Exposure-response relationship of cabozantinib in patients with metastatic renal cell carcinoma treated in routine care.

BACKGROUND: Interindividual pharmacokinetic variability may influence the clinical benefit or toxicity of cabozantinib in metastatic renal cell carcinoma (mRCC). We aimed to investigate the exposure-toxicity and exposure-response relationship of cabozantinib in unselected mRCC patients treated in routine care. METHODS: This ambispective multicenter study enrolled consecutive patients receiving cabozantinib in monotherapy. Steady-state trough concentration (Cmin,ss) within the first 3 months after treatment initiation was used for the PK/PD analysis with dose-limiting toxicity (DLT) and survival outcomes. Logistic regression and Cox proportional-hazards models were used to identify the risk factors of DLT and inefficacy in patients, respectively. RESULTS: Seventy-eight mRCC patients were eligible for the statistical analysis. Fifty-two patients (67%) experienced DLT with a median onset of 2.1 months (95%CI 0.7-8.2). In multivariate analysis, Cmin,ss was identified as an independent risk factor of DLT (OR 1.46, 95%CI [1.04-2.04]; p = 0.029). PFS and OS were not statistically associated with the starting dose (p = 0.81 and p = 0.98, respectively). In the multivariate analysis of PFS, Cmin, ss > 336 ng/mL resulted in a hazard ratio of 0.28 (95%CI, 0.10-0.77, p = 0.014). By contrast, Cmin, ss > 336 ng/mL was not statistically associated with longer OS. CONCLUSION: Early plasma drug monitoring may be useful to optimise cabozantinib treatment in mRCC patients treated in monotherapy, especially in frail patients starting at a lower than standard dose.

Effect of Serelys Homme on the Incidence and Severity of Vasomotor Symptoms and Quality-of-Life Impairments in Patients Receiving Hormone Therapy and Radiation for Localized Prostate Cancer: Results of the ESCULAPE Phase 2 Prospective Study.

Purpose: Androgen deprivation therapy (ADT) may cause vasomotor symptoms (VMS) including hot flushes and sweats, which affect quality of life (QoL). Serelys Homme is a nonhormonal and a natural origin product that could affect VMS in men undergoing ADT. We evaluated effectiveness and tolerance of Serelys Homme administration on VMS and QoL of patients undergoing combined ADT and radiation therapy for prostate cancer. Methods and Materials: Between April 2017 and July 2019, 103 patients were screened, and 53 patients refused to participate in the study. Serelys Homme therapy consisted of a daily administration of 2 tablets for 6 months. Patients were evaluated with 4 questionnaires including the adapted Modified Rankin Scale (adapted-MRS), European Quality of Life 5 Dimensions 3 Level Version (EQ 5D3L), Functional Assessment of Cancer Therapy-Prostate (FACT-P), and Hot Flash Related Daily Interference Scale (HFRDIS) at day 0, day 90 (D90), and day 180 (D180). Statistical evaluation was performed using the Wilcoxon rank sign test. A 2-sided P < .05 was considered statistically significant. Results: Among the 50 patients, 4 withdrew after inclusion. All patients (n = 46) received either postoperative or definitive radiation therapy combined with a short (n = 15) or long course (n = 31) of ADT. Serelys Homme administration significantly decreased the rate of patients who had ≥7 VMS and 3 to 6 VMS per day. The number of patients presenting with moderate or severe VMS was decreased at D90 (P = .005) and at D180 (P = .005). In addition, VMS duration was reduced at D90 (P = .002) and D180 (P < .001). Finally, at D90 and D180, 11.1% and 16.0% of patients, respectively, with initial severe or moderate VMS had a complete response without further symptoms. Among QoL parameters, fatigue decreased significantly. Effectiveness evaluated by doctors was rated as moderate or good to excellent VMS control in 20% and 60% of the patients, respectively. No side effects were recorded in the whole population. Conclusions: This study demonstrated effectiveness and excellent tolerance of Serelys Homme. We observed a significant reduction of the frequency, duration, and intensity of hot flushes and sweats induced by ADT. Serelys Homme increased QoL scores. These encouraging results open the prospect to further studies and Serelys Homme use in patients undergoing ADT for prostate cancer.

