postoperative morphine consumption and visual analog scale (VAS) pain scores were recorded. A quality of life score (Quality of life questionnaire Core 30) and a VAS score were obtained at 1, 3, and 6 mo after surgery. RESULTS: The difference in mean morphine consumption between the two groups was close to significance during the first 48 h postsurgery (P = 0.056; 10.8 ± 16.5 versus 4.8 ± 10.4 mg). At day 1, patients in the ropivacaine-infusion group had lower morphine consumption than the control group (P = 0.0026). The link between local ropivacaine infiltration and a decrease in mean postoperative VAS scores reached significance for the first 24 h postsurgery (P = 0.039). No significant difference was found between the two arms for VAS pain scores (P = 0.36) or for quality of life (overall QLQ-C30 score, P = 0.09) at 1, 3, or 6 mo. CONCLUSIONS: Continuous wound infiltration with ropivacaine is efficacious in reducing postoperative pain. Quality of life and chronic pain at 1, 3, and 6 mo were not improved by ropivacaine wound infiltration.

Effectiveness of a Global Multidisciplinary Supportive and Educational Intervention in Thermal Resort on Anthropometric and Biological Parameters, and the Disease-Free Survival after Breast Cancer Treatment Completion (PACThe).

A growing knowledge highlights the strong benefit of regular physical activity in the management of breast cancer patients, but few studies have considered biological parameters in their outcomes. In the prospective randomised trial after breast cancer treatment completion "PACThe," we determined the effects of physical activity and nutritional intervention on the biological and anthropometric status of patients after one year of follow-up, and clarified the link between biomarkers at allocation and disease-free survival. 113 patients from the population of the "PACThe" study (n = 251) were analysed for biological parameters. Patients were randomized after chemotherapy in two arms: the intervention "SPA" receiving a 2-week session of physical training, dietary education, and physiotherapy (n = 57), and the control "CTR" (n = 56). Diet questionnaire, anthropometric measures, and blood parameters were determined at allocation and one year later. Survival and recurrence were checked over 7 years. Data were considered as a function of BMI, i.e., ≤25 for normal, 25-30 for overweight, and >30 for obese patients. At allocation, the large standard deviation for nutrient-intake values reflected an unbalanced diet for some patients in the three groups. At one-year follow-up, we noticed an increase in glucose (p < 10-6), insulin (p < 10-7), and adiponectin (p < 0.022) plasma levels for both intervention arms, which were more accentuated for the >30 groups. Using the Cox model, we demonstrated that the highest testosterone plasma values were linked to an increase of the recurrence risk (HR [CI-95%] = 5.06 [1.66-15.41]; p=0.004). One-year after a global multidisciplinary supportive and educational intervention, we found few anthropometric and biological changes, mainly related to the patient's initial BMI. We highlighted the importance of plasma testosterone in the evaluation of patient's recurrence risk. Future studies would help better understand the mechanisms by which such multidisciplinary interventions could interact with breast cancer recurrence and define the most effective modalities.

Quality of life for older patients with cancer: a review of the evidence supporting melatonin use.

PURPOSE: The proportion of older populations living with cancer is on the increase. Maintaining or improving their quality of life (QoL) has become an important goal in the treatment of cancer and has become an endpoint in clinical trials. Melatonin regulates a wide variety of physiological functions and is involved in the initiation of sleep and the improvement of QoL. With age, the secretion of melatonin decreases and could lead to a deterioration in QoL. METHODS: Literature searches were conducted using the PubMed database. The search terms and derivatives of "metastatic cancer", "older patients", "quality of life" and "melatonin" were used. Titles and abstracts were screened to identify whether studies were relevant for full-text screening. RESULTS: There is major concern about the symptoms older cancer patients encounter during treatment because they can impact their QoL. Melatonin supplementation presents several benefits for older patients: improvement in survival, decrease in symptoms induced by cancer and cancer treatment, and also improvements in quality of life. CONCLUSION: It therefore seems appropriate to study the impact of melatonin supplementation during cytotoxic therapy on QoL among elderly patients with metastatic cancer. The use of melatonin as a therapeutic strategy seems particularly suitable for elderly patients, a population known to secrete significantly less melatonin. However, to date, no studies have been conducted in this population.

Association between hereditary predisposition to common cancers and congenital multimalformations.

