Prognosis and chemosensitivity of non-colorectal alimentary tract cancers with microsatellite instability.

BACKGROUND: Data on outcomes of microsatellite instable and/or mismatch repair deficient (dMMR/MSI) digestive non-colorectal tumors are limited. AIMS: To evaluate overall survival (OS) of patients with dMMR/MSI digestive non-colorectal tumor. METHODS: All consecutive patients with a dMMR/MSI digestive non-colorectal tumor were included in this French retrospective multicenter study. RESULTS: One hundred and sixteen patients were included with a mean age of 63.6 years and 32.6% with a Lynch syndrome. Most tumors were oesophago-gastric (54.3%) or small bowel (32.8%) adenocarcinomas and at a localized stage at diagnosis (86.7%). In patients with localized tumors and R0 resection, median OS was 134.0 ± 64.2 months. Median disease-free survival (DFS) was 100.3 ± 65.7 months. Considering oesophago-gastric tumors, median DFS was improved when chemotherapy was added to surgery (not reached versus 22.8 ± 10.0 months, p = 0.03). In patients with advanced tumors treated by chemotherapy, median OS was 14.2 ± 1.9 months and median progression-free survival was 7.4 ± 1.6 months. CONCLUSION: dMMR/MSI digestive non-colorectal tumors are mostly diagnosed at a non-metastatic stage with a good prognosis. Advanced dMMR/MSI digestive non-colorectal tumors have a poor prognosis with standard chemotherapy.

High-Density of FcγRIIIA+ (CD16+) Tumor-Associated Neutrophils in Metastases Improves the Therapeutic Response of Cetuximab in Metastatic Colorectal Cancer Patients, Independently of the HLA-E/CD94-NKG2A Axis.

Antibody-dependent cellular cytotoxicity (ADCC) in the anti-tumor effect of cetuximab in metastatic colorectal cancer (mCRC) is only based on the impact of FcγRIIIA (CD16) polymorphisms as predictive of therapeutic response. However, nature, density and therapeutic impact of FcγRIIIA+ (CD16) effector cells in tumor remain poorly documented. Moreover, the inhibition of cetuximab-mediated ADCC induced by NK cells by the engagement of the new inhibitory CD94-NKG2A immune checkpoint has only been demonstrated in vitro. This multicentric study aimed to determine, on paired primary and metastatic tissue samples from a cohort of mCRC patients treated with cetuximab: 1) the nature and density of FcγRIIIA+ (CD16) immune cells, 2) the expression profile of HLA-E/ß2m by tumor cells as well as the density of CD94+ immune cells and 3) their impact on both objective response to cetuximab and survival. We demonstrated that FcγRIIIA+ (CD16) intraepithelial immune cells mainly correspond to tumor-associated neutrophils (TAN), and their high density in metastases was significantly associated with a better response to cetuximab, independently of the expression of the CD94/NKG2A inhibitory immune checkpoint. However, HLA-E/ß2m, preferentially overexpressed in metastases compared with primary tumors and associated with CD94+ tumor infiltrating lymphocytes (TILs), was associated with a poor overall survival. Altogether, these results strongly support the use of bispecific antibodies directed against both EGFR and FcγRIIIA (CD16) in mCRC patients, to boost cetuximab-mediated ADCC in RAS wild-type mCRC patients. The preferential overexpression of HLA-E/ß2m in metastases, associated with CD94+ TILs and responsible for a poor prognosis, provides convincing arguments to inhibit this new immune checkpoint with monalizumab, a humanized anti-NKG2A antibody, in combination with anti- FcγRIIIA/EGFR bispecific antibodies as a promising therapeutic perspective in RAS wild-type mCRC patients.

Evaluation of a risk score based on dietary and lifestyle factors to target a population at risk in colorectal cancer screening.