Gemcitabine plus platinum-based chemotherapy in combination with bevacizumab for kidney metastatic collecting duct and medullary carcinomas: Results of a prospective phase II trial (BEVABEL-GETUG/AFU24).

BACKGROUND: Renal medullary carcinoma (RMC) and collecting duct carcinoma (CDC) are rare entities with a poor outcome. First-line metastatic treatment is based on gemcitabine + platinum chemotherapy (GC) regimen but retrospective data suggest enhanced anti-tumour activity with the addition of bevacizumab. Therefore, we performed a prospective assessment of the safety and efficacy of GC + bevacizumab in metastatic RMC/CDC. METHODS: We conducted a phase 2 open-label trial in 18 centres in France in patients with metastatic RMC/CDC and no prior systemic treatment. Patients received bevacizumab plus GC up to 6 cycles followed, for non-progressive disease, by maintenance therapy with bevacizumab until progression or unacceptable toxicity. The co-primary end-points were objective response rates (ORRs) and progression-free survival (PFS) at 6 months (ORR-6; PFS-6). PFS, overall survival (OS) and safety were secondary end-points. At interim analysis, the trial was closed due to toxicity and lack of efficacy. RESULTS: From 2015 to 2019, 34 of the 41 planned patients have been enroled. After a median follow-up of 25 months, ORR-6 and PFS-6 were 29.4% and 47.1%, respectively. Median OS was 11.1 months (95% confidence interval [CI]: 7.6-24.2). Seven patients (20.6%) discontinued bevacizumab because of toxicities (hypertension, proteinuria, colonic perforation). Grade 3-4 toxicities were reported in 82% patients, the most common being haematologic toxicities and hypertension. Two patients experienced grade 5 toxicity (subdural haematoma related to bevacizumab and encephalopathy of unknown origin). CONCLUSION: Our study showed no benefit for bevacizumab added to chemotherapy in metastatic RMC and CDC with higher than expected toxicity. Consequently, GC regimen remains a therapeutic option for RMC/CDC patients.

How did we take care of our older cancer patients during the first COVID-19 wave? The French experience.

BACKGROUND: The management of older cancer patients has been highly challenging for clinicians in a health-care system operating at maximum capacity during the COVID-19 pandemic. PATIENTS AND METHODS: We analyzed data from 9 different institutions. The primary endpoint was to assess the prevalence of adapted patient care during the pandemic for elderly cancer patients. The secondary endpoint was to assess the incidence of hospitalization and mortality due to COVID-19. All patients were older than 65years of age. RESULTS: We analyzed data from 332 outpatients' case files between 9th of March and 30th of April 2020. The median age was 75years (range: 65-101) and 53% were male. Because of the COVID-19 pandemic, more than half of the outpatients received modified patient care, defined as postponement or cancellation of surgery, irradiation scheme adapted, systemic treatment or the use of telemedicine. Among patients with localized cancer, 60% had a change in management strategy due to the pandemic. Changes in management strategy were made for 53% of patients at the metastatic stage. GCSF was used , in 83% of patients, increasing considerably in the context of the pandemic. Sixty-nine percent of physicians used telemedicine. In the final analysis, only one patient was hospitalized for COVID-19 infection. No deaths due to COVID-19 were reported in elderly cancer patients during this time period. CONCLUSION: Our study is the first to assess modification of patient care in elderly cancer outpatients during an epidemic. With this unprecedented crisis, our objective is to protect our patients from infection via protective barrier measures and social distancing, but also to guarantee the continuity of cancer care without overexposing this fragile population. Physicians were able to adapt their practice and used new forms of management, like telemedicine.

