Loss of SMARCB1 expression in colon carcinoma.

SMARCB1 is a tumor suppressor gene, which is part of SWI/SNF complex involved in transcriptional regulation. Recently, loss of SMARCB1 expression has been reported in gastrointestinal carcinomas. Our purpose was to evaluate the incidence and prognostic value of SMARCB1 loss in colon carcinoma (CC). Patients with stage III CC (n= 1695), and a second cohort of 23 patients with poorly differentiated CC were analyzed. Immunohistochemistry for SMARCB1 was performed on tissue microarrays, and cases with loss of expression were controlled on whole sections. Loss of SMARCB1 was compared with the clinico-pathological and molecular characteristics, and the prognostic value was evaluated. Loss of SMARCB1 was identified in 12 of 1695 (0.7%) patients with stage III CC. Whole section controls showed a complete loss in only one of these cases, corresponding to a medullary carcinoma. SMARCB1 loss was not associated with histological grade, tumor size nor survival. In the cohort of poorly differentiated CC, we detected 2/23 (8.7%) cases with loss of SMARCB1; one was rhabdoid while the other had medullary and mucinous histology. These 2 cases were deficient for MisMatched Repair (dMMR) and mutated for BRAF. SMARCB1 loss is rare in stage III CC, but appears more frequent in poorly differentiated CC.

Perioperative FOLFOX 4 Versus FOLFOX 4 Plus Cetuximab Versus Immediate Surgery for High-Risk Stage II and III Colon Cancers: A Phase II Multicenter Randomized Controlled Trial (PRODIGE 22).

BACKGROUND: Perioperative chemotherapy has proven valuable in several tumors, but not in colon cancer (CC). OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of perioperative chemotherapy in patients with locally advanced nonmetastatic CC. METHODS: This is a French multicenter randomized phase II trial in patients with resectable high-risk T3, T4, and/or N2 CC on baseline computed tomography (CT) scan. Patients were randomized to receive either 6 months of adjuvant FOLFOX after colectomy (control) or perioperative FOLFOX for 4 cycles before surgery and 8 cycles after (FOLFOX peri-op). In RAS wild-type patients, a third arm testing perioperative FOLFOX-cetuximab was added. Tumor Regression Grade (TRG1) of Ryan et al was the primary endpoint. Secondary endpoints were toxicity, perioperative morbidity, and quality of surgery. RESULTS: A total of 120 patients were enrolled. At interim analysis, the FOLFOX-cetuximab arm was stopped (lack of efficacy). The remaining 104 patients (control, n = 52; FOLFOX preop n = 52) represented our intention-to-treat population. In the FOLFOX perioperative group, 96% received the scheduled 4 cycles before surgery. R0 resection and complete mesocolic excision rate were 94% and 93%, respectively. Overall mortality and morbidity rates were similar in both groups. Perioperative FOLFOX chemotherapy did not improve major pathological response rate (TRG1 = 8%) but was associated with a significant pathological regression (TRG1-2 = 44% vs 8%, P < 0.001) and a trend to tumor downstaging as compared to the control group. CT scan criteria were associated with a 33% rate of overstaging in control group. CONCLUSIONS: Perioperative FOLFOX for locally advanced resectable CC is feasible with an acceptable tolerability but is not associated with an increased major pathological response rate as expected. However, perioperative FOLFOX induces pathological regression and downstaging. Better preoperative staging tools are needed to decrease the risk of overtreating patients.

Influence of Molecular Status on Recurrence Site in Patients Treated for a Stage III Colon Cancer: a Post Hoc Analysis of the PETACC-8 Trial.

