Neuropilin 2 and soluble neuropilin 2 in neuroendocrine neoplasms.

Neuropilin 2 (NRP2), a transmembrane non-tyrosine kinase receptor, has been described as a potential critical player in the tumourigenesis of several solid cancers and particularly in neuroendocrine neoplasms (NENs). A soluble form of NRP2 (sNRP2) has been previously described and corresponds to a truncated splice isoform. Its prognostic value has never been studied in NEN. NRP2 expression was studied by immunochemistry on tissue microarrays (n = 437) and on circulating tumour cells (CTCs, n = 5 patients with neuroendocrine carcinoma, NEC). We described the levels of sNRP2 in 229 patients with NEN using the ELISA method to identify the factors associated with sNRP2 levels and to evaluate its prognostic role; 90 blood donors represented the healthy control group. NRP2 was found in 97% of neuroendocrine tumours (396/410) and in 74% of NEC (20/27). NRP2 was also expressed in CTC of all the studied patients. The receiver operating characteristic (ROC) analysis showed that sNRP2 had a weak capacity to discriminate between NEN patients and healthy controls (area under curve (AUC) = 0.601, P = 0.053). Abnormal sNRP2 levels were associated with inflammatory syndrome, bone and peritoneal metastases, and abnormal chromogranin A levels. Patients with high sNRP2 levels (sNRP2Q3-Q4) had significantly poorer overall survival in multivariate analysis (HR 0.16, 95% CI (0.04-0.67), P = 0.015). In conclusion, the present study found that sNRP2 and NRP2 could represent a new prognostic biomarker and a therapeutic target, respectively, particularly in aggressive NEN.

Characteristics and treatment options of glucagonomas: a national study from the French Group of Endocrine Tumors and ENDOCAN-RENATEN network.

OBJECTIVE: Glucagonoma is a very rare functional pancreatic neuroendocrine tumor (PanNET). We aimed to provide data on the diagnosis, prognosis, and management of patients with glucagonoma. DESIGN AND METHODS: In this retrospective national cohort, we included all patients with glucagonoma, defined by at least 1 major criterion (necrolytic migratory erythema [NME] and/or recent-onset diabetes, and/or weight loss ≥ 5 kg) associated with either glucagonemia > 2 × upper limit of normal or positive glucagon immunostaining. Antisecretory efficacy was defined as partial/complete resolution of glucagonoma symptoms. Antitumor efficacy was assessed according to the time to next treatment (TTNT). RESULTS: Thirty-eight patients were included with median age 58.7 yo, primary PanNET located in the tail (68.4%), synchronous metastases (63.2%). Median Ki-67 index was 3%. Most frequent glucagonoma symptoms at diagnosis were NME (86.8%), weight loss (68.4%), and diabetes (50%). Surgery of the primary PanNET was performed in 76.3% of cases, mainly with curative intent (61.5%). After surgery, complete resolution of NME was seen in 93.8% (n = 15/16). The secretory response rates were 85.7%, 85.7%, 75%, and 60% with surgery of metastases (n = 6/7), chemotherapy (n = 6/7), liver-directed therapy (n = 6/8), and somatostatin analogs (n = 6/10), respectively. All lines combined, longer TTNT was reported with chemotherapy (20.2 months). Median overall survival (OS) was 17.3 years. The Ki-67 index > 3% was associated with shorter OS (hazard ratio 5.27, 95% CI [1.11-24.96], P = .036). CONCLUSION: Patients with glucagonoma had prolonged survival, even in the presence of metastases at diagnosis. Curative-intent surgery should always be considered. Chemotherapy, peptide receptor radionuclide therapy, or liver-directed therapy seems to provide both substantial antitumor and antisecretory efficacies.

cfDNA in pancreatic neuroendocrine carcinoma management with Cushing's syndrome.

