Thomas Aparicio

Small bowel adenocarcinoma phenotyping, a clinicobiological prognostic study

Background:Small bowel adenocarcinoma (SBA) is a rare tumour with a poor prognosis. Molecular biology data on SBA carcinogenesis are lacking.Methods:Expression of HER2, β-catenin, p53 and mismatch repair (MMR) protein was assessed by immunohistochemistry. KRAS, V600E BRAF mutations and microsatellite instability were investigated.Results:We obtained samples from 63 SBA patients (tumour stages: I–II: 30%; III: 35%; IV: 32%; locally advanced: 3%). HER2 overexpression (3+) was observed in 2 out of 62 patients, overexpression of p53 in 26 out of 62, abnormal expression of β-catenin in 12 out of 61, KRAS mutation in 21 out of 49, BRAF V600E mutation in 1 out of 40 patients, MMR deficiency (dMMR) in 14 out of 61 and was consistent with Lynch syndrome in 9 out of 14 patients. All of the dMMR tumours were in the duodenum or jejunum and only one was stage IV. Median overall survival (OS) was 36.6 months (95% CI, 26.9–72.2). For all patients, in univariate analysis, stages I–II (P<0.001), WHO PS 0–1 (P=0.01) and dMMR phenotype (P=0.02) were significantly associated with longer OS. In multivariate analysis, disease stage (P=0.01) and WHO PS 0–1 (P=0.001) independently predicted longer OS. For stage IV patients, median OS was 20.5 months (95% CI: 14.6; 36.6 months). In multivariate analysis, WHO PS 0–1 (P=0.0001) and mutated KRAS status (P=0.02) independently predicted longer OS.Conclusion:This large study suggests that molecular alterations in SBA are closer to those in colorectal cancer (CRC) than those in gastric cancer, with low levels of HER 2 overexpression and high frequencies of KRAS mutations. The seemingly higher frequency of dMMR than in CRC may be explained by the higher frequency of Lynch syndrome in SBA patients. A dMMR phenotype was significantly associated with a non-metastatic tumour (P=0.02). A trend for a good prognosis and a duodenum or jejunum primary site was associated with dMMR.

Dihydropyrimidine dehydrogenase activity in normal, inflammatory and tumour tissues of colon and liver in humans

Background/Purpose: Dihydropyridmidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). Although this catabolism is likely to occur in the liver in humans, there may be a local inactivation in tumours, modifying the efficacy of 5FU. The aim of this study was to examine the DPD activity in normal, inflammatory and malignant tissues from both the colon and the liver to assess the modifications of DPD activity in the process of tumourigenesis. Methods: DPD activity was evaluated in 107 patients, corresponding to 194 samples (70 colorectal tumour and normal colon, nine metastases secondary to a colon cancer, ten inflammatory colon, 20 samples of normal liver, seven from primary liver cancer, and eight from inflammatory liver). DPD activity was determined using an enzymatic reaction followed by analysis of 5FU and its catabolite dihydro-5FU by high-performance liquid chromatograph. Results were expressed as pmol of 5FU catabolized/minu2009·u2009mg protein. Results: DPD was highly variable in tumour and normal tissues, both from colon and liver. In colon, the correlation between DPD activity in tumour and normal mucosa was weak, even if it was statistically significant due to the higher number of samples. In inflammatory colon tissue (ulcerative colitis or Crohns disease), DPD activity was significantly higher than in normal tissue (P=0.006). In liver metastases from colon cancer, DPD activity was not significantly different from that observed in primary colon tumour (P=0.32). In liver, DPD activity was significantly lower in primary liver tumour than in uninvolved liver specimens (P=0.001). In inflammatory liver tissue (hepatitis), DPD activity ranged between normal and tumour tissues, and did not differ significantly either from normal tissue or primary liver cancer. Conclusions: DPD activity was modified in colon and in liver during a pathological process and the dysregulation of DPD increased from a benign to a malignant tissue.

FOLFOX as second-line chemotherapy in patients with pretreated metastatic pancreatic cancer from the FIRGEM study

BackgroundFOLFOX second-line treatment seems to be a validated option for patients with pancreatic cancer (PC) progressing after gemcitabine chemotherapy. However, other therapeutics strategy has developed in first-line therapy, as the FIRGEM phase II study that evaluated gemcitabine alone versus FOLFIRI.3 alternating with gemcitabine every two months. The present study assessed the efficacy and safety of FOLFOX after failure of the first-line therapy used in the FIRGEM study.MethodsIn this prospective observational cohort study, we analysed all consecutive patients who received second-line chemotherapy with FOLFOX among 98 patients with metastatic PC included in the FIRGEM study. Progression-free survival (PFS) and overall survival (OS) were estimated from the start of second-line chemotherapy using the Kaplan-Meier method.ResultsAmong 46 patients who received second-line chemotherapy, 27 patients (male, 55%; median age, 61xa0years; performance status (PS) 0–1, 44%) were treated with FOLFOX after progression to first-line gemcitabine alone (nu2009=u200920) or FOLFIRI.3 alternating with gemcitabine (nu2009=u20097). Grade 3 toxicity was observed in 33% of patients (no grade 4 toxicity). At the end of follow-up, all patients had progressed and 25 had died. No objective response was observed, and disease control rate was 36%. Median PFS and OS were 1.7 and 4.3xa0months, respectively. In multivariate analysis, PS was the only independent prognostic factor. For patients PS 0–1 versus 2–3, median PFS was 3.0 versus 1.2xa0months (log rank, pu2009=u20090.002), and median OS was 5.9 versus 2.6xa0months (log rank, pu2009=u20090.001).ConclusionsThis study suggests that FOLFOX second-line therapy offered interesting efficacy results with an acceptable toxicity profile in metastatic PC patients with a good PS.