BACKGROUND: Recurrence patterns in stage III colon cancer (CC) patients according to molecular markers remain unclear. The objective of the study was to assess recurrence patterns according to microsatellite instability (MSI), RAS and BRAFV600E status in stage III CC patients. METHODS: All stage III CC patients from the PETACC-8 randomized trial tested for MSI, RAS and BRAFV600E status were included. The site and characteristics of recurrence were analyzed according to molecular status. Survival after recurrence (SAR) was analyzed. RESULTS: A total of 1650 patients were included. Recurrence occurred in 434 patients (26.3%). Microsatellite stable (MSS) patients had a significantly higher recurrence rate (27.2% vs. 18.7%, P = 0.02) with a trend to more pulmonary recurrence (28.8% vs. 12.9%, P = 0.06) when compared to MSI patients. MSI patients experienced more regional lymph nodes compared to MSS (12.9% vs. 4%, P = 0.046). In the MSS population, the recurrence rate was significantly higher in RAS (32.2%) or BRAF (32.3%) patients when compared to double wild-type patients (19.9%) (p < 0.001); no preferential site of recurrence was observed according to RAS and BRAFV600E mutations. Finally, decreased SAR was observed in the case of peritoneal recurrence or more than two recurrence sites. CONCLUSIONS: Microsatellite, RAS and BRAFV600E status influences recurrence rates in stage III CC patients. However, only microsatellite status seems to be associated with specific recurrence patterns. More than two recurrence sites and recurrence in the peritoneum were associated with poorer SAR.

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.

FOLFIRINOX as induction treatment in rectal cancer patients with synchronous metastases: Results of the FFCD 1102 phase II trial.

AIM OF THE STUDY: The optimal therapeutic strategy in patients with rectal cancer and synchronous unresectable metastases remains unknown. We evaluated the efficacy of FOLFIRINOX induction therapy in this setting. PATIENTS AND METHODS: Chemotherapy-naïve patients received at least 8 cycles of FOLFIRINOX. The primary end-point was the 4-month disease control (4 m DC) rate. Tumour responses were centrally reviewed and assessed by computed tomography scan for metastases (Response Evaluation Criteria in Solid Tumours criteria) and magnetic resonance imaging for rectal tumorus. With a Simon 2-stage design and a targeted (H1) 4 m DC > 75%, 65 patients were enrolled from July 2012 to February 2015: male, 78%; median age, 61 years; performance status, 0-1, 98%; liver metastases, 92%; ≥2 metastatic sites, 63%. RESULTS: Fifty-six (85%) of the 65 patients received the 8 planned FOLFIRINOX cycles. The primary objective was achieved (4 m DC rate: 94%; 95% confidence interval [CI], 86.3-97.8). Primary tumour symptoms decreased from 72% at baseline to 10% at 4 months. Response rate was 86%, and a >70% primary tumour volume decrease was seen in 63% of patients. Forty-four patients (68%) had at least one grade 3 side-effect; no toxic deaths occurred. Median follow-up was 35.0 months (95% CI, 31.3-43.7). Median progression-free survival and overall survival were 10.9 m (95% CI, 8.8-12.9) and 33.4 m (95% CI, 22.6-38.2), respectively. CONCLUSION: Upfront FOLFIRINOX is feasible and allows good local and distant control. It therefore offers the opportunity to choose the best therapeutic strategy for each patient and to personalise treatment according to the local and distant efficacy results of this induction step. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01674309.

Identification of resources and skills developed by partners of patients with advanced colon cancer: a qualitative study.

PURPOSE: Family caregivers play an important role in caring for patients with advanced cancer. To become competent, individuals must draw on and mobilise an adequate combination of resources. Our goal was to identify the skills developed by caregivers of patients with advanced cancer and the associated resources mobilised. We chose to do it with partners of patients with colon cancer. METHODS: The study used a cross-sectional qualitative design based on 20 individual interviews and a focus group. Partners were recruited from patients treated in three hospitals of France. Semi-structured interviews were conducted until data saturation was achieved. Each interview was transcribed verbatim, and thematic analyses were performed to extract significant themes and subthemes. RESULTS: Results from the individual and focus group interviews showed that the skills implemented by the partners (in domains of social relationships and health, domestic, organisational, emotional and well-being dimensions) were singular constructs, dependant on if resources (personal, external and schemes) may have been missing and insufficient. In addition, partners may have had these resources but not mobilised them. CONCLUSION: The identification of the skills and associated resources could allow healthcare professionals better identifying and understanding of the difficulties met by partners in taking care of patients. This could enable them to offer appropriate support to help the caregivers in their accompaniment.