Summary: We report a case of metastatic pancreatic neuroendocrine carcinoma associated with paraneoplastic Cushing's syndrome, successively treated with five lines of treatment (platin-etoposide, LV5FU2-dacarbazine, FOLFIRINOX, pembrolizumab, and paclitaxel) and anti-secretory treatment. Circulating-free DNA (cfDNA) was analysed at each morphological evaluation starting from the second-line treatment. cfDNA changes were well correlated with the disease course, and cfDNA may be used as a predictive marker and/or as an early marker of response. In addition, the absolute count of atypical cells was elevated upon disease progression. Learning points: cfDNA changes were well correlated with the Cushing's syndrome course and with the tumour burden changes assessed by laboratory markers and by RECIST criteria.cfDNA analysis was used to determine the pharmacogenetic patterns of the present patient.An elevated number of atypical circulating cells was noticed upon disease progression.

ctDNA in Neuroendocrine Carcinoma of Gastroenteropancreatic Origin or of Unknown Primary: The CIRCAN-NEC Pilot Study.

INTRODUCTION: Gastroenteropancreatic neuroendocrine carcinomas (GEPNEC) are characterized by a heterogeneous molecular profile and a poor prognosis. Circulating tumour DNA (ctDNA) analysis may be useful for NEC management. This study aimed at describing ctDNA mutations, to assess their predictive value for response to chemotherapies, and their change according to disease progression. METHODS: The CIRCAN-NEC study included patients with GEPNEC or NEC from an unknown primary, scheduled to begin first- or second-line chemotherapy. Blood samples were collected prior to chemotherapy initiation, at first evaluation, and during disease progression. ctDNA was sequenced by next-generation sequencing (NGS). Molecular response was defined as a decrease of at least 30% of the mutant allele fraction. RESULTS: All 24 patients included received platinum-etoposide first-line chemotherapy; 19 received a FOLFIRI-based post-first-line regimen. Twenty-two patients had at least one driver mutation: TP53 (n = 21), RB1 (n = 2), KRAS (n = 4), and BRAF (n = 3). Ten (42%) had an "adenocarcinoma-like" profile. Five of 6 patients with matching ctDNA/tissue NGS harboured at least one concordant mutation (44% concordance at the gene level). The concordance rate between ctDNA mutation/immunohistochemistry profile was 64% (7/11) for TP53/p53+ and 14% (1/7) for RB1/pRb-. In this pilot study including few patients by subgroups, patients with KRAS (HR = 3.60, 95% CI [1.06-12.04]) and BRAF (HR = 4.25, 95% CI [1.11-16.40]) mutations had shorter progression-free survival (PFS) under platinum-etoposide, while the 2 patients with RB1 mutations had shorter PFS under FOLFIRI-based chemotherapy. Twenty-eight periods of treatment were assessed: 10 patients had a molecular response (7/10 had a morphological response), which was associated with longer PFS (HR = 0.37, 95% CI [0.15; 0.91]). CONCLUSION: This pilot study shows a high sensitivity of ctDNA assessment, which is encouraging for the future management of GEPNEC (tumour molecular diagnosis and evaluation of disease progression).

Retrospective evaluation of FOLFIRI3 alone or in combination with bevacizumab or aflibercept in metastatic colorectal cancer.

BACKGROUND: The treatment of metastatic colorectal cancer (mCRC) relies of chemotherapy. The efficacy of the standard FOLFIRI-therapy could be improved by a modification of the regimen by splitting the dose of irinotecan on day 1 and day 3 in the FOLFIRI3 regimen. AIM: To determine safety and efficacy of FOLFIRI3 regimen. METHODS: This is a monocentric retrospective study evaluating the efficacy and safety of the FOLFIRI3 regimen given alone or in combination with bevacizumab or aflibercept in patients with previously treated mCRC. RESULTS: One hundred and fifty-three consecutive patients were included (18 treated with FOLFIRI3, 99 with FOLFIRI3 plus bevacizumab and 36 with FOLFIRI3 plus aflibercept). The overall response rate (ORR) and disease control rate were 51% and 62%, respectively. Similar ORRs were observed in all 3 cohorts. Median progression-free survival (PFS) and overall survival (OS) were 3.9 mo (95%CI: 3.2-4.9) and 9.4 mo (95%CI: 6.6-12), respectively. Median PFS and OS values were improved in the FOLFIRI3 plus aflibercept group. The most common grade 3-4 adverse events were diarrhoea (21.6%) and neutropenia (11.8%), and these toxicities were more frequent in the FOLFIRI3 plus aflibercept group. According to the multivariate Cox proportional model, previous surgery of metastasis and aflibercept were associated with outcomes. CONCLUSION: The modification of the FOLFIRI regimen impacted treatment response of mCRC patients. The addition of an antiangiogenic agent, in particular aflibercept, enhanced the clinical benefit and improved survival.

