Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiotherapy in patients with locally advanced rectal cancer: long-term results of the UNICANCER-PRODIGE 23 trial.

BACKGROUND: The standard of care for the treatment of locally advanced rectal cancer results in an excellent local disease control but the metastasis rates remain high. PRODIGE 23 demonstrated improved disease-free and metastatic-free survival with total neoadjuvant therapy versus standard of care in this population. Long-term analysis of overall survival is reported here. PATIENTS AND METHODS: The study design, participants, and primary endpoint disease-free survival (DFS) have been reported for this multicenter, randomized, open-label, phase 3 trial investigating the neoadjuvant chemotherapy with mFOLFIRINOX (6 cycles) followed by chemoradiotherapy, surgery, and adjuvant chemotherapy (6 cycles), versus chemoradiotherapy, surgery, and adjuvant chemotherapy (12 cycles) in patients with locally advanced rectal adenocarcinoma under peritoneal reflection on MRI, and staged cT3/T4. Key secondary endpoints included overall survival (OS), metastasis-free survival (MFS), and local and metastatic recurrence rate. RESULTS: With a median follow-up of 82.2 months, the 7-year DFS were 67.6% (95% CI 60.7%-73.9%) and 62.5% (95% CI 55.6%-68.6%) (RMST difference 5.73 months; 95% CI 0.05-11.41; p=0.048) in the neoadjuvant chemotherapy and the standard of care groups, respectively. The 7-year MFS was 79.2% (95% CI 73.0%-84.4%) in the neoadjuvant chemotherapy group and 72.3% (95% CI 65.8%-77.8%) in the standard of care group (RMST difference 6.1 months; 95% CI 0.93-11.37; p=0.021). The 7-year OS was 81.9% (95% CI 75.8%-86.6%) in the neoadjuvant chemotherapy group and 76.1% (95% CI 69.7-81.2) in the standard of care group (RMST difference 4.37 months; 95% CI 0.35-8.38; p=0.033). The safety profile remained unchanged since the previous analysis. CONCLUSION(S): Neoadjuvant chemotherapy with mFOLFIRINOX followed by chemoradiotherapy improved OS, confirmed long-term DFS and MFS benefits in locally advanced rectal cancer patients and should be considered as a one of the best options of care for these patients.

Leucovorin and Fluorouracil With or Without Oxaliplatin as First-Line Treatment in Advanced Colorectal Cancer.

PURPOSE: In a previous study of treatment for advanced colorectal cancer, the LV5FU2 regimen, comprising leucovorin (LV) plus bolus and infusional fluorouracil (5FU) every 2 weeks, was superior to the standard North Central Cancer Treatment Group/Mayo Clinic 5-day bolus 5FU/LV regimen. This phase III study investigated the effect of combining oxaliplatin with LV5FU2, with progression-free survival as the primary end point. PATIENTS AND METHODS: Four hundred twenty previously untreated patients with measurable disease were randomized to receive a 2-hour infusion of LV (200 mg/m2/d) followed by a 5FU bolus (400 mg/m2/d) and 22-hour infusion (600 mg/m2/d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin 85 mg/m2 as a 2-hour infusion on day 1. RESULTS: Patients allocated to oxaliplatin plus LV5FU2 had significantly longer progression-free survival (median, 9.0 v 6.2 months; P = .0003) and better response rate (50.7% v 22.3%; P = .0001) when compared with the control arm. The improvement in overall survival did not reach significance (median, 16.2 v 14.7 months; P = .12). LV5FU2 plus oxaliplatin gave higher frequencies of National Cancer Institute common toxicity criteria grade 3/4 neutropenia (41.7% v 5.3% of patients), grade 3/4 diarrhea (11.9% v 5.3%), and grade 3 neurosensory toxicity (18.2% v 0%), but this did not result in impairment of quality of life (QoL). Survival without disease progression or deterioration in global health status was longer in patients allocated to oxaliplatin treatment (P = .004). CONCLUSION: The LV5FU2-oxaliplatin combination seems beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged progression-free survival with acceptable tolerability and maintenance of QoL.