[Outcomes after a 2-year pharmaceutical care program for patients taking vitamin K antagonist therapy? Community pharmacist's perception]. / Quel bilan à deux ans de la mise en place de l'accompagnement des patients traités par anti-vitamines K ? Le point de vue du pharmacien d'officine.

OBJECTIVES: Since 2013 French community pharmacist are involved in pharmaceutical care program (PCP) for patients treated with vitamin K antagonist (VKA). While PCPs are now extending to other patient populations, we aimed to evaluate pharmacists' perception after 2-years implementation and leading of PCP. METHODS: A prospective investigational survey from 1st August to 31st December, 2015 from 400 community pharmacies in Champagne-Ardenne Region. Survey focuses on 3 points: first about implementation and leading of PCP; secondly about patient's population description; finally on the global perception by CP about new tasks. RESULTS: Among n=47, 72% of pharmacists performed VKA PCP. Almost all received appropriate training (96%). Remuneration appears to be insufficient given the time spent for 73%. Ninety-five percent met patient's refusal mainly because of interest lacking or time lacking (54% and 22%, respectively). Pharmacists reported 3 main lacks of knowledges of patients: drugs, which increase drug-drug interaction risk (28%), VKA overdose effects (27%) and VKA-food interactions (23%). Overall view of pharmacist for PCP appears to be positive (81%) in part because of improvement of pharmacist-patient relationship perception for 66%. CONCLUSIONS: Community pharmacists' perception for PCP for patients treated by VKA is broadly positive. However, organizational or economic constraints can lead to a decreasing adherence by pharmacists to PCPs. A global issue about amount of compensation and communications campaigns to patients and others health professionals will be useful in order to reinforced PCP implementation and leading taxonomy.

[Benefits of volumetric to facial rejuvenation. Part 1: Fat grafting]. / Apport de la volumétrie au rajeunissement facial. Partie 1 : greffe adipocytaire.

For a number of years, a volumetric approach using autologous fat injection has been implemented to improve cosmetic outcome in face-lift procedures and to achieve lasting rejuvenation. Autologous fat as filling tissue has been used in plastic surgery since the late 19th century, but has only recently been associated to face lift procedures. The interest of the association lies on the one hand in the pathophysiology of facial aging, involving skin sag and loss of volume, and on the other hand in the tissue induction properties of grafted fat, "rejuvenating" the injected area. The strict methodology consisting in harvesting, treating then injecting an autologous fat graft is known as LipoStructure® or lipofilling. We here describe the technique overall, then region by region. It is now well known and seems simple, effective and reproducible, but is nevertheless delicate. For each individual, it is necessary to restore a harmonious face with well-distributed volumes. By associating volumetric to the face lift procedure, the plastic surgeon plays a new role: instead of being a tailor, cutting away excess skin, he or she becomes a sculptor, remodeling the face to restore the harmony of youth.

[Benefits of volumetric to facial rejuvenation. Part 2: Dermal fillers]. / Apport de la volumétrie au rajeunissement facial. Partie 2 : produits de comblement.

Injectable substances known as fillers are used to palliate age-related atrophy and ptosis, and for their so-called "pseudo-lifting" action. They do not replace face and neck lift, but allow it to be postponed or, when injected after surgical lifting, make the result durable. Hyaluronic acid has a predominant and unchallenged place among fillers, well ahead of poly-L-lactic acid or calcium hydroxyapatite. Approaches and injection methods are the same for all fillers, corresponding to those for autologous fat injection, the reference substance, with a few particularities. The substance used, the level of hyaluronic acid reticulation, and the depth of the injection depend on the injection site and intended effect. Effects range from smoothing superficial wrinkles to remodeling whole parts of the face. Complications related to such fillers are well known, especially in the case of hyaluronic acid, where overcorrection is the most frequent. To limit the risk of complications and also to offer each patient the most individually adapted corrections, before any procedure, the plastic surgeon needs to question the patient and perform precise medical examination.