BACKGROUND: The aim of our study was to assess three risk scores to predict lesions, advanced neoplasia (high-risk adenomas and colorectal cancer (CRC)) and CRC in individuals who participate to colorectal cancer screening. METHODS: The data of dietary and lifestyle risk factors were carried out during 2 mass screening campaigns in France (2013-2016) and the FOBT result was collected until December 2018. The colonoscopy result in positive FOBT was recovered. Three risk scores (Betés score, Kaminski score and adapted-HLI) were calculated to detect individuals at risk of lesions. RESULTS: The Betés score had an AUROC of 0.63 (95% CI, [0.61-0.66]) for lesions, 0.65 (95% CI, [0.61-0.68]) for advanced neoplasia and 0.65 (95% CI, [0.58-0.72]) for predicting screen-detected CRC. The adapted HLI score had an AUROC of 0.61 (95% CI, [0.58-0.65]) for lesions, 0.61 (95% CI, [0.56-0.65]) for advanced neoplasia and 0.55 (95% CI, [0.45-0.65]) for predicting screen-detected CRC. The Kaminski score had an AUROC of 0.65 (95% CI, [0.63-0.68]) for lesions, 0.65 (95% CI, [0.61-0.68]) for advanced neoplasia and 0.69 (95% CI, [0.62-0.76]) for predicting screen-detected CRC. CONCLUSION: A simple questionnaire based on CRC risk factors could help general practitioners to identify participants with higher risk of significant colorectal lesions and incite them to perform the fecal occult blood test.

A predictive score of inadequate bowel preparation based on a self-administered questionnaire: PREPA-CO.

INTRODUCTION: Inadequate bowel preparation before colonoscopy has a 20-30% rate and impedes on the quality of the procedure. The aim of this study was to develop a predictive score of inadequate bowel preparation, using a patient questionnaire on potential risk factors. METHODS: In this single center study, consecutive patients with colonoscopy indication were enrolled. The primary outcome was inadequate bowel preparation defined by Boston Bowel Preparation Scale (BBPS) score <7 or a score ≤1 in any of the 3 colonic segments. RESULTS: A total of 561 patients were included. Inadequate bowel preparation was seen in 25.0% of cases. Seven risk factors were selected into the prediction model of inadequate bowel preparation: diabetes or obesity, irregular physical activity, cirrhosis, use of antidepressants or neuroleptics, use of opiate medication, history of surgery and history of inadequate bowel preparation. The risk score, named PREPA-CO, had an AUROC of 0.621, adequately predicted bowel cleanliness in 68.3% of cases, with a specificity of 75.8% and a negative predictive value of 80.8%. CONCLUSION: We developed a predictive score named "Prepa-Co", allowing the identification of patients at high risk of inadequate bowel preparation. In clinical practice, this score could help tailor the prescription of the preparation to the patient.

Renal function in patients receiving streptozocin for locally advanced or metastatic digestive neuroendocrine tumours: results of the Streptotox-FFCD 0906 study.

INTRODUCTION: Streptozocin can impair renal function. The purpose of this study was to evaluate the evolution of renal function in patients receiving this anti-mitotic for the treatment of locally advanced/metastatic digestive well differentiated neuroendocrine tumours. METHODS: A prospective and a retrospective cohort of patients with normal baseline renal function were analysed. The primary endpoint was the incidence of a decrease in the estimated glomerular filtration rate ≥ 25% during treatment. Secondary endpoints were the evaluation of glomerular filtration rate changes, the impact of combined nephrotoxic treatments, other toxicities, compliance, and the objective response rate. RESULTS: After screening 142 patients, 27 were included in the prospective and 84 in the retrospective cohort. A decrease in estimated glomerular filtration rate ≥ 25% was observed in 32 patients (30%): respectively four (15.4%) and 28 patients (34.1%) among respectively 26 and 82 patients with numerous measures (P = 0.0097). Altogether, 39 patients (35%) experienced grade 1-2 renal toxicity, while no grade 3-4 occurred in the prospective and 1 occurred in the retrospective cohort. Renal toxicity was more frequent in the retrospective cohort with a less careful follow up. As best responses, objective response was achieved in 27% of patients with pancreatic primary tumours, disease control in 78.9% of patients with pancreatic primary tumours, in 87% of those with small bowel tumours and in 72.7% of patients with other primary locations. CONCLUSIONS: Strongly recommended for pancreatic NET, streptozocin is associated with frequent mild renal toxicity but low occurrence of renal impairment in patients with baseline normal renal function and under adequate hydration.