In a previous article we reported that mutations favoring cancer at adulthood seemed to improve fertility and limit miscarriages. Because spontaneous abortion may result from anomalies in embryo, we questioned if an increased frequency of congenital malformation could be evidenced among cancer-prone families. Oncogenetics database (≈193 000 members) of the comprehensive cancer center Jean Perrin was crossed with regional registry of congenital malformations (≈10 000). Among children born between 1986 and 2011, 176 children with malformation matched in both databases. In breast/ovaries cancer-prone families, the risk for malformations was multiplied by 2.4 [1.2-4.5] in case of a BRCA1 mutation. Frequencies of malformation in BRCA2 and MMR mutated families were similar to families without a cancer syndrome. In comparison to malformations concerning a unique anatomical system, multimalformations were significantly more frequent in case of BRCA or MMR mutations: compared to families without cancer syndrome, the risk of multimalformations was multiplied by 4.1 [0.8-21.7] for cancer-prone families but with no known deleterious mutation, by 6.9 [1.2-38.6] in families with a known mutation but an unknown parental mutational status and by 10.4 [2.3-46.0] when one parent carried the familial mutation. No association with the type of anatomical system was found, nor with multiple births. These results suggest that BRCA and MMR genes play an important role in human embryogenesis and that if their function is lowered because of heterozygote mutations, congenital malformations are either more likely (BRCA1 mutations) and/or more susceptible to concern several anatomical systems.

Decision of adjuvant chemotherapy in intermediate risk luminal breast cancer patients: A prospective multicenter trial assessing the clinical and psychological impact of EndoPredict® (EpClin) use (UCBG 2-14).

PURPOSE: Genomic tests can identify ER-positive HER2-negative localized breast cancer patients who may not benefit from adjuvant chemotherapy. Such tests seem especially interesting in "intermediate" clinico-pathological risk categories. The psychological impact of the decision uncertainty in these women remains largely unexplored. We assessed the clinical and psychological impact of EndoPredict® (EpClin), a clinico-genomic test, in these patients. METHODS: This multicenter, single arm prospective study (NCT02773004) enrolled patients for which adjuvant chemotherapy was uncertain, based on predefined criteria. The primary endpoint was the proportion of change between initial adjuvant decision and final administration of chemotherapy. Secondary endpoints included post-test (Day 17) and 1-year patient reported outcomes. RESULTS: One third of 200 evaluable patients had a high EpClin score (≥3.32867; 10 years cumulative risk of distance failure ≥10%). The overall change rate of chemotherapy decision was 72/200 (35.8%, 95% CI 29.2-42.4). Chemotherapy was withdrawn in 57 cases (28.4% [22.2-34.8]) and added in 15 (7.5% [3.8-11.2]. 6 changes (8%) were based on patients' decisions. Anxiety and distress levels increased at Day 17 when adding chemotherapy after the test result (p < 10-7 and 0.00022 respectively), while stable in other situations. At 1-year, all patients had returned to the baseline anxiety and distress levels (mean anxiety 51.5, +/- SD = 2.5 [max. 80], mean distress 3±1 [max. 10]). CONCLUSIONS: EndoPredict ® (EpClin) is clinically useful in deciding whether or not to administer adjuvant chemotherapy in patients with intermediate risk. A single-step decision is preferable since adding chemotherapy at a later stage increases anxiety and distress.

Improvement in adherence to Capecitabine and Lapatinib by way of a therapeutic education program.

PURPOSE: A patient non-adherence with oral anticancer agents is a well-recognized barrier to effective treatment. The aim of this prospective study was to evaluate the efficacy of a therapeutic education program among non-adherent patients treated with Capecitabine alone or associated with Lapatinib. METHODS: Sixty-five cancer patients were enrolled. Among them, 55 participated in the first observational phase of the study, measuring adherence using electronic MEMS pillboxes (medication event monitoring system). An adherence score was assessed in the form of a composite adherence score including intake dose and intake intervals. Ten non-adherent patients (adherence score < 80%) were included in the intervention phase of the study and were enrolled on a therapeutic education program. The efficacy of the program was evaluated on the basis of an improvement in adherence scores. We also studied factors influencing adherence. RESULTS: The average adherence score was 83.6 ± 15.7% in the overall population. Forty-one patients were adherent (adherence score > 80%) and 14 patients were non-adherent (adherence score < 80%). The therapeutic education program for non-adherent patients (n = 10) increased their adherence score by 17.8% and led 60% of these patients to become adherent. The number of toxicities during the first cycles was a predictive factor for non-adherence. CONCLUSION: This study showed an improvement in adherence to Capecitabine ± Lapatinib among non-adherent patients by way of a therapeutic education program.