Limited efficacy of lenvatinib in heavily pretreated anaplastic thyroid cancer: a French overview.

Anaplastic thyroid cancer (ATC) is a rare lethal disease. Lenvatinib is an off-label therapeutic option for ATC in most countries, except in Japan. The aim of this multicenter retrospective survey was to analyze the efficacy and the toxicity profile of off-label lenvatinib treatment in all adults advanced ATC patients, in France. Of the 23 patients analysed (14 males; mean age 64 years), 15 were pure ATC and 8 were mixed tumors (i.e. with a differentiated or poorly differentiated component). Prior treatments included neck external beam irradiation in 74%, at least one line of chemotherapy in 22 cases, two lines of chemotherapy in 11 patients, other TKI in 4 cases. A central RECIST assessment was performed. Since lenvatinib initiation, median PFS was 2.7 months (95% CI; 1.9-3.5) and median OS was 3.1 months (95% CI; 0.6-5.5). OS was significantly longer in case of mixed tumors compared with pure ATC (6.3 vs 2.7 months, P = 0.026). Best tumor response was partial response in two cases and stable disease in seven. Clinical improvement was achieved in seven patients. Lethal adverse events occurred in three patients, consisting in haemoptysis in two cases and pneumothorax in one case. Among long-surviving ATC patients (>6 months), four underwent biopsy of distant metastasis, revealing poorly differentiated histology; three of them had initial mixed ATC histology. Efficacy of lenvatinib appears limited, although pure vs mixed ATC disclose differences in disease aggressiveness and treatment response. Long-surviving ATC patients might benefit from biopsy of persistent disease, searching for histological transition or molecular target.

Heme-Iron-Induced Production of 4-Hydroxynonenal in Intestinal Lumen May Have Extra-Intestinal Consequences through Protein-Adduct Formation.

Some epidemiological studies show that heme iron consumption, in red meat, is associated to the development of several chronic diseases, including cancers and cardio-metabolic diseases. As heme iron intestinal absorption is finely regulated, we hypothesized that heme iron may act indirectly, through the peroxidation of dietary lipids, in food or in the intestinal lumen during digestion. This heme-iron-induced lipid peroxidation provokes the generation of toxic lipid oxidation products that could be absorbed, such as 4-hydroxynonenal (HNE). In a first experiment, heme iron given to rats by oral gavage together with the linoleic-acid-rich safflower oil induced the formation of HNE in the intestinal lumen. The HNE major urinary metabolite was elevated in the urine of the treated rats, indicating that this compound has been absorbed. In a second experiment, we showed that stable isotope-labeled HNE given orally to rats was able to reach non-intestinal tissues as a bioactive form and to make protein-adducts in heart, liver and skeletal muscle tissues. The presence of HNE-protein adducts in those tissues suggests a putative biological role of diet-originating HNE in extra-intestinal organs. This finding could have major consequences on the onset/development of chronic diseases associated with red meat over-consumption, and more largely to peroxidation-prone food consumption.

Evaluation of medical practices in oncology in the context of the COVID-19 pandemic in France: Physicians' point of view: the PRATICOVID study.

The cancer population seems to be more susceptible to COVID-19 infection and have worse outcomes. We had to adapt our medical practice to protect our patients without compromising their cancer prognosis. The national PRATICOVID study aims to describe the adaptation of cancer patient care for this population. We analyzed data from nine different institutions. The primary endpoint was to assess the prevalence of adapted patient care during the pandemic. The secondary endpoints were to describe the point of view of clinicians and patients during and after the pandemic. We analyzed 435 medical procedures between 9th of March and 30th of April. Because of the COVID-19 pandemic, 47.6% of the outpatients received modified patient care. Twenty-four percent of scheduled surgeries were postponed, or were performed without perioperative chemotherapy, 18.4% followed a hypofractioned schedule, and 57% had an adaptive systemic protocol (stopped, oral protocol, and spacing between treatments). Seventy percent of physicians used telemedicine. During this period, 67% of the physicians did not feel distressed taking care of their patients. However, 70% of physicians are worried about the aftermath of the lockdown, as regards future patient care. The PRATICOVID study is the first to assess modification of patient care in cancer outpatients during an epidemic. With this unprecedented crisis, physicians were able to adapt their practice in order to protect their patients against the virus while ensuring continuity of patient care. But physicians are worried about the aftereffects of the lockdown specifically in regard to care pathway issues.