KI and TEDA influences towards the retention of radiotoxic CH3I by activated carbons.

Activated carbons (AC) are widely used within the ventilation networks of nuclear facilities to trap volatile iodine species. In this paper, the performances of various commercial activated carbons towards the trapping of γ-labelled methyl iodide were evaluated in semi-pilot scale under different R.H. according to normalized procedures. A combination between the retention performances and the physico-chemical properties as deduced from several techniques was performed to gain insights about the AC influencing parameters on γ-CH3I capture. Different trends were obtained depending on the impregnant nature and the studied conditions. A high sensitivity of KI/AC towards water vapor was outlined. At R.H. = 40%. The enhancement of water uptake by KI/AC as deduced from water adsorption experiments, leads to decrease the available microporosity for CH3I physisorption, inducing therefore the reduction of performances as a function of KI content at these conditions. At R.H. = 90%, the adsorption mechanism was found to be governed by isotopic exchange reaction since 90% of the microporosity was occupied by water molecules. Therefore, a slight increase of DF was obtained in these conditions. This sensitivity was found to be of a lesser extent for TEDA/AC displaying the highest retention performances whatever the studied condition.

Tumor budding is an independent prognostic factor in stage III colon cancer patients: a post-hoc analysis of the IDEA-France phase III trial (PRODIGE-GERCOR).

BACKGROUND: Histological characteristics at the invasive front may reflect tumor aggressiveness; specifically, tumor budding (Bd) is an emerging prognostic biomarker in colon cancer (CC). We explored further the significance of Bd for risk stratification by evaluating survival of stage III CC patients included in the IDEA-France phase III trial. PATIENTS AND METHODS: This post-hoc study was conducted on tissue slides from 1048 stage III CC patients. Bd was scored by central review by the Bd criteria of the 2016 International Tumor Budding Consensus Conference (ITBCC 2016) and classified as Bd1 (0-4 buds/0.785 mm2), Bd2 (5-9 buds), and Bd3 (≥10 buds) categories. Disease-free survival (DFS) and overall survival (OS) were analyzed by the log-rank test. Clinicopathological features and Immunoscore® were correlated with Bd. RESULTS: Overall, Bd1, Bd2, and Bd3 were observed in 39%, 28%, and 33% of CC, respectively. Bd2 and Bd3 were associated with vascular (P = 0.002) and perineural invasions (P = 0.0009). The 3-year DFS and the 5-year OS rates for Bd (1 versus 2-3) were 79.4% versus 67.2% (P = 0.001) and 89.2% versus 80.8% (P = 0.001), respectively. This was confirmed after adjustment for relevant clinicopathological features for DFS [hazard ratio (HR) 1.41, 95% confidence interval (CI) 1.12-1.77, P = 0.003] and OS (HR 1.65, 95% CI 1.22-2.22, P = 0.001). When combined with pTN stage and Immunoscore® subgroups, Bd significantly improved disease prognostication. CONCLUSIONS: Bd demonstrated its independent prognostic value for DFS and OS. Given these findings, Bd as per the ITBCC 2016 should be mandatory in every pathology report in stage III CC patients. Bd and Immunoscore® could play a complementary role in personalized health care in this setting.

%TTD and %TUDD: New SAS macro programs to calculate the survival data of the time to deterioration for patient-reported outcomes data in oncology.