Re-treatment With Adjuvant Radioactive Iodine Does Not Improve Recurrence-Free Survival of Patients With Differentiated Thyroid Cancer.

Introduction: Loco regional persistence or recurrence of differentiated thyroid cancer (DTC) is frequent despite initial thyroidectomy and radioactive iodine therapy (RAI). The aim of this study was to analyze the impact of a complementary adjuvant RAI (Ad-RAI) on disease recurrence following re-operation on patients with locally persistent or recurrent DTC. Patients and Methods: A retrospective study of 85 patients with DTC was conducted. All patients were initially treated with total thyroidectomy and RAI, and re-operated for a locally persistent or recurrent disease. Propensity score was calculated to predict the impact of Ad-RAI on survival after reoperation, and to reduce the bias of the limited sample size and the prognostic tests. Results: 49 (58%) patients were re-treated with Ad-RAI after re-operation while 36 (42%) were only followed up. Disease recurrence after re-treatment (re-operation ± Ad-RAI) was detected in 31 patients (36.5%). In multivariate analysis, age >55 years (HR: 3.9 [1.6; 9.5]; p < 0.00001) was the main poor prognostic factor for recurrence-free survival. Three parameters independently influenced the decision to administer ad-RAI: low number of previous RAI administrations, Nx before re-operation, and pTg > 30 µg/l. These parameters were incorporated in the Propensity score calculation. If ad-RAI tended to improve recurrence-free survival (median survival 17.4 vs. 10.9 months), adjustment using the Propensity score removed any difference between the groups (p = 0.54), confirming the limited value of ad-RAI. Conclusion: In patients with locally persistent or recurrent DTC, age is the main independent prognostic factor. Adjuvant RAI does not improve recurrence-free survival of DTC patients.

Age, thyroglobulin levels and ATA risk stratification predict 10-year survival rate of differentiated thyroid cancer patients.

INTRODUCTION: Differentiated thyroid cancer (DTC) is the most common of endocrine cancers. Many studies have focused on recurrence-free survival of DTC patients, however, few studies have addressed overall survival rates. Given its very good prognosis, estimating overall or long-term survival in patients with DTC seems rational. So far, neither the impact of pre- and post-ablation thyroglobulin, nor that of initial American Thyroid Association (ATA) risk stratification on long-term disease-specific survival, have been sufficiently studied. OBJECTIVE: The aim of this study was to determine the factors that influence long-term disease-specific survival and thyroglobulin levels in patients with DTC who have been previously treated with thyroidectomy and radioactive iodine (RAI) remnant ablation. PATIENTS AND METHODS: This observational retrospective study included 1093 patients who were treated for DTC between 1995 and 2010 and are still monitored in our tertiary center. Only patients who needed RAI ablation after thyroidectomy were included in this study. Patients who were treated with RAI following rhTSH stimulation, patients who presented positive anti-thyroglobulin antibodies, and patients who had micro-cancers were excluded. Pre-ablation stimulated thyroglobulin (Pre-ablation sTg) was measured after thyroid hormone withdrawal (THW), just before RAI. RESULTS: According to ATA standards, 29 patients (2.7%) were classified as high-risk patients. Initial ATA high-recurrence risk rating (HR 21.9; 95% CI: 8.5-56.3), age>55 years (HR 23.8; 95%-CI: 7.5-75.3) and pre-ablation sTg≥30 µg/l (HR 8.4; 95% CI: 4.6-15.3) significantly impacted ten-year survival. Moreover, age over 45 years, ATA moderate-risk and follicular DTC were also significant. Ten-year survival was lower in ATA high-risk patients (51% vs 95% and 93% for the low and intermediate risk; p<10-7), patients older than 55 years (82% vs 98%; p<10-7), and in patients with pre-ablation sTg≥30 (78% vs 95%; p<10-7). Three rates of long-term survival were distinguished: excellent (survival rate of 99% in patients<55 years with pre-ablation sTg <30µg/l) representing 59% of the cohort, moderate (survival rate of 94.5% in patients <55 years with pre-ablation sTg ≥30µg/l or ≥55 years with pre-ablation sTg <30 µg/l) representing 38% of the cohort, and low (survival rate of 49% in patients ≥55 years with pre-ablation sTg ≥30µg/l) representing 3% of the cohort. CONCLUSION: Initial ATA high-risk classification, age over 55 years old and pre-ablation sTg ≥30 µg/l are the main negative factors that influence the ten-year survival in DTC. We suggest three categories of overall survival rates. Patients older than 55 years with pre-ablation sTg ≥30 µg/l have the worst survival rate.