The patient, the doctor, and the patient's loyalty: a qualitative study in French general practice.

BACKGROUND: The term loyalty can be defined as the attachment that characterises someone who consistent in their feelings, affections, or habits. By introducing the Declaration of General Practitioner (or preferred doctor declaration) in 2004, France adopted a formal incentive for patients to be faithful to their doctor since it entailed optimal coverage of medical care by their national health insurance There has been no research evaluating the impact of this measure and to determine the components of doctor-patient loyalty. AIM: To explore what builds and maintains patients' loyalty to their GP. DESIGN AND SETTING: Qualitative study based on semi-structured interviews close to Paris (the département of Yvelines'), France. METHOD: Twenty-eight patients were interviewed in five surgeries of self-employed GPs with different demographics. Interviews were transcribed and a thematic analysis conducted to categorise the data. Phenomenological analysis was used to analyse the transcripts. RESULTS: Patient loyalty is based mainly on trust. Trust can be reinforced by certain comforting factors such as the ability to listen, a sense of carefulness, and the quality of care. Loyalty is both a dynamic construct and a relational exchange subject to various influences. Patients find advantages in being loyal. The model of the 'family doctor' has always been the archetype of loyalty for several generations within one family. A GP's inability to meet all of the patient's requirements is not necessarily a determining factor in breaking the patient's loyalty. CONCLUSION: Loyalty is more complex than commonly assumed and involves dimensions of trust, listening, quality of care, availability, and familiarity. The observations drawn out from this study warrant a larger scale investigation.

Outcomes of bacteremia due to Pseudomonas aeruginosa with reduced susceptibility to piperacillin-tazobactam: implications on the appropriateness of the resistance breakpoint.

BACKGROUND: Bacteremia due to Pseudomonas aeruginosa is associated with grave clinical outcomes. Recent studies have emphasized the importance of appropriate empirical therapy, but controversy arises when piperacillin-tazobactam is used against isolates with reduced susceptibility. METHODS: We performed a retrospective cohort study of pseudomonal bacteremia from 2002 to 2006. Patients were identified by the microbiology laboratory database, and pertinent clinical data (demographic characteristics, baseline Acute Physiology and Chronic Health Evaluation [APACHE] II scores, source of bacteremia, and therapy) were retrieved from the electronic medical records. All patients received appropriate empirical therapy within 24 h of positive culture results. Patients receiving piperacillin-tazobactam were compared with those receiving other agents (control subjects). The primary outcome was 30-day mortality from the first day of bacteremia. RESULTS: A total of 34 bacteremia episodes were identified involving isolates with reduced susceptibility to piperacillin-tazobactam (minimum inhibitory concentration, 32 or 64 mg/L, reported as susceptible); piperacillin-tazobactam was empirically given in 7 episodes. There was no significant difference in baseline characteristics between the 2 groups. Thirty-day mortality was found to be 85.7% in the piperacillin-tazobactam group and 22.2% in the control group (P = .004). Time to hospital mortality was also found to be shorter in the piperacillin-tazobactam group (P < .001). In the multivariate analysis, 30-day mortality was found to be associated with empirical piperacillin-tazobactam therapy (odds ratio, 220.5; 95% confidence interval, 3.8-12707.4; P = .009), after adjustment for differences in age and APACHE II score. CONCLUSIONS: In P. aeruginosa bacteremia due to isolates with reduced piperacillin-tazobactam susceptibility, empirical piperacillin-tazobactam therapy was associated with increased mortality. Additional studies are warranted to examine the appropriateness of the current Clinical Laboratory Standards Institute resistance breakpoint of piperacillin-tazobactam.