Aflibercept in Combination With FOLFIRI as First-line Chemotherapy in Patients With Metastatic Colorectal Cancer (mCRC): A Phase II Study (FFCD 1302).

BACKGROUND: FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) + aflibercept improves median overall survival (OS) and progression-free survival (PFS) in patients with previously treated metastatic colorectal cancer (mCRC). Our aim was to investigate efficacy and tolerability of this combination in the first line. PATIENTS AND METHODS: Patients with untreated documented mCRC received aflibercept plus FOLFIRI every 14 days until progression or unacceptable toxicity in an open, phase II single-arm, multicenter trial. The primary endpoint was the 6-month PFS rate. Secondary endpoints were OS and tolerability. A 2-step Simon design was used with H0: 55% and H1= 75%. Data were analyzed in intention to treat. RESULTS: Forty-one patients were included, and 40 were analyzed (1 consent withdrawal) in 9 French centers between October 2014 and February 2017. The median age was 65 years (range, 46-81 years), 55% had ≥ 2 metastatic sites, and 50% and 15% had RAS and BRAF mutations, respectively. Twenty-two (54.5%; 95% confidence interval, 38.9%-68.5%) patients were alive and non-progressive at 6 months. FOLFIRI + aflibercept was considered ineffective, resulting in the cessation of inclusions. The median follow-up was 34 months. The overall response rate was 55%, and the disease control rate was 80%. The median duration of treatment was 5.3 months; the median PFS and OS were 8.2 and 18.6 months, respectively. Grade 3 to 4 adverse events were mainly gastrointestinal (47.5%) and vascular (32.5%). Of the patients, 87.5% had at least 1 dose modification. CONCLUSION: Although the primary objective was not met, first-line FOLFIRI + aflibercept for mCRC leads to median PFS and OS close to those reported with classical doublet and targeted agents, but with significant toxicities needing dose reduction.

Baseline Splenic Volume as a Prognostic Biomarker of FOLFIRI Efficacy and a Surrogate Marker of MDSC Accumulation in Metastatic Colorectal Carcinoma.

BACKGROUND: Predictive biomarkers of response to chemotherapy plus antiangiogenic for metastatic colorectal cancer (mCRC) are lacking. The objective of this study was to test the prognostic role of splenomegaly on baseline CT scan. METHODS: This study is a sub-study of PRODIGE-9 study, which included 488 mCRC patients treated by 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and bevacizumab in first line. The association between splenic volume, and PFS and OS was evaluated by univariate and multivariable Cox analyses. The relation between circulating monocytic Myeloid derived suppressor cells (mMDSC) and splenomegaly was also determined. RESULTS: Baseline splenic volume > 180 mL was associated with poor PFS (median PFS = 9.2 versus 11.1 months; log-rank p = 0.0125), but was not statistically associated with OS (median OS = 22.6 versus 28.5 months; log-rank p = 0.1643). The increase in splenic volume at 3 months had no impact on PFS (HR 0.928; log-rank p = 0.56) or on OS (HR 0.843; log-rank p = 0.21). Baseline splenic volume was positively correlated with the level of baseline circulating mMDSC (r = 0.48, p-value = 0.031). CONCLUSION: Baseline splenomegaly is a prognostic biomarker in patients with mCRC treated with FOLFIRI and bevacizumab, and a surrogate marker of MDSC accumulation.