Homoharringtonine, an approved anti-leukemia drug, suppresses triple negative breast cancer growth through a rapid reduction of anti-apoptotic protein abundance.

Triple negative breast cancers (TNBC) without BRCA1/2 gene mutation or BRCAness are nowadays the breast malignancies most difficult to treat. Improvement of their treatment, for all phases of the disease, is an important unmet medical need. We analyzed the effect of homoharringtonine (HHT), a natural protein synthesis inhibitor approved for treatment of chronic myeloid leukemia, on four cell lines representing aggressive, BRCA1/2 non-mutated, TNBC genomic categories. We show that HHT inhibits in vitro growth of all cell lines for more than 80%, after 48-72 h exposure to 20-100 ng/mL, the concentrations achievable in human plasma after subcutaneous administration of the drug. HHT, at 100 ng/mL, strongly reduced levels of a major TNBC survival factor, anti-apoptotic protein Mcl-1, after only 2 h of exposure, in all cell lines except MDA-MB-231. Other anti-apoptotic proteins, Bcl-2, survivin and XIAP, were also strongly downregulated. Moreover, in vivo growth of the least sensitive cell line to HHT in vitro, MDA-MB-231, was inhibited for 36.5% in mice, by 1 mg/kg of the drug, given subcutaneously, bi-daily, over 7 days. These results demonstrate marked antineoplastic activity of homoharringtonine in TNBC, making further development of the drug in this disease highly warranted.

BRACAVENIR: an observational study of expectations and coping in young women with high hereditary risk of breast and ovarian cancer.

BACKGROUND: In families with high risk of hereditary breast/ovarian cancer (HBOC), women before age 30 do not yet undergo clinical screening, but they are exposed to contradictory information from diverse sources. They may be presented with surgical prevention options at a key moment of their identity construction, the start of a marital relationship and/or at the onset of procreation projects. We tested an original psychoeducational intervention to help these women better cope with these difficult issues. METHODS: Seven young female counselees (26.4 ± 2.9 years [23-30]) from the Oncogenetics Department at Jean Perrin Comprehensive Cancer Center were enrolled. A weekend group workshop composed of short conferences, group sharing and role playing activities was supervised by a psychotherapist. A longitudinal analysis of questionnaires over one year of follow-up was performed. The Herth Hope Inventory was evaluated, as well as self-esteem, anxiety, perceived control, coping, and quality of life. Participants' comments were collected by a genetic counselor throughout the workshop. RESULTS: All participants were BRCA mutation carriers and six had lived with a close relative affected by breast/ovarian cancer. Hope, self-esteem and quality of life increased during the year after the workshop (p = 0.0003). Coping by focus on the problem increased in the first 6 months (p = 0.011) and returned to baseline values at one year, while coping by focus on emotions decreased steadily (p = 0.021). Debriefing from the workshop highlighted the new medical opportunities proposed and the challenges these young women face, such as whether to have prophylactic surgery, and if so before or after having children, and how surgery might affect their relationship with their partner. CONCLUSION: A tailored two-day psychoeducational workshop may be sufficient to improve the way young women with BRCA mutations deal with the implications of HBOC risk. TRIAL REGISTRATION: BRACAVENIR was registered in ClinicalTrials.gov with no NCT02705924.

Stimulated Thyroglobulin and Thyroglobulin Reduction Index Predict Excellent Response in Differentiated Thyroid Cancers.