BACKGROUND AND OBJECTIVE: Longitudinal analysis of patient-reported outcome (PRO) data remains challenging, as no standardization of statistical methods has been proposed, making comparison of PRO results between clinical trials difficult. In this context, the time to deterioration approach has recently been proposed and is regularly used as a modality of longitudinal PRO analysis in oncology. METHODS: Two new SAS macro programs were developed, %TTD and %TUDD, which implement longitudinal analysis of PRO data according to the time to deterioration approach. These programs implement the recommended deterioration definitions. We described the programs with their different functionalities. RESULTS: The %TTD macro calculates the time to first or transient deterioration, and the %TUDD macro calculates the time until definitive deterioration. These macros allow to obtain the survival variables from the time to deterioration approach. We illustrate our programs by presenting different applications on the randomized phase II AFUGEM GERCOR clinical trial. CONCLUSION: The implementation of the deterioration definitions in SAS software allows the dissemination of this approach, in order to move toward the goal of standardization of longitudinal PRO analysis in oncology clinical trials.

Effects of water vapour and temperature on the retention of radiotoxic CH3I by silver faujasite zeolites.

In this work, Ag/X and Ag/Y faujasite zeolites were evaluated as candidate sorbents for the retention of methyl iodide under conditions close to those expected in a severe nuclear accident. Different categories of tests were conducted from laboratory to semi-pilot scales. First, the effects of temperature and water vapour on the CH3I retention/decomposition mechanism were investigated under lab-scale conditions. More specifically, the CH3I adsorption capacities and the fate of its main decomposition products (oxygenated compounds and alkanes) were measured under dynamic conditions at different temperatures (35, 100 and 250 °C). Then, the decontamination factors of Ag/X and Ag/Y silver faujasites exchanged with different silver contents were monitored according to the time on stream using a very low CH3I concentration (1 ppmv). Finally, a parametric study was conducted at semi-pilot scale using realistic [CH3I]/[H2O] molar ratio ≈ 10-6 and temperatures in the range 20-90 °C. Those experiments were helpful in order to assess the effects of some important parameters relevant to the adsorbents or operating conditions.

Bariatric surgery affects obesity-related protein requirements.

CONTEXT: Following bariatric surgery, protein deficiency intakes are reported in morbidly obese patients, whereas post-bariatric protein requirements are not specifically defined with validated method in this population. OBJECTIVE: To assess average protein requirement (APR) in obese subjects, before, 3 months and 12 months after bariatric surgery using the validated method of nitrogen balance. DESIGN AND SETTING: Prospective longitudinal study conducted in 21 morbidly obese patients (BMI 43.9 ± 1.4 kg/m2) before (M0), 3 months (M3) and 12 months (M12) after sleeve gastrectomy or Roux-en-Y gastric by-pass. An additional larger cross-sectional study was performed to validate APR before surgery in non-operated matched obese patients (n = 106). APR was evaluated at M0, M3, M12 by measuring 3 days dietary intakes together with losses of nitrogen in urine and stools. MAIN OUTCOME MEASURE: APR was defined as the mean value of protein intake required to achieve balance nitrogen equilibrium. RESULTS: Before surgery, APR in morbidly obese patients was 0.76 [95%CI, 0.66-0.92] g/kg Body Weight (BW)/d in the experimental group, and 0.74 [0.70-0.80] g/kg BW/d in the validation group. APR was 0.62 [0.51-0.75] g/kg/d at M3 and 0.87 [0.75-0.98] g/kg/d at M12, with no difference between surgical procedures. Spontaneous protein intakes were respectively 0.80 ± 0.05, 0.43 ± 0.03 and 0.71 ± 0.04 g/kg BW/d respectively at M0, M3 and M12. CONCLUSION: This study demonstrates a temporal change in protein requirement after bariatric surgery whatever the type of surgery. Spontaneous protein intakes following bariatric surgery does not cover protein requirements for most patients, suggesting that specific dietary protein recommandations have to be adapted in obese patients with bariatric surgery. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01249326.

Prognostic and predictive value of the Immunoscore in stage III colon cancer patients treated with oxaliplatin in the prospective IDEA France PRODIGE-GERCOR cohort study.