Complete response in anaplastic lymphoma kinase-rearranged oncocytic thyroid cancer: A case report and review of literature.

BACKGROUND: Oncocytic carcinoma of the thyroid is a rare disease, characterized by a poor prognosis and low response rate to radioiodine therapy. Crizotinib is a specific anaplastic lymphoma kinase (ALK) inhibitor, which was initially developed in non-small cell lung cancer. Other solid tumors harboring a translocation in ALK have been described, such as renal carcinoma, thyroid, colorectal, ovarian cancers, and spitzoid melanoma. The research of ALK rearrangements in thyroid tumor is a promising therapeutic track, and treatments need to be explored. CASE SUMMARY: We report the case of a 76-year-old woman with a history of multinodular goiter, who was hospitalized for impairment of her general condition. She was diagnosed with metastatic oncocytic thyroid cancer. Synchrone metastases were found: Multiple mediastinal lymphadenopathies, lytic bone lesions and bilateral mammary lumps. Fluorescence in situ hybridization analysis revealed an ALK rearrangement in 61% of cells. No other mutation was found. A tumor board discussion based on molecular characteristics of the tumor suggested initiating a daily treatment by crizotinib, a specific ALK inhibitor. A positron emission tomography scan performed 4 mo after the initiation of crizotinib showed a complete metabolic response. CONCLUSION: This case highlights an unexpected efficacy of crizotinib in an ALK-rearranged thyroid tumor, and the need of further assessments.

Denosumab Toxicity When Combined With Anti-angiogenic Therapies on Patients With Metastatic Renal Cell Carcinoma: A GETUG Study.

BACKGROUND: About one-third of patients with renal cell carcinoma (RCC) have detectable metastases at diagnosis. Among them, bone is the second most frequent metastatic site. Treatment of metastatic RCC mostly relies on anti-angiogenic (AA) therapies and, more recently, immunotherapy. Skeletal-related events (SREs) can be prevented with bone-targeted therapies such as denosumab (Dmab), which has demonstrated superiority when compared with zoledronic acid in solid tumors. However, there is limited available data on Dmab toxicity in combination with AA therapies in patients with kidney cancer. The objective of this study was to retrospectively analyze the toxicity profile (mainly osteonecrosis of the jaw [ONJ] and hypocalcemia) in patients with metastatic renal cell carcinoma (mRCC) treated with Dmab and AA therapy combination. PATIENTS AND METHODS: We conducted a multicenter retrospective study among centers from the French Groupe d'Etudes des Tumeurs Uro Genitales (GETUG). Patients with bone metastases who received concurrently or sequentially AA therapy and Dmab were included in this study. RESULTS: A total of 41 patients with mRCC were enrolled. Although no patient presented with severe hypocalcemia, ONJ occurred in 7 (17%) of 41 patients. Interestingly, all patients with ONJ received the Dmab and AA combination in the first line of treatment; among these patients, 3 patients had no risk factor other than the Dmab and AA combination. CONCLUSION: The incidence of ONJ was high in this real-life population of patients with mRCC treated with AA therapies combined with Dmab. This toxicity signal should warn physicians about this combination in the mRCC population.

Metabolomics Reveals that the Type of Protein in a High-Fat Meal Modulates Postprandial Mitochondrial Overload and Incomplete Substrate Oxidation in Healthy Overweight Men.