High prevalence of deficient mismatch repair phenotype and the V600E BRAF mutation in elderly patients with colorectal cancer.

AIMSnColorectal cancer (CRC) occurs mostly in the elderly. However, the biology of CRC in elderly has been poorly studied. This study examined the prevalence of deficient mismatch repair phenotype (dMMR) and BRAF mutations according to age.nnnPATIENTS AND METHODSnMMR phenotype was prospectively determined by molecular analysis in patients of all ages undergoing surgery for CRC. BRAF V600E mutation status was analysed in a subset of dMMR tumours.nnnRESULTSnA total of 754 patients who underwent surgery between 2005 and 2008 were included in the study. Amongst them, 272 (36%) were ≥75years old. The proportion of women <75 was 38% and that ≥75 was 53% (p<0.0001). The prevalence of dMMR was 19.4% in patients ≥75 and 10.7% in patients <75 (p=0.0017). For patients ≥75, the prevalence of dMMR was significantly higher in women than in men (27% vs 10.2%, respectively; p=0.003) but was similar in women and men <75 (12.5% vs 9.7%, respectively; p=0.4). We examined BRAF mutation status in 80 patients with dMMR tumours. The V600E BRAF mutation was significantly more frequent in patients ≥75 than in patients <75 (72.2% vs 11.4%, respectively; p<0.001). In patients ≥75, there was no difference in the prevalence of the BRAF V600E mutation according to sex (78% in women and 70% in men, p=0.9).nnnCONCLUSIONSnThe prevalence of dMMR in CRC is high in patients over 75. In elderly patients, dMMR tumours are significantly more frequent in women than in men. The BRAF mutation is frequent in elderly patients with CRC.

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

BACKGROUNDnDiagnosis 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.nnnPATIENTS AND METHODSnAll 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.nnnRESULTSn253 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 survivalxa0was 15.6 (13.6-17.0) months. Significant adverse prognostic factors in univariate analysis were PSxa0>xa01 (hazard ratio [HR]xa0=xa02.5), metastatic disease (HRxa0=xa01.6), NSE>2 upper limit of normal [ULN]; HRxa0=xa03.2), CgA>2 ULN (HRxa0=xa01.7) and lactate dehydrogenase >2 ULN (HRxa0=xa02.1). After first-line palliative chemotherapy (CT1) with platinum-etoposide (nxa0=xa0152), objective response, progression-free survivalxa0and overall survival were 50%, 6.2 and 11.6 months; they were 24%, 2.9 and 5.9, respectively, after post-CT1 FOLFIRI regimen (nxa0=xa072).nnnCONCLUSIONSnWe 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.

Magnetic resonance imaging diffusion-weighted imaging for diagnosis of a gastric hepatoid adenocarcinoma

A 63-year-old man consulted his general practitioner (GP) for bdominal pain in March 2010. Laboratory examination revealed n elevated alpha-fetoprotein and the GP referred the patient for uspected hepatocellular carcinoma. A computed tomography scan howed no tumour. Magnetic resonance imaging (MRI) confirmed he absence of hepatic tumour but showed irregular thickening of tomach wall on T2-weighted image with an increased signal on igh b-value (1000 s/mm2) in diffusion-weighted imaging (Fig. 1). pper endoscopy revealed a large ulcerated tumour of the distal tomach. Biopsy samples revealed hepatoid adenocarcinoma (HAC) nd the patient underwent subtotal gastrectomy. The tumour was a

Aspirin versus placebo in stage III or high-risk stage II colon cancer with PIK3CA mutation: A French randomised double-blind phase III trial (PRODIGE 50-ASPIK)

Oxaliplatin-based adjuvant chemotherapy is standard of care for radically resected stage III colon cancer and an accepted option for high-risk stage II. Two recent retrospective studies strongly suggested that low-dose aspirin used (100u202fmg/d) after surgical resection of colorectal cancer with a PIK3CA mutation could act as a targeted therapy with a major protective effect on the risk of recurrence. We propose a double-blind randomized phase III study to evaluate aspirin (100u202fmg/d during 3 years or until recurrence) versus placebo. Main inclusion criteria are patients aged 18 or 20, stage III or high risk stage II. The primary endpoint of the study is 3-year disease-free survival (DFS). Hypotheses are to improve 3-years DFS from placebo: 72% to aspirin: 83% (HRu202f=u202f0.56). 94 events and 264 patients with PIK3CA mutation are required. The secondary endpoints are DFS at 5 years, the overall survival rate at 5 years, grade 3-4 severe bleeding.