BACKGROUND: The Immunoscore (IS), which prognostically classifies stage I-III colon cancer (CC) patients, was evaluated in the International Duration Evaluation of Adjuvant Therapy (IDEA) France cohort study investigating 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy in stage III CC patients. PATIENTS AND METHODS: Densities of CD3+ and CD8+ T cells in the tumor and invasive margin were determined by immunohistochemistry, quantified by digital pathology, and converted to IS. Mismatch repair status was determined by immunohistochemistry or by pentaplex PCR. Prediction of disease-free survival (DFS) by IS was analyzed by a multivariable Cox regression model in each study arm. Harrell's C-statistics were used to investigate the IS performance. RESULTS: Samples of 1322 patients were available. IS Low, Intermediate (Int), and High were observed in 43.6%, 47.0%, and 9.4% of patients, respectively. IS Low identified patients at higher risk of relapse or death compared with Int + High [hazard ratio (HR) = 1.54; 95% confidence interval (CI) 1.24-1.93, P = 0.0001]. The 3-year DFS was 66.80% (95% CI 62.23-70.94) for IS Low and 77.14% (95% CI 73.50-80.35) for IS Int + High. In multivariable analysis, IS remained significantly independently associated with DFS (P = 0.003) when adjusted for sex, histological grade, T/N stage, and microsatellite instability. For mFOLFOX6-treated patients (91.6% of the cohort), a statistical significant interaction was observed for the predictive value of IS for treatment duration (3 versus 6 months) in terms of DFS (P = 0.057). IS Int + High significantly predicted benefit of 6 months of treatment (HR = 0.53; 95% CI 0.37-0.75; P = 0.0004), including clinically low- and high-risk stage III CC (all P < 0.001). Conversely, patients with IS Low (46.4%) did not significantly benefit from the 6-month mFOLFOX6 versus the 3-month mFOLFOX6. CONCLUSIONS: The prognostic value of IS for DFS was confirmed in patients with stage III CC treated with oxaliplatin-based chemotherapy. Its predictive value for DFS benefit of longer duration of mFOLFOX6 adjuvant treatment was found in IS Int + High. These results will be validated in an external independent cohort. CLINICALTRIALS. GOV REGISTRATION: NCT03422601; EudraCT Number: 2009-010384-16.

Investigations of the MGy dose level radiation effects on the photometric budget of a radiation-hardened CMOS-based camera.

We studied the impact of ionizing radiation at high dose levels (megagray, MGy) on the photometric budget of a radiation-resistant complementary metal oxide semi-conductor (CMOS)-based camera. This is achieved by measuring the radiation-induced degradation of each subpart, namely its illumination system, its optical system, and its CMOS image sensor. The acquired experimental results allow performing a rather realistic simulation of the radiation effects at the system level. Thanks to appropriate mitigation techniques, limited image darkening and color change are obtained at MGy dose levels. The presented results confirm the feasibility of a CMOS-based camera able to resist to MGy dose level of ionizing radiations with an acceptable degradation of the image quality, opening the way to its implementation in the most challenging harsh environments.

Prognostic factors in patients treated with second-line chemotherapy for advanced gastric cancer: results from the randomized prospective phase III FFCD-0307 trial.