CONTEXT: Despite its good prognosis, differentiated thyroid cancer (DTC) is characterized by high rates of disease persistence and recurrence. Estimation of long-term remission (excellent response) thanks to specific parameters could help to individualize the active surveillance schedule. OBJECTIVE: Evaluation of the ability of stimulated thyroglobulin (Tg) and Tg reduction index (TRI) to predict long-term remission in patients with DTC managed by thyroidectomy and radioactive iodine (RAI) remnant ablation. PATIENTS AND INTERVENTIONS: Observational retrospective study of 1093 patients treated for DTC between 1995 and 2010. Preablation stimulated thyroglobulin (presTg) was measured under thyroid hormone withdrawal just before RAI. Recombinant human TSH-stimulated thyroglobulin (sTg) was measured at first evaluation of the initial management 6 to 12 months after RAI. TRI was calculated based on pre-Tg and sTg. RESULTS: After univariate and multivariate analyses, lymph node invasion (N1, OR = 2.08; 95% CI, 1.19 to 3.64), presTg (OR = 4.04; 95% CI, 2.56 to 6.38), sTg (OR = 2.62; 95% CI, 2.05 to 3.34), and TRI (OR = 0.43; 95% CI, 0.21 to 0.88) were identified as independent prognostic factors influencing the rate of disease persistence or recurrence after the initial management. Receiver operating characteristic analysis identified presTg cutoff (<10 µg/L) to predict excellent response, with a negative predictive value of 94%, and validated for higher stages (T3/T4, N1). Furthermore, sTg <1 µg/L predicts excellent response. TRI >60% for the entire cohort and 62.5% for locally advanced disease (T3/T4, N1) was sensitive predictor for excellent response. CONCLUSION: This study identifies presTg, sTg, and TRI as highly sensitive predictors of excellent response in patients with DTC and subsequently disease-free status. The cutoff of such parameters is also adapted for patients with higher tumor stages (T3/T4, N1).

Impact of Chemotherapy-induced Menopause in Women of Childbearing Age With Non-metastatic Breast Cancer - Preliminary Results From the MENOCOR Study.

BACKGROUND: Young patients with breast cancer treated with chemotherapy can experience ovarian failure, which can lead to chemotherapy-induced menopause (CIM) impacting the quality of life (QoL). A prospective study was set out to evaluate the impact of CIM on QoL in women of childbearing age with non-metastatic breast cancer, and this article reports results of the interim analysis conducted to evaluate feasibility and to see preliminary results. PATIENTS AND METHODS: A total of 58 women (age, 18-46 years) with newly diagnosed breast cancer and treated with chemotherapy were eligible. QoL was assessed by self-administered questionnaires (Quality of Life Questionnaire-Core 30 [QLQ-C30], Quality of Life Questionnaire-Breast 23 [QLQ-BR23], and Kupperman index) and hormonal variations (anti-Müllerian hormone [AMH], follicle-stimulating hormone, and estradiol) were explored. We compared patients with ≥ 12 months amenorrhea (CIM) (n = 41) to patients with < 12 months of amenorrhea (non-CIM) (n = 17). RESULTS: A good inclusion rate (approximately 4/month) and sufficient data enabled us to perform this analysis. QLQ-C30 failed to show any difference between CIM and non-CIM patients (P = .5). In contrast, at 6 months post-chemotherapy, CIM patients tended to have lower QoL as shown by QLQ-BR23 (P = .16) and more severe climacteric symptoms (P = .01). Regarding hormonal variations, AMH pre-treatment level was higher in non-CIM patients (P = .0032). We also noted that CIM patients were older (P = .00013), had shorter menstruation cycle (P = .082), and experienced faster amenorrhea (P = .088). CONCLUSIONS: The study is technically feasible, and our preliminary results underline that age in association with pre-treatment AMH level could be helpful to predict ovarian function. QLQ-BR23 seemed to be stronger, more precise, and appropriate to evaluate QoL changes in patients with breast cancer than the QLQ-C30.

Characterisation of gut, lung, and upper airways microbiota in patients with non-small cell lung carcinoma: Study protocol for case-control observational trial.