Background: A meal rich in saturated fatty acids induces a postprandial metabolic challenge. The type of dietary protein may modulate postprandial metabolism. Objective: We studied the effect of dietary protein type on postprandial changes in the metabolome after a high-fat meal. Methods: In a 3-period, crossover, postprandial study, 10 healthy overweight men with an elevated waist circumference (>94 cm) ingested high-fat meals made up of cream fat (70% of energy), sucrose (15% energy), and protein (15% energy) from either casein (CAS), whey protein (WHE), or α-lactalbumin-enriched whey protein (LAC). Urine collected immediately before and 2, 4, and 6 h after the meal was analyzed for metabolomics, a secondary outcome of the clinical study. We used mixed-effect models, partial least-square regression, and pathway enrichment analysis. Results: At 4 and 6 h after the meal, the postprandial metabolome was found to be fully discriminated according to protein type. We identified 17 metabolites that significantly explained the effect of protein type on postprandial metabolomic changes (protein-time interaction). Among this signature, acylcarnitines and other acylated metabolites related to fatty acid or amino acid oxidation were the main discriminant features. The difference in metabolic profiles was mainly explained by urinary acylcarnitines and some other acylated products (protein type, Ps < 0.0001), with a dramatically greater increase (100- to 1000-fold) after WHE, and to a lesser extent after LAC, as compared with CAS. Pathway enrichment analysis confirmed that the type of protein had modified fatty acid oxidation (P < 0.05). Conclusion: Taken together, our results indicate that, in healthy overweight men, the type of protein in a high-fat meal interplays with fatty acid oxidation with a differential accumulation of incomplete oxidation products. A high-fat meal containing WHE, but not CAS, resulted in this outpacing of the tricarboxylic acid cycle. This study was registered at clinicaltrials.gov as NCT00931151.

Simultaneous analysis of regorafenib and sorafenib and three of their metabolites in human plasma using LC-MS/MS.

A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, performed by electrospray ionization in positive mode using a triple quadrupole mass spectrometry, has been developed and validated for the simultaneous determination of regorafenib (REGO), its two metabolites regorafenib-M2 and regorafenib-M5, sorafenib (SORA), and its N-oxide metabolite in human plasma. Separation is achieved on an Hypersil Gold® column using a gradient elution of 10mM ammonium formate containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B) at a flow rate of 0.3mL/min. After addition of two internal standards and a protein precipitation, the supernatant is diluted two-fold in a 0.1% (v/v) formic acid solution. Two selected reaction monitoring transitions are used, for each analyte, one for quantitation and the second one for confirmation. The standard curves are ranged from 50 to 5 000ng/mL for REGO and its metabolites and 80 to 5 000ng/mL for SORA and its metabolite and were fitted to a 1/x weighted linear regression model. The method also showed satisfactory results in terms of sensitivity, specificity, precision (intra- and inter-day CV from 2.4 to 10.2%), accuracy (from 91.0 to 111.7%), recovery as well as stability of the analytes under various conditions. The method is usually used in clinical practice in order to improve the SORA treatment for renal carcinoma, REGO treatment for colorectal cancer and both for hepatocellular carcinoma.

Polymerase proofreading domain mutations: New opportunities for immunotherapy in hypermutated colorectal cancer beyond MMR deficiency.

Immune checkpoint inhibition is a new therapeutic strategy that has shown promising efficacy in many cancer types. Significant activity associated with mismatch repair (MMR) deficiency has been observed in hypermutated, microsatellite unstable (MSI) metastatic colorectal cancer (CRC). Beyond deficient-MMR tumors, somatic or germline DNA polymerase D1 (POLD1) or DNA polymerase E (POLE) alterations cause a hypermutated phenotype in CRC. This recently identified and rare subgroup of proficient-MMR tumors may also benefit from immunotherapy. In this review, we provide a comprehensive overview of recent data on CRC tumors harboring POLD1 or POLE mutations, with a focus on their molecular, histological, and clinical features. We also examine the evidence supporting the development of immune checkpoint inhibitors in this specific subgroup of CRC patients.