Impact of Driver Mutations on the Evolution of Isolated Metachronous Lung Metastasis of Pancreatic Ductal adenocarcinoma.

BACKGROUND: The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing sharply. The survival of patients with metastases is usually about a year. However, the occurrence of isolated lung metastases after resection of the primary tumor, although rare, seems to indicate a better prognosis, with an average survival ranging from 40 to 80 months. KRAS, TP53, CDK2NA, and SMAD4 are the most common driver genes in pancreatic adenocarcinoma. OBJECTIVE: Our objectives were to determine whether a link exists between survival and mutations of driver genes in patients with isolated pulmonary metastases. METHODS: All patients who underwent curative surgery in our institution between 2010 and 2018 were included in the study. From these, we identified patients for whom recurrence was only pulmonary and those with metastases at other sites. KRAS, TP53, CDK2NA, and SMAD4 were analyzed on the primary tumor of patients with pulmonary metastases. RESULTS: Among 233 patients diagnosed with PDAC in our institution over 8 years, 41 (17.5%) underwent curative surgery. Of these, seven (3%) developed isolated pulmonary metastases, 32 developed other metastases, and two did not recur. Median survival was 59 months for patients with isolated lung metastases and 25.3 months for patients with metastases at other sites. An absence of mutations of two driver genes in primary tumors (CDK2NA and SMAD4) was observed in patients with isolated pulmonary metastases. CONCLUSIONS: The absence of mutations in the CDK2NA and SMAD4 tumor-suppressor genes in patients with isolated pulmonary metastases contrasts with the commonly observed high rates of driver gene mutations and suggests a link with overall survival.

Everolimus after hepatic arterial embolisation therapy of metastases from gastrointestinal neuroendocrine tumours: The FFCD 1104-EVACEL-GTE phase II study.

BACKGROUND: Hepatic arterial embolisation therapy (HAET) is a treatment of liver metastases of gastrointestinal neuroendocrine tumours (GI-NETs). HAET increases circulating vascular endothelial growth factor levels. Everolimus is a treatment in NETs that may have antiangiogenic activity. METHODS: This phase II study was conducted in patients with predominant and progressive liver metastases from GI-NETs. Everolimus was initiated 7-30 days after HAET. The hypothesis was that everolimus after HAET would increase hepatic progression-free survival (hPFS) rate at 24 months from 35% to 50%. RESULTS: Among the 74 patients included, 88% had small-bowel primary tumour, 43% had grade I and 57% grade II tumour, and 51% had extrahepatic metastases. Patients underwent one (n = 19), two (n = 54), or three (n = 1) HAET procedures. hPFS at 24 months was 33% (95% confidence interval [CI], 22.5-43.7); 40 (54%) patients had objective response. Median (95% CI) hPFS, PFS, and overall survival were 19 (14-23), 17 (13-22), and 51 (33-60) months. The most common grade III-IV toxicities (>5%) in patients receiving both HAET and everolimus (n = 67) were elevated liver enzymes (55%), fatigue (18%), diarrhoea (16%), anaemia (12%), hypertriglyceridaemia (7%) and mucositis (6%). CONCLUSIONS: The primary end-point was not reached. This sequence allows high liver response with HAET, and everolimus controls the extrahepatic disease. TRIAL REGISTRATION: NCT01678664 (clinicaltrials.gov).

Contribution of the OC Sensor® immunoassay in comparison to the Hemoccult II® guaiac-test in organized colorectal cancer screening.