BACKGROUND: Several studies have confirmed the important role of the gut microbiota in the regulation of immune functions and its correlation with different diseases, including cancer. While brain-gut and liver-gut axes have already been demonstrated, the existence of a lung-gut axis has been suggested more recently, with the idea that changes in the gut microbiota could affect the lung microbiota, and vice versa. Likewise, the close connection between gut microbiota and cancer of proximal sites (intestines, kidneys, liver, etc.) is already well established. However, little is known whether there is a similar relation when looking at world's number one cause of death from cancer-lung cancer. OBJECTIVE: Firstly, this study aims to characterise the gut, lung, and upper airways (UAs) microbiota in patients with non-small cell lung cancer (NSCLC) treated with surgery or neoadjuvant chemotherapy plus surgery. Secondly, it aims to evaluate a chemotherapy effect on site-specific microbiota and its influence on immune profile. To our knowledge, this is the 1st study that will analyse multi-site microbiota in NSCLC patients along with site-specific immune response. METHODS: The study is a case-controlled observational trial. Forty NSCLC patients will be divided into 2 groups depending on their anamnesis: Pchir, patients eligible for surgery, or Pct-chir, patients eligible for neoadjuvant chemotherapy plus surgery. Composition of the UAs (saliva), gut (faeces), and lung microbiota (from broncho-alveolar lavage fluid (BALF) and 3 lung pieces: "healthy" tissue distal to tumour, peritumoural tissue and tumour itself) will be analysed in both groups. Immune properties will be evaluated on the local (evaluation of the tumour immune cell infiltrate, tumour classification and properties, immune cell phenotyping in BALF; human neutrophil protein (HNP) 1-3, ß-defensin 2, and calprotectin in faeces) and systemic level (blood cytokine and immune cell profile). Short-chain fatty acids (SCFAs) (major products of bacterial fermentation with an effect on immune system) will be dosed in faecal samples. Other factors such as nutrition and smoking status will be recorded for each patient. We hypothesise that smoking status and tumour type/grade will be major factors influencing both microbiota and immune/inflammatory profile of all sampling sites. Furthermore, due to non-selectivity, the same effect is expected from chemotherapy.

Weight Evolution During Endocrine Therapy for Breast Cancer in Postmenopausal Patients: Effect of Initial Fat Mass Percentage and Previous Adjuvant Treatments.

BACKGROUND: Weight changes during adjuvant treatment for early-stage breast cancer has been associated with a poor prognosis. The long-term evolution of body composition during adjuvant treatment for breast cancer, in particular, endocrine therapy, is not well known, and new data on this topic are required. The present study assessed the evolution of weight and body composition among 33 postmenopausal breast cancer patients receiving endocrine therapy after standard adjuvant chemotherapy that included taxanes. PATIENTS AND METHODS: Dual-energy x-ray absorptiometry was used to measure the fat and lean body mass. Body water was assessed using multifrequency bioelectrical impedance analysis. The Hospital Anxiety and Depression questionnaire and the short version of the International Physical Activity Questionnaire were also administered. RESULTS: During endocrine therapy, 5 of the 33 patients (15.2%) lost weight and 12 (36.4%) gained weight. The overall average gain was 2.0 ± 5.5 kg (P = .04). During this period, the fat mass, lean body mass, and body water increased. The factors linked to fat mass gain included an excess fat mass (≥ 36%) before treatment and weight loss during chemotherapy. In the overall period of adjuvant cancer treatment, 30% of the population gained > 5% of their initial weight. The average gain was the same as that during the endocrine therapy period (2.0 ± 5.4 kg; P = .031) and was characterized by an increase in total lean body mass, mainly localized in the trunk region. CONCLUSION: Endocrine therapy appears as a pivotal period in weight and body composition management. Overfat and obese patients and those who lose weight during chemotherapy were more subject to weight and fat mass gain during endocrine therapy.

Analysis of tumour-infiltrating lymphocytes reveals two new biologically different subgroups of breast ductal carcinoma in situ.