Poorly differentiated gastro-entero-pancreatic neuroendocrine carcinomas: Are they really heterogeneous? Insights from the FFCD-GTE national cohort.

BACKGROUND: Diagnosis and management of poorly differentiated gastro-entero-pancreatic (GEP) neuroendocrine carcinomas (NECs) remain challenging. Recent studies suggest prognostic heterogeneity. We designed within the French Group of Endocrine Tumours a prospective cohort to gain insight in the prognostic stratification and treatment of GEP-NEC. PATIENTS AND METHODS: All patients with a diagnosis of GEP-NEC between 1st January 2010 and 31st December 2013 could be included in this national cohort. Adenoneuroendocrine tumours were excluded. RESULTS: 253 patients from 49 centres were included. Median age was 66 years. Main primary locations were pancreas (21%), colorectal (27%), oesophagus-stomach (18%); primary location was unknown in 20%. Tumours were metastatic at diagnosis in 78% of cases. Performance status (PS) at diagnosis was 0-1 in 79% of patients. Among the 147 (58%) cases reviewed by an expert pathological network, 39% were classified as small cell NEC and 61% as large cell NEC. Median Ki67 index was 75% (range, 20-100). Median overall survival was 15.6 (13.6-17.0) months. Significant adverse prognostic factors in univariate analysis were PS > 1 (hazard ratio [HR] = 2.5), metastatic disease (HR = 1.6), NSE>2 upper limit of normal [ULN]; HR = 3.2), CgA>2 ULN (HR = 1.7) and lactate dehydrogenase >2 ULN (HR = 2.1). After first-line palliative chemotherapy (CT1) with platinum-etoposide (n = 152), objective response, progression-free survival and overall survival were 50%, 6.2 and 11.6 months; they were 24%, 2.9 and 5.9, respectively, after post-CT1 FOLFIRI regimen (n = 72). CONCLUSIONS: We report a large prospective series of GEP-NEC which show the predominance of large cell type and advanced stage at diagnosis. Prognosis was found more homogeneous than previously reported, mainly impacted by PS and tumour burden.

Adjuvant FOLFOX +/- cetuximab in full RAS and BRAF wildtype stage III colon cancer patients.

Background: RAS mutations have been shown to confer resistance to anti- epidermal growth factor receptor (EGFR) treatment. We analysed the results of the PETACC8 trial (cetuximab + FOLFOX vs FOLFOX) in full RAS and BRAF wildtype (WT) patients (pts) with resected stage III colon cancer. Patients and methods: Exons 2, 3 and 4 of KRAS and NRAS, and BRAF exons 11 and 15, were sequenced using the Ampliseq colon-lung cancer panel version 2, in PETACC8 trial pts who consented to translational research. The impact of cetuximab on time to recurrence (TTR), disease-free survival (DFS) and overall survival (OS) was investigated in pts with tumours harbouring RAS and BRAF WT, and RAS mutations. The prognostic value of each individual mutation was also tested. Results: Among the 2559 pts analysed, 745 pts (29%) were known to have KRAS exon 2 mutations and 163 pts (6.4%) the BRAF V600E mutation. Of the remaining 1651 pts, 1054 were assessed by NGS, showing that a further 227 pts (21%) had KRAS exon 2, 3, 4 or NRAS exon 2, 3, 4 mutations, and that 46 pts (4.4%) had a newly diagnosed BRAF mutation. Cetuximab added to FOLFOX did not significantly improve TTR, DFS or OS in pts with RAS WT or RAS and BRAF WT tumours (HR 0.77-1.03, all P > 0.05). Cetuximab addition was not either significantly deleterious in RAS mutant pts or in pts with rare RAS or BRAF mutations. In the overall trial population, NRAS and KRAS codon 61 mutations were the only rare mutations with the same pejorative prognostic value as KRAS exon 2 or BRAF V600E mutations. Conclusion: Though not significant, the clinically relevant 0.76 adjusted HR observed for DFS in favour of adding cetuximab to FOLFOX, in full RAS and BRAF WT stage III colon cancer pts, may justify a new randomized controlled trial testing EGFR inhibitors in this setting. Clinical trial number: This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.