Colorectal cancer (CRC) is a major cause of cancer-related death of worldwide with high incidence and mortality rate, accessible to a screening program in France, first with guaiac- based fecal occult blood test (g-FOBT) then with fecal immunochemical tests (FIT), since 2015, because of better accuracy. The aim of our study was to compare the characteristics of screen-detected lesions in two successive CRC screening campaigns, using two different tests (Hemoccult II® and OC Sensor®) in the department of Maine-et-Loire, and to precise the performance of these tests [participation rate, detection rates (DR), positive predictive value (PPV)]. Participants, invited by CAP SANTE 49, with polyps or cancer at the colonoscopy after a positive screening test between 01/01/2013 and 31/12/2016 were included. A guaiac-based fecal occult blood test (g-FOBT) was used from January 2013 to December 2014 and a FIT was used from June 2015 to December 2016). 2575 participants, 642 in g-FOBT group and 1933 in FIT group had lesions. Participation rate was not different between tests (p = 0.104), whereas DR and PPV were statistically higher in FIT for all lesions (2.61, 95% CI [2.50-2.70] vs 0.93, 95% CI [0.90-1.00], p < 0.0001 and 64.84, 95% CI [63.10-66.60], 50.00, 95% CI [47.30-52.70], p < 0.0001 respectively). FIT detects more precancerous lesions (adenomas, p < 0.001, and advanced adenomas, p < 0.001) than g-FOBT but g-FOBT detects more serrated polyps (p = 0.025). AAs were more in right colon in FIT than g-FOBT (p = 0.035). No different participation rate was detected between FIT and g-FOBT but DR and PPV of all lesions was higher with FIT.

Chemotherapy for Well-Differentiated Pancreatic Neuroendocrine Tumours with a Ki-67 Index ≥10%: Is There a More Effective Antitumour Regimen? A Retrospective Multicentre Study of the French Group of Endocrine Tumours (GTE).

BACKGROUND: The best chemotherapy regimen for well- differentiated pancreatic neuroendocrine tumours (pNETs) with a Ki-67 index ≥10% is still debated. We evaluated the antitumour efficacy of various first-line chemotherapy regimens (streptozocin based, platinum based, or dacarbazine/temozolomide based) in this situation. METHODS: In this retrospective multicentre study of the French Group of Endocrine Tumours (GTE), we recruited consecutive patients with advanced well-differentiated pNETs and a Ki-67 index ≥10% receiving chemotherapy between 2000 and 2012. The primary endpoint was progression-free survival (PFS) according to RECIST. RESULTS: Seventy-four patients (42 men, median age 55.5 years) were enrolled from 10 centres. Fifty-one patients (69%) had grade 2 NET and 61 (82%) were stage IV. Median overall survival was 36.3 months. Forty-four patients (59%) received streptozocin-based, 18 (24%) platinum-based, and 12 (16%) dacarbazine/temozolomide-based chemotherapy regimens. These 3 groups were similar regarding age, functioning tumours, grade, the number of metastatic sites, and surgery for primary tumours, but not regarding surgery for metastases and time since diagnosis. Grade 3 NET (HR 2.15, 95% CI: 1.18-3.92, p = 0.012) and age above 55 years (HR 1.84, 95% CI: 1.06-3.18, p = 0.030) were associated with shorter median PFS in the multivariate analyses. Compared to streptozocin-based chemotherapy, no difference was found in terms of PFS for the platinum-based or for the dacarbazine/temozolomide-based chemotherapy regimen: median PFS was 7.2, 7.5, and 7.2 months, respectively (p = 0.51). CONCLUSIONS: Patients with intermediate or highly proliferative well-differentiated pNETs may benefit from 1 of the 3 chemotherapy regimens. Increased age and grade 3 were associated with shorter median PFS. Randomised studies searching for response predictors and the best efficacy-tolerance ratio are required to personalise the strategy.

Relationship Between the Expression of O6-Methylguanine-DNA Methyltransferase (MGMT) and p53, and the Clinical Response in Metastatic Pancreatic Adenocarcinoma Treated with FOLFIRINOX.