BACKGROUND: Tumour-infiltrating lymphocytes (TILs) have been demonstrated to significantly influence prognosis and response to therapy of invasive breast cancer (IBC). Thus, it has been suggested that TIL density or/and immunophenotype could serve as biomarkers for selection of IBC patients for immunotherapy. However, much less is known about significance of TILs in breast ductal carcinoma in situ (DCIS). METHODS: We retrospectively investigated TIL density and immunophenotype in 96 pure DCIS and 35 microinvasive carcinomas (miCa). TIL density was assessed on H&E-stained breast biopsy sections as the percentage of tumour stromal area occupied by TILs, and classified into 4 grades: 0 (0%-9%), 1 (10-29%), 2 (30-49%) and 3 (50%-100%). TIL immunophenotype was assessed by immunohistochemistry for CD8, CD4, FoxP3, CD38 or CD20. RESULTS: Compared to pure DCIS, miCa contained significantly more cases with TIL density grade 3 (p = 0.028). Concordantly, CD8+, CD4+ and CD38+ cells were more numerous in miCa than in pure DCIS. In the pure DCIS subgroup with TIL density grades 2 and 3, all TIL subpopulations were more numerous than in the pure DCIS with TIL density grades 0 and 1, however the ratio between T-lymphocytes (CD8+ and CD4+) and B-lymphocytes (CD20+) was significantly lower (p = 0.029). On the other side, this ratio was significantly higher in miCa, in comparison with pure DCIS having TIL density grades 2 and 3 (p = 0.017). By cluster analysis of tumour cell pathobiological features we demonstrated similarity between miCa and the pure DCIS with TIL density grades 2 and 3. The only significant difference between those two categories was in the ratio of T- to B-TILs, higher in miCa. CONCLUSION: Results indicate that TIL density level can distinguish 2 biologically different DCIS subgroups, one of which (DCIS with ≥30% TILs, the TIL-rich DCIS) is like miCa. Similarity of TIL-rich pure DCIS and miCa as well as the role of B-lymphocytes in DCIS invasiveness are worth further investigating with regards to the potential development of immunotherapy-based prevention of DCIS progression.

Intraprostatic Fiducials Compared with Bony Anatomy and Skin Marks for Image-Guided Radiation Therapy of Prostate Cancer.

Purpose Prostate motion occurs during radiotherapy for localized prostate cancer. We evaluated the input of intraprostatic fiducials for image-guided radiation therapy and compared it with bony anatomy and skin marks. Methods Eleven patients were implanted with three fiducial markers in the prostate. Daily sets of orthogonal kV-kV images were compared with digitally reconstructed radiography. Data were recorded for skin marks, bony anatomy, and fiducial markers. The variations were analyzed along three principal axes (left-right: LR, superoinferior: SI, and anteroposterior: AP). Results A total of 2,417 measures were recorded over 38 fractions of radiotherapy (76 Gy). Fiducial marker movements from bony anatomy were ≤ 5 mm for 84.2% (confidence interval: CI 95%±1.5), 91.3% (CI 95%±1.1), and 99.5% (CI 95%±0.4) of the measures along the AP, SI, and LR axes, respectively. Ninety-five percent of the shifts between a fiducial marker and the bony anatomy were < 8 mm in the AP and SI axes, and < 3 mm in the LR axis. Fiducial marker movements from skin marks were ≤ 5 mm for 64.8% (CI 95%±1.9), 79.2% (CI 95%±1.6), and 87.2% (CI 95%±1.3) of the measures along the AP, SI, and LR axes, respectively. Bony anatomy movements from skin marks were ≤ 5 mm for 84% (CI 95%±1.4), 92% (CI 95%±1.1), and 87% (CI 95%±1.3) of the measurements along the AP, SI, and LR axes, respectively. Conclusion Using fiducial markers provides better accuracy of repositioning of the prostate than using bony anatomy and skin marks for image-guided radiotherapy of prostate cancer.

TERT promoter status and gene copy number gains: effect on TERT expression and association with prognosis in breast cancer.

Upregulation of the telomerase reverse transcriptase (TERT) gene in human cancers leads to telomerase activation, which contributes to the growth advantage and survival of tumor cells. Molecular mechanisms of TERT upregulation are complex, tumor-specific and can be clinically relevant. To investigate these mechanisms in breast cancer, we sequenced the TERT promoter, evaluated TERT copy number changes and assessed the expression of the MYC oncogene, a known transcriptional TERT regulator, in two breast cancer cohorts comprising a total of 122 patients. No activating TERT promoter mutations were found, suggesting that this mutational mechanism is not likely to be involved in TERT upregulation in breast cancer. The T349C promoter polymorphism found in up to 50% of cases was not correlated with TERT expression, but T349C carriers had significantly shorter disease-free survival. TERT gains (15-25% of cases) were strongly correlated with increased TERT mRNA expression and worse patient prognosis in terms of disease-free and overall survival. Particularly aggressive breast cancers were characterized by an association of TERT gains with MYC overexpression. These results evidence a significant effect of gene copy number gain on the level of TERT expression and provide a new insight into the clinical significance of TERT and MYC upregulation in breast cancer.