TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-based chemotherapy.

Recent studies have suggested that activation of the EGFR pathway leads to malignant transformation only if the p53 protein is inactivated. Therefore, we evaluated the impact of TP53 mutations on cetuximab-based chemotherapy (CT) sensitivity in combination with KRAS mutations that have been associated with cetuximab resistance. KRAS and TP53 status were assessed in tumours from 64 metastatic colorectal cancer patients treated with cetuximab-based CT and correlated to clinical response using the Fisher's exact test. Times to progression (TTPs) according to gene status were calculated using the Kaplan-Meier method and compared with log-rank test. TP53 mutations were found in 41 patients and were significantly associated with controlled disease (CD), as defined as complete response, partial response or stable disease (P=0.037) and higher TTP (20 vs 12 weeks, P=0.004). Remarkably, in the subgroup of 46 patients without KRAS mutation, but not in patients with KRAS mutation, TP53 mutations were also associated with CD (P=0.008) and higher TTP (24 vs 12 weeks, P=0.0007). This study suggests that TP53 mutations are predictive of cetuximab sensitivity, particularly in patients without KRAS mutation, and that TP53 genotyping could have a clinical interest to select patients who should benefit from cetuximab-based CT.

National multicentric evaluation of quality of pathology reports for rectal cancer in France in 2016.

The quality of pathologic assessment of rectal cancer specimens is crucial for treatment efficiency and survival. The Royal College of Pathologists (RCP) recommends evaluating the quality of the pathology report in routine practice using three quality indicators (QIs): the number of lymph nodes (LNs) analyzed (≥ 12), the rate of venous invasion (VI ≥ 30%), and peritoneal involvement (pT4a ≥ 10%). In this study, we evaluated the three QIs of the French national pathology reports and compared them with British guidelines and assessed the influence of neoadjuvant radiochemotherapy on QIs. From January 1 to December 31, 2016, all pathology reports for rectal adenocarcinoma were collected from French departments. Neoadjuvant radiochemotherapy included long-course radiotherapy with concomitant 5-FU-based chemotherapy. A total of 983 rectal cancer pathology reports were evaluated. A median of 15 LNs were analyzed and 81% of centers had ≥ 12 LNs. The rate of VI was 30% and 41% of centers had ≥ 30% VI. The rate of pT4a was 4% and 18% of centers reported ≥ 10% pT4a. None of the centers reached the threshold for the three QIs. All three QIs were lower after radiochemotherapy compared to surgery alone. In conclusion, in French routine practice, the values of two of the three QIs (LNs analyzed and VI) were globally in line with RCP guidelines. However, the rate of pT4a was very low, particularly after radiochemotherapy, suggesting its low value in rectal cancer.

Combined resection of the pancreas and inferior vena cava for pancreatic metastasis from renal cell carcinoma.

Indications for pancreatic resections for metastatic disease have not yet been defined to date, and few guidelines exist for the management of these lesions. However, most authors recommend surgery as the treatment of choice for pancreatic metastasis (PM). Resection of the inferior vena cava (IVC) is rarely done during removal of peripancreatic cancer. This report presents the first case of metachronous PM from renal cell carcinoma (RCC) with IVC involvement successfully treated by en-bloc resection in a 70-year-old asymptomatic woman. The abdominal computed tomography (CT) scan showed a 4.0-cm mass in the tail and a 5.0-cm mass in the head of the pancreas with a suspected involvement of vena cava. An en-bloc total pancreatectomy was performed with excision of the involved portion of the cava vein. Histology confirmed the presence of two metastases from RCC with neoplastic infiltration of the IVC and without lymph node involvement. All surgical margins were tumor-free. At most recent follow-up 12 months after pancreatectomy, the patient has no evidence of disease. We believe that a multidisciplinary approach and careful evaluation and treatment of these patients is a mandatory component for patient selection. IVC resection should be performed only when a margin-negative resection is expected to be achieved.

Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer.

We report the association of CDH1/E-cadherin mutations with cleft lip, with or without cleft palate (CLP), in two families with hereditary diffuse gastric cancer (HDGC). In each family, the CDH1 mutation was a splicing mutation generating aberrant transcripts with an in-frame deletion, removing the extracellular cadherin repeat domains involved in cell-cell adhesion. Such transcripts might encode mutant proteins with trans-dominant negative effects. We found that CDH1 is highly expressed at 4 and 5 weeks in the frontonasal prominence, and at 6 weeks in the lateral and medial nasal prominences of human embryos, and is therefore expressed during the critical stages of lip and palate development. These findings suggest that alteration of the E-cadherin pathway can contribute to human clefting.