BACKGROUND: To date, no predictive biomarker for the efficacy of FOLFIRINOX in metastatic pancreatic adenocarcinoma has been demonstrated. Deficiency in O6-methylguanine-DNA methyltransferase (MGMT) has been associated with a therapeutic response in endocrine tumors of the pancreas and the lack of expression of protein 53 (p53) could interfere with the action of MGMT. OBJECTIVE: The aim of our study was to assess the prevalence of MGMT and p53 in patients with metastatic pancreatic adenocarcinoma treated with FOLFIRINOX as a first-line treatment and to investigate their association with therapeutic response and survival. PATIENTS AND METHODS: The immunohistochemical expression of MGMT was recorded as present or absent and the expression of p53 was semi-quantitatively scored in 30 patients with metastatic pancreatic adenocarcinoma, at Angers Hospital in France between September 2011 and June 2015. Clinical and radiologic data were collected retrospectively. RESULTS: The presence or absence of MGMT expression entailed no significant differences in response rate. Median values of progression-free survival (PFS) and overall survival (OS) were lower in patients with MGMT expression, but sample size is too small to conclude that there is a statistically significant difference. No significant relationship for response rate and PFS was observed in relation with p53 expression. By contrast, patients with a strong tumor expression of p53 had a significantly lower OS compared to patients with no or weak expression of the protein (p = 0.027). There was a positive correlation between the expression of p53 and MGMT (p = 0.08). CONCLUSIONS: These preliminary findings suggest that for patients treated with FOLFIRINOX as a first-line treatment for metastatic pancreatic adenocarcinoma, the immunohistochemical evaluation of MGMT could not predict the clinical outcome; however, the survival was not significant probably because of the under-powered study (due to small sample size). A strong tumor expression of p53 is associated with a poor prognosis of OS.

Short article: Evaluation of O6-methylguanine-DNA methyltransferase as a predicting factor of response to temozolomide-based chemotherapy in well-differentiated metastatic pancreatic neuroendocrine tumors.

OBJECTIVE: Temozolomide (TMZ) is an alkylating agent frequently used in well-differentiated metastatic pancreatic neuroendocrine tumors (PNETs) with very variable responses. O-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme whose loss of expression has been suggested to be predictive of response to TMZ in various human tumors. We evaluated the predictive value of MGMT status, assessed by immunohistochemistry (IHC) and methylation-specific PCR (MS-PCR), in well-differentiated metastatic PNETs treated by a TMZ-based chemotherapy. PATIENTS AND METHODS: All patients with metastatic PNETs treated with TMZ-based chemotherapy between 2010 and 2016 in two academic centers, for whom the tumor samples were available, were included. Clinical data were collected and the MGMT status of the tumors was analyzed using MS-PCR and IHC. RESULTS: Twenty-two patients (nine men, median age 61 years) were included. The loss of MGMT protein expression detected by IHC was observed in 13 (59%) patients and MGMT promoter hypermethylation was detected by MS-PCR in three (15%) out of 20 interpretable cases. MGMT status did not correlate significantly with the best radiological response according to the Response Evaluation Criteria In Solid Tumors criteria or with progression-free survival. There was no correlation between MGMT protein expression and MGMT gene promoter methylation. CONCLUSION: These results indicate that a deficient MGMT status in PNETs, determined by loss of protein expression in IHC or by the presence of MGMT gene promoter methylation measured by MS-PCR, is not associated with a better response to TMZ-based chemotherapy and cannot be used as a predictive marker to lead treatment decisions.

Intraoperative Contrast-Enhanced Ultrasound in Colorectal Liver Metastasis Surgery Improves the Identification and Characterization of Nodules.