The multidisciplinary management of gastro-oesophageal junction tumours: European Society of Digestive Oncology (ESDO): Expert discussion and report from the 16th ESMO World Congress on Gastrointestinal Cancer, Barcelona.

BACKGROUND AND SCOPE: The management of GOJ cancers remains controversial and may vary between countries. Evidence-based attitudes and guidelines are not easy to elaborate since most of the trials and studies reported mixed cases of oesophageal (both adenocarcinoma and squamous cell tumours), GOJ and gastric cancers. The aim of this expert discussion and position paper is to elaborate practical recommendations that integrate evidence-reported literature and experience-based attitude covering all clinical aspects of GOJ cancer across different specialities and countries in Europe. METHODOLOGY: Opinion leaders, selected on scientific merit were asked to answer to a prepared set of questions covering the approach of GOJ tumours from definition to therapeutic strategies. All answers were then discussed during a plenary session and reported here in providing a well-balanced reflection of both clinical expertise and updated evidence-based medicine. RESULTS: Definition, classification, diagnosis and staging of GOJ tumours were updated and debated. Therapeutic aspects including endoscopic therapy, surgical management, both multimodal curative and palliative management were also reviewed for proposing practical and consensual positions and recommendations whenever possible. CONCLUSION: GOJ tumours deserve specific attention,not only for uniformising clinical management across countries but also for performing specific clinical and translational research,mainly in the curative perioperative setting.

Ipsilateral breast cancer recurrence after Deep Inferior Epigastric Perforator (DIEP) flap reconstruction: Incidence and radiological presentation.

PURPOSE: To assess the incidence and presentation of ipsilateral cancer recurrences (ICR) after deep inferior epigastric perforator (DIEP) flap reconstruction for breast cancer. PATIENTS AND METHODS: Data of 247 consecutive women with DIEP flap reconstruction after breast cancer in our institution between 1997 and 2009 were retrospectively reviewed. RESULTS: Mean follow-up time was 4.1years±3.2 (SD) (median: 3years; range: 1month - 14years). Thirty-one patients (12.5%, 95%CI: =8.7-17.3) presented 34 relapses, in average 4.1years±2.6 after mastectomy: 14 (41%) were ipsilateral, 6 (18%) contralateral and 14 (41%) metastatic. ICRs occurred earlier (3.9 vs. 5.8years; P<0.05) than non-ICRs. Most ICRs (10/14, 71%) involved the periphery of the flap and presented as palpable nodules. The remaining (4/14, 29%) involved the axilla and 3/4 (75%) were palpable. Imaging procedures detected infra-clinical ICRs in 3 of 10 imaged patients (30%). CONCLUSION: ICRs after DIEP flap reconstruction are more frequent than contralateral recurrences suggesting the need for imaging follow-up of the reconstructed breast.

[Setting of a breast autologous microsurgical reconstructive surgery evolution in 20 years and review of 1138 cases]. / Mise en place d'une activité de reconstruction microchirurgicale du sein par tissus autologues. Évolution sur 20 ans et revue de 1138 cas.