Cell proliferation in colorectal adenocarcinomas: comparison between Ki-67 immunostaining and bromodeoxyuridine uptake detected by immunohistochemistry and flow cytometry.

We compared three different means of assaying tumor proliferative activity in 30 human colorectal adenocarcinomas labeled in vivo with bromodeoxyuridine (BrdUrd). The labeling indices (LI) of BrdUrd obtained both by flow cytometry (FCM) and immunohistochemistry (IH) were also compared with the labeling index of Ki-67. These methods were then related to tumor ploidy and pathological features. Flow cytometry was performed in accordance with Begg's method after intravenous infusion of BrdUrd four hours before surgery. Immunohistology was carried out on paraffin-embedded sections with monoclonal antibodies against BrdUrd and Ki-67. A positive correlation was found between BrdUrd LI obtained by both FMC and IH (p<0.0001), a finding that complies with the literature. However, we report on a correlation between Ki-67 LI and BrdUrd LIs in colorectal tumors (p=0.012). The results were valid for all tumors when they were subdivided into diploid and aneuploid groups. The labeling indices were significantly higher in the aneuploid tumor group than in the diploid group (p=0.047). No relationship between proliferation parameters and tumor stage or grade was found. To our knowledge, this is the first report on a positive correlation between tumor proliferation indices in BrdUrd LIs and Ki-67 in colorectal carcinomas. This finding validates the value of Ki-67 immunostaining, which, however, should be confirmed in a larger series under the same technical conditions.

[A case of primitive meningeal rhabdomyosarcoma. Histological, immunohistochemical and ultrastructural study]. / Un cas de rhabdomyosarcome primitivement méningé. Etude histologique, immunohistochimique et ultrastructurale.

A 64 year-old patient, complained of headache and neurological disorders. CT scan found a voluminous solitary tumor of the posterior part of the left cavernous sinus. Removal of tumor was followed by a rapid recurrence and by the patient's death. Histologic study found a malignant undifferentiated tumoral proliferation, with strap-like cells. Immunohistochemical stains were positive for conjunctival and muscular differentiation. Ultrastructural study revealed intracytoplasmic filamentous striated structure. The primary meningeal rhabdomyosarcoma is an exceptional tumor, generally affecting young patients. Its prognosis is poor and its histogenesis remains unclear.

[Erdheim-Chester disease. Apropos of a case with autopsy findings]. / La maladie d'Erdheim-Chester. A propos d'un cas avec étude autopsique.

Erdheim-Chester's Disease is a very uncommon variety of non-Langerhans histiocytosis of unknown etiology, which characteristically affects long bones bilaterally and symmetrically in adults. It may be accompanied by visceral foci of variable localization and extension determining prognosis. Bone scintigraphy is characteristic enough to evoke the disease but histologic examination of a peripheral specimen is required to confirm the diagnosis: spumous histiocytes CD68+, PS100+/-, CD1a-. We describe a case revealed by a severe lung disease with detailed autopsy.

[Primary breast MALT lymphoma : apropos of one case]. / Lymphome du MALT primatif du sein. A propos d'une observation.

A 46-year-old patient was referred for a right mammary nodule associated with a chronic mastopathy. Cytological examination suggested an inflammatory process but frozen sections concluded to carcinoma with lymphoid stroma. Histological examination found characteristic features of MALT lymphoma: reactive lymphoid follicles, lymphoplasmocytoid lymphoid proliferation and lymphoepithelial lesions. Immunohistochemistry and in situ hybridation revealed a monotypic IgGk immunoglobulin. Molecular biology techniques found a rearrangement of IgH locus. Lymphocytic perigalactophoritis was found in the remaining breast tissue. After 33 months, no tumoral recurrence occurred. Primary MALT lymphoma of the breast is exceptional and its histogenesis is unclear. The role of pre-existent inflammatory lesions in the genesis of this tumour is not established. Our observation illustrates the diagnostic difficulty and the usefulness of complementary techniques in this diagnosis. The existence of inflammation close to tumour is interesting to emphasize.

Ganglioneuromatosis: an unusual cause of ileal stricture mimicking Crohn's disease.

Ileal idiopathic forms of ganglioneuromatosis in adults are extremely rare and represent a challenging pathologic condition for the clinician. We present two cases of ileal ganglioneuromatosis consisting of stricturing lesions that mimicked clinical and radiologic features commonly observed in Crohn's disease patients with ileal involvement.

Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy.