INTRODUCTION: The sensitivity of preoperative assessment of colorectal liver metastases (CRLM) ranges from 74 to 80%. Intraoperative ultrasound (IOUS) associated with contrast-enhanced intraoperative ultrasound (CE-IOUS) may be able to improve this. Thus, the aims of this study were to assess the value of IOUS and CE-IOUS for the surgical approach and to determine risk factors both for the detection of new nodules and for the modification of the surgical strategy. MATERIALS AND METHODS: Forty-three patients who underwent CRLM surgery were included. These patients had an MRI in the 8 weeks preceding surgery and benefited from intraoperative IOUS and CE-IOUS. RESULTS AND DISCUSSION: The use of IOUS/CE-IOUS permitted the identification of 43 additional lesions and an improved characterization of nodules in 23 patients with a resulting modification of surgical strategy. Lesions were down-staged in six patients and up-staged in six patients. Chemotherapy (p = 0.02) and the presence of nodules in the left lobe (p = 0.04) were predictive factors for finding new nodules at IOUS/CE-IOUS. The discovery of a new nodule systematically modified surgical management. IOUS/CE-IOUS improved intraoperative management of liver metastases. The techniques enable pertinent modification of surgical resections and a reduction of residual lesions.

Metastatic hepatocellular carcinoma: when surgery and successive palliative treatments lead to remission.

Hepatocellular carcinoma (HCC) is the third leading cause of death by cancer worldwide. The prognosis of patients with metastatic HCC remains limited, with an expected median survival lower than 50% at 1 year. Here, we report the case of a 63-year-old man who suffered from a small HCC in the liver and a large unique metastasis in the right adrenal gland. A surgical resection of both lesions was performed. Seven months later, HCC recurred with an isolated right renal metastatic lymphadenopathy and a high alpha-fetoprotein level. HCC was brought under control by sorafenib; the alpha-fetoprotein level was greatly reduced but remained moderately elevated and stable over 2 years after the onset of chemotherapy. Additional external radiotherapy on the metastatic lymphadenopathy led to a normalization of the alpha-fetoprotein level and discontinuation of sorafenib treatment. One year after the end of radiotherapy, a second isolated metastasis occurred in the right lung. This tumor was surgically removed. Twenty-one months after this second surgical procedure, i.e., more than 5.5 years after the initial diagnosis of metastatic HCC, the patient was asymptomatic and tumor free.

Efficacy of everolimus in patients with metastatic insulinoma and refractory hypoglycemia.

BACKGROUND: Refractory hypoglycemia in patients with metastatic insulinoma is an important cause of morbidity and mortality. Everolimus could be a new therapeutic option. METHODS: Within the French Group, we conducted a retrospective, multicentric study of endocrine tumors to evaluate the time to the first recurrence of symptomatic hypoglycemia, after everolimus initiation, in patients with metastatic insulinoma and refractory hypoglycemia. Ongoing hyperglycemic medical options, tumor response, and safety information were recorded. RESULTS: Twelve patients with metastatic insulinoma and refractory hypoglycemia who were treated with everolimus between May 2007 and June 2011 were reviewed. Everolimus (starting dose, 10 mg/day, except in one patient, 5 mg/day) was given after a median of four previous therapeutic lines. Medication aimed at normalizing blood glucose levels in 11 patients. After a median duration of 6.5 months (range 1-35+ months), median time to the first recurrence of symptomatic hypoglycemia was 6.5 months (range 0 to 35+ months). Three patients discontinued everolimus because of cardiac and/or pulmonary adverse events at 1, 1.5, and 7 months after initiation, which led to two deaths. Three patients discontinued everolimus because of tumor progression at 2, 3, and 10 months after initiation, without recurrence of hypoglycemia. CONCLUSION: Everolimus appears to be a new effective treatment for patients with metastatic insulinoma and refractory hypoglycemia. Tolerance should be carefully monitored.

Calpain 2-dependent IκBα degradation mediates CPT-11 secondary resistance in colorectal cancer xenografts.

