[Tumour deposition (TD), a probably underestimated poor prognostic criterion, to be taken into account in the therapeutic management of patients with stage III colon cancer]. / Les dépôts tumoraux (DT), un critère pronostique péjoratif probablement sous-estimé, à prendre en compte dans la prise en charge thérapeutique des malades atteints de cancer colique de stade III.

The management of colorectal cancer (CRC) relies heavily on TNM staging. In order to improve this staging, it is essential to identify all histological markers bearing a significant prognostic value. Among these, tumor deposits (TDs), defined as tumor foci in the pericolonic or perirectal adipose tissue with no residual lymph node tissue, have been shown to be associated with poor prognosis in cohort studies leading to their individualization in the TNM7 classification as pN1c. However, TDs are only considered in the absence of lymph node metastases. There is no consensus on this particular way of integrating TDs in the TNM classification. Indeed, at the time when the choice of the type of adjuvant treatment and its duration in stage III colon cancers (i.e. with lymph node metastases) is based on pT and pN criteria, taking into account TDs only in the absence of concomitant lymph node metastases is potentially responsible for a misclassification of some patients and wrong therapeutic decisions. In addition, many questions concerning the true definition of TDs, their origin, their prognostic value and the optimization of their consideration remain open. The objective of this review is to provide a synthesis of current knowledge on TDs in CRC, in view of their prognostic importance, their biological complexity and the scientific interest they are currently the subject of.

A comprehensive overview of tumour deposits in colorectal cancer: Towards a next TNM classification.

The management of colorectal cancer (CRC) highly relies on the TNM staging system. Tumour deposits (TDs), important histoprognostic factors, are detected in approximately 20% of CRCs and associated with poor prognosis. Integration of TDs in the TNM staging remains a subject of lively debate and differs over the successive TNM classifications. Currently TDs, whatever their number, are considered in pathologic staging only in the absence of lymph node metastasis (LNM; subcategory pN1c). However, the medical community is divided over this way of integrating TDs in the TNM staging system. Considering the personalization of the type and duration of adjuvant chemotherapy in stage III colon cancer according to the number of LNM, this issue has become of growing importance. Thus, ignoring TDs in the presence of LNM represents a major prognostic underestimation and leads to wrong therapeutic decisions. Hence, considering the growing significance of prognostic role, the scientific complexity, and a potential therapeutic effect of TDs, we provide an overview of current knowledge about TDs. Based on the results from recent publications, we also provide plausible scenarios of integration of TDs into the next TNM classification system.

Targeting the Tumor Microenvironment through mTOR Inhibition and Chemotherapy as Induction Therapy for Locally Advanced Head and Neck Squamous Cell Carcinoma: The CAPRA Study.

Mammalian target of rapamycin (mTOR) regulates cellular functions by integrating intracellular signals and signals from the tumor microenvironment (TME). The PI3K-AKT-mTOR pathway is activated in 70% of head and neck squamous cell carcinoma (HNSCC) and associated with poor prognosis. This phase I-II study investigated the effect of mTOR inhibition using weekly everolimus (30 mg for dose level 1, 50 mg for dose level 2) combined with weekly induction chemotherapy (AUC2 carboplatin and 60 mg/m2 paclitaxel) in treatment-naïve patients with locally advanced T3-4/N0-3 HNSCC. Patients received 9 weekly cycles before chemoradiotherapy. Objectives were safety and antitumor activity along with tissue and blood molecular biomarkers. A total of 50 patients were enrolled. Among 41 evaluable patients treated at the recommended dose of 50 mg everolimus weekly, tolerance was good and overall response rate was 75.6%, including 20 major responses (≥50% reduction in tumor size). A significant decrease in expression of p-S6K (p-value: 0.007) and Ki67 (p-value: 0.01) was observed in post-treatment tumor tissue. Pro-immunogenic cytokine release (Th1 cytokines IFN-γ, IL-2, and TNF-ß) was observed in the peripheral blood. The combination of everolimus and chemotherapy in HNSCC was safe and achieved major tumor responses. This strategy favorably impacts the TME and might be combined with immunotherapeutic agents.

Tumor infiltrating and peripheral CD4+ILT2+ T cells are a cytotoxic subset selectively inhibited by HLA-G in clear cell renal cell carcinoma patients.