[De novo cancer after solid organ transplantation: Epidemiology, prognosis and management]. / Cancers solides après transplantation d'organe : épidémiologie, pronostic et spécificités de prise en charge.

The risk of cancer after solid organ transplantation is increased by 2.6 compared to overall population. Cancer is currently the third leading cause of death in solid organ transplanted patients, making screening and early management of de novo cancers a major challenge. This increased risk of cancer in this population results from the combination of known environmental risk factors of cancer, comorbidities of transplanted patients, and exposure to chronic immunosuppression. The prognosis of cancer in these patients seems poorer as compared to other cancer patients owing to their comorbidities, the immunosuppression and patient's poorer tolerance to oncologic treatment. Moreover, interactions between immunosuppressive agents and antitumor therapies must be taken into account in the therapeutic strategy. Better knowledge of the specificities of solid organ transplanted patients with de novo cancer is required to improve cancer care in this patient population. This article aims to review the current data available on de novo cancers in solid organ transplanted patients, with a focus on epidemiology, risks factors of de novo cancers, impact of immunosuppressive drugs and oncologic prognosis.

First-line antiangiogenics for metastatic renal cell carcinoma: A systematic review and network meta-analysis.

BACKGROUND: Sunitinib, pazopanib, sorafenib, axitinib and bevacizumab are the five recommended antiangiogenic agents in first-line therapy for metastatic renal cell carcinoma (mRCC). Because these drugs underwent simultaneous clinical development, no direct efficacy and safety comparison was ever conducted, thus preventing optimal therapy choices. METHODS: We performed a traditional and network meta-analysis to evaluate the efficacy and safety of mRCC-recommended first-line antiangiogenic agents. After a systematic review of Medline and Embase up to July 2014, we identified randomized clinical trials (RCTs) evaluating the outcomes of mRCC patients treated with sunitinib, pazopanib, sorafenib, axitinib and bevacizumab as first-line treatment. Endpoints of interest were response rate, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: We screened 769 abstracts and included nine RCTs with a total of 4282 patients. In the weighted pooled analysis, first-line antiangiogenic agents showed significant improvement in PFS (HR=0.6; 95% IC, 0.51-0.72) and OS (HR=0.85; 95% IC, 0.78-0.93) compared to control (placebo or interferon-alpha2a (INF)). Network meta-analysis showed no significant differences among antiangiogenic drugs in 6-month PFS, 1-year OS, disease control rate and drug-related safety for all-grade hypertension, diarrhea, weight-loss, nausea or anorexia. However, pazopanib showed a lower incidence of fatigue, anemia and hand foot skin reaction. CONCLUSIONS: This meta-analysis confirms the benefits of first-line antiangiogenic therapy in mRCC, with an improvement in OS. Sunitinib, pazopanib, axitinib and bevacizumab + INF offer similar efficacy but different safety profiles which can help clinicians to better personalize treatment decisions in patients with mRCC.

Red meat and colorectal cancer: Nrf2-dependent antioxidant response contributes to the resistance of preneoplastic colon cells to fecal water of hemoglobin- and beef-fed rats.