CPT-11 (irinotecan), the first-line chemotherapy for advanced stage colorectal cancer, remains inactive in about half of patients (primary chemoresistance) and almost all initial responders develop secondary resistance after several courses of treatment (8 months on average). Nude mice bearing HT-29 colon cancer xenografts were treated with CPT-11 and/or an NF-κB inhibitor for two courses. We confirm that NF-κB inhibition potentiated CPT-11 anti-tumoural effect after the first course of treatment. However, tumours grew again at the end of the second course of treatment, generating resistant tumours. We observed an increase in the basal NF-κB activation in resistant tumours and in two resistant sublines, either obtained from resistant HT-29 tumours (HT-29R cells) or generated in vitro (RSN cells). The decrease of NF-κB activation in HT-29R and RSN cells by stable transfections with the super-repressor form of IκBα augmented their sensitivity to CPT-11. Comparing gene expression profiles of HT-29 and HT-29R cells, we identified the S100A10/Annexin A2 complex and calpain 2 as over-expressed potential NF-κB inducers. SiRNA silencing of calpain 2 but not of S100A10 and/or annexin A2, resulted in a decrease in NF-κB activation, an increase in cellular levels of IκBα and a partial restoration of the CPT-11 sensitivity in both HT-29R and RSN cells, suggesting that calpain 2-dependent IκBα degradation mediates CPT-11 secondary resistance. Thus, targeted therapies directed against calpain 2 may represent a novel strategy to enhance the anti-cancer efficacy of CPT-11.

Fatigue in irritable bowel syndrome: characterization and putative role of leptin.

OBJECTIVES: Fatigue has received little attention in the irritable bowel syndrome. Emerging evidence exists that leptin may be involved in the pathogenesis of fatigue in several conditions. We aimed to evaluate the occurrence of fatigue and its characteristics in irritable bowel syndrome and to analyze the relationship between fatigue and leptin. METHODS: We enrolled 51 consecutive irritable bowel syndrome patients and 22 healthy controls without fatigue. None of them were depressed. The Fatigue Impact Scale was used to evaluate fatigue. RESULTS: In all, 62.7% of irritable bowel syndrome patients verbally expressed fatigue and rated more than 4 on the visual analog scale. The total score of fatigue was significantly higher in irritable bowel syndrome than in controls. In irritable bowel syndrome patients, but not in controls, a significant association was found between the total score of fatigue and leptin and this association was more pronounced in 32 irritable bowel syndrome patients who verbally expressed fatigue (r=0.60; P=0.0003). In irritable bowel syndrome, leptin correlated with fatigue independently from age, sex, fat mass and body mass index. CONCLUSIONS: Our study shows that fatigue occurs in 62.7% of irritable bowel syndrome patients when systematically asked for. Fatigue influences all three domains of the Fatigue Impact Scale in irritable bowel syndrome, the most being the physical and the psychosocial domains. Fatigue is associated with circulating leptin levels independently from age, sex, fat mass and body mass index in irritable bowel syndrome. The metabolic sequence involved in the occurrence of fatigue remains to be determined.

Gallbladder motility and gut hormone plasma levels in subjects with and without gallstones.

Hormonal control of gallbladder motility is still unclear in patients with cholelithiasis. In a case-control study, we determined the characteristics of gallbladder emptying evaluated sonographically and the hormone levels of somatostatin, gastrin, and pancreatic polypeptide, before and after a fatty meal in 10 gallstone patients compared with 20 healthy subjects. Patients with lithiasis had a larger residual volume (median 12,0 ml vs 6,5 ml; P = 0.01) and a lower gallbladder ejection fraction (43% vs 70%, P = 0.02) than healthy subjects. During fasting, plasma pancreatic polypeptide concentrations were significantly higher in lithiasis patients (P < 0.03). In contrast, no differences between the two groups of patients were observed during the post prandial period. Somatostatin and gastrin plasma levels were similar in the two groups. Lastly, the serum bile salt levels were in the normal range and were not different between groups both during fasting and postprandial states. We conclude that large basal plasma concentrations of pancreatic polypeptide, a gut peptide inducing gallbladder relaxation, may constitute a factor facilitating lithogenesis.