AIM: The aim of this study was to determine prognostic factors in patients treated with second-line therapy (L2) for locally advanced or metastatic gastric and gastro-esophageal junction (GEJ) adenocarcinoma in a randomized phase III study with predefined L2. METHODS: In the FFCD-0307 study, patients were randomly assigned to receive in L1 either epirubicin, cisplatin, and capecitabine (ECX arm) or fluorouracil, leucovorin, and irinotecan (FOLFIRI arm). L2 treatment was predefined (FOLFIRI for the ECX arm and ECX for the FOLFIRI arm). Chi square tests were used to compare the characteristics of patients treated in L2 with those of patients who did not receive L2. Prognostic factors in L2 for progression-free survival (PFS) and overall survival (OS) were analyzed using a Cox model. RESULTS: Among 416 patients included, 101/209 (48.3%) patients in the ECX arm received FOLFIRI in L2, and 81/207 (39.1%) patients in the FOLFIRI arm received ECX in L2. Patients treated in L2, compared with those who only received L1 had : a better ECOG score (0-1: 90.4% versus 79.7%; p = 0.0002), more frequent GEJ localization (40.8% versus 27.6%; p = 0.005), and lower platelet count (median: 298000 versus 335000/mm3; p = 0.02). In multivariate analyses, age < 60 years at diagnosis (HR 1.49, 95% CI 1.09-2.03, p = 0.013) and ECOG score 2 before L2 (HR 2.62, 95% CI 1.41-4.84, p = 0.005) were the only significant poor prognostic factors for OS. CONCLUSION: Age ≥ 60 years at diagnosis and ECOG score 0/1 before L2 were the only favorable prognostic factors for OS.

Oxaliplatin, 5-Fluorouracil and Nab-paclitaxel as perioperative regimen in patients with resectable gastric adenocarcinoma: A GERCOR phase II study (FOXAGAST).

BACKGROUND: 5-Fluorouracil (5-FU) and platinum-based perioperative chemotherapy is standard of care for resectable gastric adenocarcinoma (RGA). Nanoparticle albumin-bound (Nab-) paclitaxel is active in advanced disease but has never been evaluated in the perioperative setting. The objective was to evaluate the efficacy of Nab-paclitaxel in combination with FOLFOX for RGA patients. METHODS: We performed a non-randomised, open-label, phase II study. RGA patients were assigned to receive neoadjuvant Nab-paclitaxel (150 mg/m2) and FOLFOX q2w for six cycles. Six additional post-operative cycles were kept at the investigator's discretion. The primary end-point was complete pathological response (tumour regression grade [TRG1]) rate. According to Fleming design, 49 patients were required to test H0 (10% TRG1) and H1 (25% TRG1). To reject H0, TRG1 had to be achieved in 8 patients. RESULTS: Forty-nine patients were included. Median number of neoadjuvant chemotherapy cycles was 6 (range, 3-6). Median dose intensity for Nab-paclitaxel, oxaliplatin and 5-FU was 96% (38-103%), 97% (47-103%) and 99% (50-112%), respectively. Surgery could not be performed in 5 (10.2%) patients. Tumour resection was R0 for 42 of 44 (95.5%) patients. Pathological review classified tumours as TRG1 to TRG5 for 8 (16.3%), 11 (22.5%), 4 (8.2%), 18 (36.7%) and 3 (6.1%) patients, respectively. Grade 3 or worse toxicities during neoadjuvant chemotherapy were non-febrile neutropenia (20.4%), nausea (8.2%), diarrhoea (8.2%) and neuropathy (6.1%). Of 44 patients, 14 (31.8%) experienced surgery-related complications and three (6.8%) died of surgical complications. CONCLUSION: This regimen shows promising activity. Toxicity is manageable but a meaningful rate of surgical complications was observed. This strategy deserves investigation in phase III studies.

Accuracy of staging laparoscopy in detecting peritoneal dissemination in patients with gastroesophageal adenocarcinoma.