Epidemiological studies have associated red meat intake with risk of colorectal cancer. Experimental studies explain this positive association by the oxidative properties of heme iron released in the colon. This latter is a potent catalyst for lipid peroxidation, resulting in the neoformation of deleterious aldehydes in the fecal water of heme-fed rats. The toxicity of fecal water of heme-fed rats was associated to such lipid peroxidation. This study demonstrated that fecal water of hemoglobin- and beef-fed rats preferentially induced apoptosis in mouse normal colon epithelial cells than in those carrying mutation on Apc (Adenomatous polyposis coli) gene, considered as preneoplastic. Highlighting the importance of lipid peroxidation and neoformation of secondary aldehydes like 4-hydroxy-2-nonenal (HNE), we optimized the depletion of carbonyl compounds in the fecal water which turned out to abolish the differential apoptosis in both cell lines. To explain the resistance of preneoplastic cells towards fecal water toxicity, we focused on Nrf2, known to be activated by aldehydes, including HNE. Fecal water activated Nrf2 in both cell lines, associated with the induction of Nrf2-target genes related to aldehydes detoxification. However, the antioxidant defense appeared to be higher in preneoplastic cells, favoring their survival, as evidenced by Nrf2 inactivation. Taken together, our results suggest that Nrf2-dependent antioxidant response was involved in the resistance of preneoplastic cells upon exposure to fecal water of hemoglobin- and beef-fed rats. This difference could explain the promoting effect of red meat and heme-enriched diet on colorectal cancer, by initiating positive selection of preneoplastic cells.

Assessment of protein modifications in liver of rats under chronic treatment with paracetamol (acetaminophen) using two complementary mass spectrometry-based metabolomic approaches.

Liver protein can be altered under paracetamol (APAP) treatment. APAP-protein adducts and other protein modifications (oxidation/nitration, expression) play a role in hepatotoxicity induced by acute overdoses, but it is unknown whether liver protein modifications occur during long-term treatment with non-toxic doses of APAP. We quantified APAP-protein adducts and assessed other protein modifications in the liver from rats under chronic (17 days) treatment with two APAP doses (0.5% or 1% of APAP in the diet w/w). A targeted metabolomic method was validated and used to quantify APAP-protein adducts as APAP-cysteine adducts following proteolytic hydrolysis. The limit of detection was found to be 7ng APAP-cysteine/mL hydrolysate i.e. an APAP-Cys to tyrosine ratio of 0.016‰. Other protein modifications were assessed on the same protein hydrolysate by untargeted metabolomics including a new strategy to process the data and identify discriminant molecules. These two complementary mass spectrometry (MS)-based metabolic approaches enabled the assessment of a wide range of protein modifications induced by chronic treatment with APAP. BIOLOGICAL SIGNIFICANCE: APAP-protein adducts were detected even in the absence of glutathione depletion and hepatotoxicity, i.e. in the 0.5% APAP group, and increased by 218% in the 1% APAP group compared to the 0.5% APAP group. At the same time, the untargeted metabolomic method revealed a decrease in the binding of cysteine, cysteinyl-glycine and GSH to thiol groups of protein cysteine residues, an increase in the oxidation of tryptophan and proline residues and a modification in protein expression. This wide range of modifications in liver proteins occurred in rats under chronic treatment with APAP that did not induce hepatotoxicity.

[Primary mediastinal germs cells tumors: a twenty years experience in a comprehensive cancer center]. / Tumeurs germinales primitives du médiastin : expérience de l'Institut de cancérologie de Lorraine sur une période de 20 ans (1990-2012).

UNLABELLED: The aim of this study is to report treatments results of patients with primary germ cell tumors (GCTs) of mediastinum. METHODS: A retrospective review was done of 19 consecutive patients with mediastinal GCTs treated in "Institut de cancérologie de Lorraine" between 1990 and 2012. RESULTS: A total of 19 patients were enrolled in this study. Three patients had pure seminoma and 16 patients had non-seminomatous germ cell tumors. All patients were treated with cisplatinum based chemotherapy at a dose of 33.48 mg/m(2)/week. At the end of chemotherapy, three patients (15.8%) had complete response and negative marker, seven of them (36.8%) had partial response and negative marker, five of them (26.32%) had partial response and positive marker, three of them (15.8%) had progressive disease (refractory disease) and one patient died because of the disease during treatment. The 1-year and 5-year overall survival rates were respectively 78 and 36% and the progression-free survival rate was 43%. When relapse occurred, this happened within a 13 month period. CONCLUSION: Our study confirmed the good management of mediastinal GCTs in our institute with similar results compared to literature.