HLA-G: ILT2 has recently been positioned as a major immune checkpoint in urologic cancers. In clear cell renal cell carcinoma (ccRCC), tumor-infiltrating CD8+ T cells expressing ILT2 are a highly cytotoxic cell population, distinct from PD1+ T cells, and whose function is inhibited by HLA-G+ targets. Here we report that ILT2 receptor can also be expressed by CD4+ T cells in urologic cancer patients. In the course of deciphering the role of these ILT2+CD4+ T cells, we found a statistical association between the tumor context and these T cells, and a positive correlation between the levels of peripheral and intra-tumoral CD4+ILT2+ T cells. Phenotypic analyses revealed that CD4+ILT2+ T cells express memory T cell (CD27-CD28-CD57+) and cytotoxicity (Tbet+Perforin+KLRG1+NKp80+GPR56+) markers, consistent with a CD4+CTL phenotype. Functional assays showed that ccRCC-infiltrating CD4+ILT2+ T cells indeed have high cytolytic properties and therefore function as proper CD4+CTLs, but are selectively inhibited by HLA-G+ targets. Clinical relevance was provided by immunohistochemical analyses on ccRCC tumor lesions with HLA-G+ HLA class II+ tumor cells next to CD4+ T cell infiltrates. Our findings provide evidence supporting that ILT2+ T cells constitute a reservoir of intratumor cytotoxic T cells that is not targeted by the current checkpoint inhibitors, but could be by anti-HLA-G/anti-ILT2 antibodies as novel immunotherapy in HLA-G+ tumors.

Molecular Targets for the Treatment of Metastatic Colorectal Cancer.

Over the past years, colorectal cancer (CRC) was subtyped according to its molecular and genetic characteristics, allowing the development of therapeutic strategies, based on predictive biomarkers. Biomarkers such as microsatellite instability (MSI), RAS and BRAF mutations, HER2 amplification or NTRK fusions represent major tools for personalized therapeutic strategies. Moreover, the routine implementation of molecular predictive tests provides new perspectives and challenges for the therapeutic management of CRC patients, such as liquid biopsies and the reintroduction of anti-EGFR monoclonal antibodies. In this review, we summarize the current landscape of targeted therapies for metastatic CRC patients, with a focus on new developments for EGFR blockade and emerging biomarkers (MSI, HER2, NTRK).

Prognostic Value of Tumor Deposits for Disease-Free Survival in Patients With Stage III Colon Cancer: A Post Hoc Analysis of the IDEA France Phase III Trial (PRODIGE-GERCOR).

PATIENTS AND METHODS: A post hoc analysis of all pathologic reports from patients with stage III CC included in the IDEA France phase III study (ClinicalTrials.gov identifier: NCT00958737) investigating the duration of adjuvant fluorouracil, leucovorin, and oxaliplatin or capecitabine and oxaliplatin therapy (3 v 6 months) was performed. The primary objective was to determine the prognostic impact of TD on disease-free survival (DFS). The effect of the addition of TD to LNM count on pN restaging was also evaluated. A multivariable analysis was performed to establish the association between TD and DFS. RESULTS: Of 1,942 patients, 184 (9.5%) had TDs. The pN1a/b and pN1c populations showed similar DFS. TD-positive patients had worse prognosis compared with TD-negative patients, with 3-year DFS rates of 65.6% (95% CI, 58.0% to 72.1%) and 74.7% (95% CI, 72.6% to 76.7%; P = .0079), respectively. On multivariable analysis, TDs were associated with a higher risk of recurrence or death (hazard ratio [HR], 1.36; P = .0201). Other adverse factors included pT4 and/or pN2 disease (HR, 2.21; P < .001), the 3 months of adjuvant treatment (HR, 1.29; P = .0029), tumor obstruction (HR, 1.28; P = .0233), and male sex (HR, 1.24; P = .0151). Patients restaged as having pN2 disease (n = 35, 2.3%) had similar DFS as patients initially classified as pN2. CONCLUSION: The presence of TDs is an independent prognostic factor for DFS in patients with stage III CC. The addition of TD to LNM may help to better define the duration of adjuvant therapy.

Double ischemic ileal stenosis secondary to mesenteric injury after blunt abdominal trauma.

The authors describe a rare case in which blunt abdominal trauma resulted in mesenteric injury with delayed double ischemic ileal stenosis. Abdominal computed tomography demonstrated stenotic ileal loop with mural thickening. At surgery, a double stenotic bowel loop was found adjacent to a healed defect in the mesentery. Histological examination of the two resected segments showed fibrotic and ischemic lesions within the mesentery. Ischemic intestinal stenosis from mesenteric injury should be considered in the differential diagnosis in patients suffering from intestinal occlusion with a history of blunt abdominal trauma.