Despite staging laparoscopy (SL) with peritoneal lavage is recommended in US Guidelines in patients with potentially resectable gastroesophageal adenocarcinoma, this procedure is not systematically proposed in French Guidelines. Therefore, we decided to analyze the results of systematic SL in patients considered for preoperative chemotherapy. From 2005 to 2011, 116 consecutive patients with distal esophagus, esogastric junction, and gastric adenocarcinoma ≥T3 or N+ without detectable metastatic dissemination by computed tomography (CT) scan imaging underwent SL before neoadjuvant chemotherapy. Positive and negative SLs were compared according to tumor characteristics. SL was positive in 15 cases (12.9%) including 14 with peritoneal seeding (localized in five, diffuse in nine). SL was positive in 7 (24.1%) of 29 patients with poorly differentiated tumor, in 9 (32.1%) of 28 patients with signet ring cells, in 7 (50%) of 14 patients with gastric linitis tumor, and in 15 (16.3%) of 92 patients with T3 or T4 tumor. All the lesions of distal esophagus extending to the cardia had a negative SL. Among the 14 patients with peritoneal carcinomatosis at SL, nine (65%) had signs of peritoneal seeding on initial CT scan. One (0.8%) patient had a small bowel perforation closed laparoscopically. If systematic SL before preoperative chemotherapy does not seem justified because of its low accuracy, it should be performed in patients with poorly differentiated tumor, signet ring cell, and gastric linitis plastica components on biopsy and when CT scan is suggestive of T4 tumor, ascites, or peritoneal nodule.

Laparoscopic two-stage hepatectomy for bilobar colorectal liver metastases.

BACKGROUND: Despite the gradual diffusion of laparoscopic liver resection, the feasibility and results of laparoscopic two-stage hepatectomy (TSH) for bilobar colorectal liver metastases (CRLM) have not been described frequently. This study aimed to evaluate the feasibility, safety and oncological outcomes of laparoscopic TSH for bilobar CRLM. METHODS: All patients eligible for laparoscopic TSH among those treated for bilobar CRLM from 2000 to 2013 were included. Demographics, tumour characteristics, surgical procedures, and short- and long-term outcomes were analysed. RESULTS: Laparoscopic TSH was planned in 34 patients with bilobar CRLM, representing 17·2 per cent of all 198 patients treated for bilobar CRLM. Thirty patients received preoperative chemotherapy, and 20 had portal vein occlusion to increase the volume of the remnant liver. Laparoscopic resection of the primary colorectal tumour was integrated within the first-stage hepatectomy in 11 patients. After a median interval of 3·1 months, 26 patients subsequently had a successful laparoscopic second-stage hepatectomy, including 18 laparoscopic right or extended right hepatectomies. The mortality rate for both stages was 3 per cent (1 of 34), and the overall morbidity rate for the first and second stages was 50 per cent (17 of 34) and 54 per cent (14 of 26) respectively. Mean length of hospital stay was 6·1 and 9·0 days respectively. With a median follow-up of 37·8 (range 6-129) months, 3- and 5-year overall survival rates in patients who completed TSH were 78 and 41 per cent respectively. The 3- and 5-year disease-free survival rates were 26 and 13 per cent respectively. CONCLUSION: Laparoscopic TSH for bilobar CRLM is safe and does not jeopardize long-term outcomes in selected patients.

Production of reference sources of radioactive aerosols in filters for proficiency testing.

In the framework of the organization of proficiency testing, filters with deposits of 137Cs and 90Sr+90Y radioactive aerosols have been submitted to laboratories for radionuclide measurement. Procedures for the special preparation and characterization of filters have been developed. The different steps of filter preparation, determination of the deposited radionuclide activity and characterization of the homogeneity of these deposits are presented. This method of filter preparation can also be used in the production of secondary standards, whose properties are more adapted to the needs of laboratories measuring radioactivity in filters than are the solid sources that they typically use.

FOLFOX4 versus sequential dose-dense FOLFOX7 followed by FOLFIRI in patients with resectable metastatic colorectal cancer (MIROX): a pragmatic approach to chemotherapy timing with perioperative or postoperative chemotherapy from an open-label, randomized phase III trial.