The predictive value of KRAS mutation in metastatic colorectal cancer (MCRC) patients treated with cetuximab plus chemotherapy has recently been suggested. In our study, 59 patients with a chemotherapy-refractory MCRC treated with cetuximab plus chemotherapy were included and clinical response was evaluated according to response evaluation criteria in solid tumours (RECIST). Tumours were screened for KRAS mutations using first direct sequencing, then two sensitive methods based on SNaPshot and PCR-ligase chain reaction (LCR) assays. Clinical response was evaluated according to gene mutations using the Fisher exact test. Times to progression (TTP) were calculated using the Kaplan-Meier method and compared with log-rank test. A KRAS mutation was detected in 22 out of 59 tumours and, in six cases, was missed by sequencing analysis but detected using the SNaPshot and PCR-LCR assays. Remarkably, no KRAS mutation was found in the 12 patients with clinical response. KRAS mutation was associated with disease progression (P=0.0005) and TTP was significantly decreased in mutated KRAS patients (3 vs 5.5 months, P=0.015). Our study confirms that KRAS mutation is highly predictive of a non-response to cetuximab plus chemotherapy in MCRC and highlights the need to use sensitive molecular methods, such as SNaPshot or PCR-LCR assays, to ensure an efficient mutation detection.

Endoscopic markers of villous atrophy are not useful for the detection of celiac disease in patients with dyspeptic symptoms.

BACKGROUND AND STUDY AIMS: Celiac disease can manifest with nonspecific symptoms, including functional gastrointestinal disorders such as dyspepsia. The aim of our study was to assess the usefulness of duodenal endoscopic markers of villous atrophy for the selection of dyspeptic patients for histological assessment. PATIENTS AND METHODS: Esophagogastroduodenoscopy was performed in dyspeptic patients, in patients considered to be at risk of having celiac disease, and in healthy controls. At least three duodenal biopsies were performed for histological assessment of villous atrophy in all patients and controls. We looked for the following four duodenal endoscopic markers of celiac disease: reduction in the number of folds, scalloping of folds, mosaic-pattern mucosa, and nodular mucosa. RESULTS: A total of 175 people were enrolled (75 patients with dyspepsia; 75 patients who were "at risk" of having celiac disease; and 25 healthy volunteers, or "controls"). Of the dyspeptic patients, four had endoscopic markers of celiac disease with no histologically confirmed villous atrophy, while one patient without endoscopic markers was found to have Marsh type I villous atrophy. Of the patients at risk of having celiac disease, 16 had at least one endoscopic marker and 10/16 were found to have histological villous atrophy. In this group, the sensitivity and specificity of the endoscopic markers were 100 % and 90.8 % respectively. "At-risk" patients with two or more endoscopic markers all had histologically confirmed villous atrophy. Neither endoscopic markers nor villous atrophy were found in any of the control patients. CONCLUSIONS: Additional endoscopic markers are valuable for diagnosis in patients with clinical symptoms suggestive of celiac disease. In contrast, endoscopic markers of villous atrophy are not useful for selecting a subgroup of dyspeptic patients for screening for celiac disease by duodenal histological assessment. These patients should be screened using other protocols.

Influence of glutamine on cytokine production by human gut in vitro.

BACKGROUND: glutamine modulates cytokine production by immune cells in vitro and protects the gut from experimental enterocolitis, but data on the effect of glutamine on cytokine production in human gut are lacking. AIM: to assess the effect of glutamine pre-treatment in vivo and in vitro on cytokine production by intestinal mucosa. METHODS: nine fasted volunteers received either enteral glutamine or saline over 6 h in a cross-over design. Duodenal biopsies were cultured for 24 h with or without glutamine. Cytokine content of culture media was analysed by ELISA, and the expression of cytokine mRNA in biopsies was assessed by semi-quantitative RT-PCR. RESULTS: glutamine given in vivo and in vitro significantly decreased IL-6 [1.4 (0.8-8.5) vs 8.9 (1.0-43.9)] and IL-8 production [5.8 (0-51.4) vs. 53.0 (2.5-114.6), pg/mg wet tissue], median (range), both P< or =0.01, in comparison to no glutamine experiments. Glutamine did not influence IL-4 production. IL-1beta, IL-10 and TNF-alpha were not detectable in culture media. The expression of any cytokine mRNA was not influenced by glutamine. CONCLUSIONS: glutamine reduces pro-inflammatory cytokine production by human intestinal mucosa, probably by a post-transcriptional pathway. Glutamine could be useful to modulate inflammatory conditions with imbalanced cytokine production.