Outcome after surgical treatment of gastrointestinal stromal tumors.

OBJECTIVES: The objectives were to determine among gastrointestinal mesenchymal tumors treated surgically in our unit which were gastrointestinal stromal tumors (GISTs) and to describe their characteristic features and prognostic factors. METHODS: A second histological and immunohistochemical reading was performed for 56 gastrointestinal mesenchymal tumors, treated surgically in the Reims University Hospital between 1990 and 2005 in order to determine which ones were GISTs. A statistical descriptive and analytical analysis of the demographic, pathological, therapeutic and prognostic factors was performed. RESULTS: Eighty-seven percent of the tumors were GISTs. The 5-year specific survival rate was 66.8%. The factors of good prognosis were small tumor size, low mitotic count, complete primary tumor resection without tumor effraction, age less than 60 years, absence of mucosal necrosis, ulceration, and invasion. Type of surgical resection had no impact in terms of survival. CONCLUSION: GISTs are the most common mesenchymal tumors of the digestive tract. Even thought treatment with imatinib is currently available, surgery (preferably total resection without effraction) is the mainstay treatment for GISTs.

Long-term outcome of laparoscopic antireflux surgery in the elderly.

The aim of this retrospective study was to compare results and five-year surgical outcome of laparoscopic antireflux surgery (LARS) in patients younger than 65 years and elderly patients aged 65 years or older. From January 1992 to December 1998, 2684 patients underwent LARS in 31 surgical units; 369 elderly patients (group 1) were compared with 2315 younger patients (group 2). Elderly patients have a higher American Society of Anesthesiologists score (mean, 2.38 versus 1.98). The conversion rate was higher in group 1 (10.2%, n = 38 versus 6.1%, n = 142), as was the morbidity rate (7.6% in group 1 versus 4.5% in group 2). Mean hospital stay was longer for group 1 (7.6 +/- 5.6 days versus 5.9 +/- 2.8 days). Functional evaluation was excellent in both groups (91-93%) at 3 months and 2 and 5 years. LARS in the elderly is a safe and efficient procedure. Good results appear to be sustainable in the long term.

Laparoscopic antireflux surgery: five-year results and beyond in 1340 patients.

BACKGROUND: Although the long-term results of open fundoplication for gastroesophageal reflux disease are well documented, few reports exist on the long-term results of laparoscopic fundoplication. DESIGN: Retrospective study with clinical evaluation or mailed survey for patients unable to return to the hospital center. SETTING: Multicenter studies (ie, private medical centers, institutional hospitals, and university hospitals). PATIENTS: Between January 1992 and December 1998, 2684 patients with gastroesophageal reflux disease underwent laparoscopic fundoplication in 31 hospital centers. Outcome data covering a period of 5 or more years after surgery were available for 1340 patients: 711 who underwent complete fundoplication, 559 who underwent partial posterior fundoplication, and 70 who underwent partial anterior fundoplication. MAIN OUTCOME MEASURES: Evaluation of clinical and quality-of-life actions used to treat the symptoms of gastroesophageal reflux disease. RESULTS: The overall residual severe dysphagia rate was 5.1% (n = 68). A further surgical procedure was required for 59 patients (4.4%) for a total of 63 interventions. Subsequent operation was performed laparoscopically in 32 cases (50.8%). Twelve of these procedures were for the repair of a paraesophageal hiatus hernia, 11 were for dysphagia (4 because of a tight esophageal hiatus and 7 for conversion of Nissen fundoplication to a posterior partial fundoplication procedure), 31 were for recurrent reflux (wrap undone), 2 were for intestinal obstruction (adhesiolysis), 1 was for incisional hernia, 1 was for abdominal abscess (drainage), and 1 was for gastroparesis (pyloroplasty). The recurrence rate was 10.1% (n = 136), and 122 patients (9.1%) resumed taking antisecretory medication. Gas bloat syndrome was present in 101 patients (7.5%). A total of 93.1% of the patients were satisfied (Visick classification, grades 1 and 2) and 6.9% were unsatisfied, with no difference among the 3 procedures. CONCLUSION: After 5 years of experience, laparoscopic fundoplication remains an effective antireflux procedure.