BACKGROUND: Perioperative FOLFOX4 (oxaliplatin plus 5-fluorouracil/leucovorin) chemotherapy is the current standard in patients with resectable metastases from colorectal cancer (CRC). We aimed to determine whether a sequential chemotherapy with dose-dense oxaliplatin (FOLFOX7) and irinotecan (FOLFIRI; irinotecan plus 5-fluorouracil/leucovorin) is superior to FOLFOX4. The chemotherapy timing was not imposed, and was perioperative or postoperative. PATIENTS AND METHODS: In this open-label, phase III trial, patients with resectable or resected metastases were randomly assigned either to 12 cycles of FOLFOX4 (oxaliplatin 85 mg/m(2)) or 6 cycles of FOLFOX7 (oxaliplatin 130 mg/m(2)) followed by 6 cycles of FOLFIRI (irinotecan 180 mg/m(2)). Randomization was done centrally, with stratification by chemotherapy timing, type of local treatment (surgery versus radiofrequency ablation with/without surgery), and Fong's prognostic score. The primary end point was 2-year disease-free survival (DFS). RESULTS: A total of 284 patients were randomized, 142 in each treatment group. Chemotherapy was perioperative in 168 (59.2%) patients and postoperative in 116 (40.8%) patients. Perioperative chemotherapy was preferentially proposed for synchronous metastases, whereas postoperative chemotherapy was more frequently used for metachronous metastases. Two-year DFS was 48.5% in the FOLFOX4 group and 50.0% in the FOLFOX7-FOLFIRI group. In the multivariable analysis, more than one metastasis [hazard ratio (HR) = 2.15] and synchronous metastases (HR = 1.63) were independent prognostic factors for shorter DFS. Five-year overall survival (OS) rate was 69.5% with FOLFOX4 versus 66.6% with FOLFOX7-FOLFIRI. CONCLUSIONS: FOLFOX7-FOLFIRI is not superior to FOLFOX4 in patients with resectable metastatic CRC. Five-year OS rates observed in both groups are the highest ever reported in this setting, possibly reflecting the pragmatic approach to chemotherapy timing. CLINICAL TRIALS NUMBER: NCT00268398.

[Concurrent association of reirradiation therapy with everolimus for lymph node metastasis of gastroesophageal junction cancer: a case report]. / Réirradiation de métastases ganglionnaires d'un adénocarcinome œsogastrique par une technique de tomothérapie associée à de l'évérolimus.

Advanced gastric cancer or gastro-oesophageal junction cancer after a failure of first line chemotherapy have poor outcome. Hereby, we present the first patient treated by radiotherapy with concurrent everolimus, a mTor inhibitor, for a reirradiation of metastasis invading left axillary, infraclavicular and supraclavicular lymph nodes in progression despite several lines of chemotherapy. After 6 months of follow-up, this association provided a satisfactory anti-tumor efficiency and tolerance. Nevertheless, clinical trials are needed in order to confirm this strategy for the treatment of gastric cancer metastasis.

Autologous dendritic cells prolong allograft survival through Tmem176b-dependent antigen cross-presentation.

The administration of autologous (recipient-derived) tolerogenic dendritic cells (ATDCs) is under clinical evaluation. However, the molecular mechanisms by which these cells prolong graft survival in a donor-specific manner is unknown. Here, we tested mouse ATDCs for their therapeutic potential in a skin transplantation model. ATDC injection in combination with anti-CD3 treatment induced the accumulation of CD8(+) CD11c(+) T cells and significantly prolonged allograft survival. TMEM176B is an intracellular protein expressed in ATDCs and initially identified in allograft tolerance. We show that Tmem176b(-/-) ATDCs completely failed to trigger both phenomena but recovered their effect when loaded with donor peptides before injection. These results strongly suggested that ATDCs require TMEM176B to cross-present antigens in a tolerogenic fashion. In agreement with this, Tmem176b(-/-) ATDCs specifically failed to cross-present male antigens or ovalbumin to CD8(+) T cells. Finally, we observed that a Tmem176b-dependent cation current controls phagosomal pH, a critical parameter in cross-presentation. Thus, ATDCs require TMEM176B to cross-present donor antigens to induce donor-specific CD8(+) CD11c(+) T cells with regulatory properties and prolong graft survival.