UNLABELLED: The authors conducted a retrospective study of breast reconstruction with DIEP free flap between 1994 and 2014 by a single team. MATERIAL AND METHOD: A retrospective analysis of all operative charts and hospitalization was conducted for the period from 1994 to 2014. The number of cases per year, the complication rate of the donor site and recipient site, and surgery time were recorded. Sequence analysis was conducted to determine the elements that have enabled to implement this technique reliably and effects of the learning curve. The series was split into two periods (1994/2011 and 2012/2014) corresponding to two different hospitals with the same team. RESULTS: The total number of shreds of 1138 between November 1994 and December 2014 respectively with 477 and 661 the period 1994/2011 to 2012/2014 period. The failure rate increased from 8% to 2.2%. CONCLUSION: The establishment of units mainly dedicated to microsurgical reconstruction can offer the DIEP technique reliably and reproducibly.

Epidemiology, Management, and Survival of Peritoneal Carcinomatosis from Colorectal Cancer: A Population-Based Study.

BACKGROUND: Modern chemotherapy aims to improve long-term survival for selected patients with peritoneal carcinomatosis. Publications suggest promising results, but the spread of these new aggressive treatment strategies in the general population is not well known. OBJECTIVE: The aim of this study was to draw a picture of epidemiology, management, and survival in synchronous and metachronous peritoneal carcinomatosis from colorectal cancer. DESIGN: The cumulative risk of metachronous peritoneal carcinomatosis was estimated in patients resected for cure. Net survival rates were calculated for synchronous and metachronous peritoneal carcinomatosis. SETTINGS: The study was conducted with the use of the Burgundy Digestive Cancer Registry. PATIENTS: Overall, 9174 primary colorectal cancers registered between 1976 and 2011 by the population-based digestive cancer registry were considered. RESULTS: In total, 7% of patients were diagnosed with synchronous peritoneal carcinomatosis. The 5-year cumulative risk of metachronous peritoneal carcinomatosis was 6%, and the stage of the colorectal cancer at diagnosis was the major risk factor. Other independent risk factors were mucinous adenocarcinoma, ulceroinfiltrating tumors, and diagnosis after obstruction or perforation. The proportion of patients resected for cure was 11% and 9% for synchronous and metachronous peritoneal carcinomatosis, and 3-year overall net survival was 8% and 5%. The corresponding rates after resection for cure were 21% and 17%. There was a dramatic increase in the proportion of patients receiving systemic chemotherapy: from 11% before 1997 to 48% in 2011 for synchronous peritoneal carcinomatosis and from 3% to 38% for metachronous peritoneal carcinomatosis. LIMITATIONS: This is a retrospective observational population-based study. CONCLUSION: Peritoneal carcinomatosis complicating colorectal cancer is a major reason for treatment failure. This study identified patients at a high risk of developing peritoneal carcinomatosis who may benefit from specific surveillance. New therapeutic modalities are also needed to improve the prognosis.

Adaptations to a diet-based weight-reducing programme in obese women resistant to weight loss.

The aim of this study was to assess energy intake, resting metabolic rate (RMR), appetite sensations, eating behaviours and sleep duration and quality in obese women resistant to body weight loss when subjected to a diet-based weight-reducing programme. A pooled cohort of obese women (n = 75; aged 39 ± 8 years; body mass index: 33 ± 4 kg m(-2)) participated in a 12-16-week diet-based weight loss programme targeting a daily energy deficit of 500-700 kcal d(-1). Women were classified in tertiles a posteriori based on the response of their body weight to dietary supervision (high, moderate and low responders). Post-intervention, mean weight loss was 3.3 ± 2.8 kg and explained by the 2.9 ± 2.6 kg reduction in fat mass. Mean weight loss was 6.2 ± 1.6, 3.4 ± 0.6 and 0.2 ± 1.4 kg in participants classified in the high, middle and low tertiles, respectively. Women in the low tertile reduced their daily energy intake and susceptibility to hunger during the programme to a lesser extent than those in the high tertile and had higher fasting hunger in response to the dietary intervention. Women in the high tertile maintained their RMR, which was in contrast to the significant decrease predicted by their weight loss. They also reported a significant improvement in sleep quality and an increase in sleep duration compared with other tertiles. The differences in the response of body weight to dietary supervision may be explained, in part, by variations in energy intake, eating behaviours, appetite sensations and sleep duration and quality.