Prevalence of diarrhea at a university hospital and association with modifiable risk factors.

OBJECTIVE: To assess the prevalence of diarrhea at a university-affiliated medical center and the presence of modifiable risk factors. METHODS: A point prevalence survey was conducted. All patients hospitalized for more than 24 hours were asked if they were experiencing diarrhea. Stools of patients not previously tested were assessed for Clostridium difficile (CD) toxins A and B. Univariate analysis and multivariate logistic regression analyses were used to identify modifiable variables associated with diarrhea (significance defined as p < 0.05). RESULTS: Four hundred eighty-five hospitalized patients were interviewed, of whom 60 (12.4%) reported 2 or more loose, unformed stools in the last 24 hours. Six of 81 (7.4%) patients tested positive for CD toxin. Three (50%) of the CD toxin-positive patients had not previously been tested during the current admission. Patients with diarrhea were more likely to have tested CD toxin-positive (OR 10.6; p = 0.01), received antibiotics (OR 1.79; p = 0.04), or been hospitalized for a longer period of time (p = 0.04). CONCLUSIONS: Diarrhea was prevalent in 12.4% of hospitalized patients at a large university hospital at one point in time. Patients with diarrhea were more likely to have CD infection, receive antibiotics, or experience a longer hospitalization. Half of the CD diarrhea cases occurring in the hospital had been previously unidentified. Hospitalized patients should be evaluated for diarrhea on an ongoing basis with appropriate interventions instituted.

An integrated pharmacoeconomic approach to antimicrobial formulary decision-making.

PURPOSE: The utility of a novel interdisciplinary approach to antimicrobial formulary decision-making was studied. METHODS: Pseudomonas aeruginosa minimum inhibitory concentration (MIC) distribution data for cefepime and ceftazidime were retrieved from nonrepeat isolates obtained from November 2002 to October 2003. Unbound drug exposures were simulated for 5000 patients using the Monte Carlo method. Weighted target attainment rates (TARs) were calculated for cefepime and ceftazidime 1 g every 8 hours and 1 g every 12 hours (infused over 0.5, 2, and 4 hours), using three representative pharmacodynamic targets (percentage of time above the MIC of 67%, 100%, and 400%). RESULTS: MIC data for 1230 nonrepeat P. aeruginosa were analyzed. The MIC at which 90% of the P. aeruginosa isolates were inhibited was 16 and 32 mg/L for cefepime and ceftazidime, respectively. Drug acquisition cost was the highest with cefepime 1 g given every 8 hours (37.56 dollars/day), followed by cefepime 1 g every 12 hours (25.04 dollars/day) and ceftazidime 1 g every 8 hours (22.26 dollars/day). When infused over 0.5 hour, the highest TAR was achieved with cefepime 1 g every 8 hours (82%), followed by ceftazidime 1 g every 8 hours (77%) and cefepime 1 g every 12 hours (66%); ceftazidime 1 g every 8 hours was 70% more cost-effective than cefepime 1 g every 8 hours. Cefepime 1 g every 12 hours, infused over 4 hours, increased the TAR to 89% and was similar in cost-effectiveness to ceftazidime 1 g every 8 hours infused over 0.5 hour. CONCLUSION: An integrated pharmacoeconomic approach to antimicrobial formulary decision-making addressed local resistance patterns, population pharmacokinetics, pharmacodynamics, dosing regimens, and drug acquisition costs. This method appeared to be more realistic and objective than the conventional approach of considering only drug acquisition costs, especially for agents in a similar structural or functional class.

Rifaximin: a nonabsorbable rifamycin antibiotic for use in nonsystemic gastrointestinal infections.

Rifaximin is a poorly water-soluble and minimally absorbed (<0.4%) rifamycin with in vitro activity against enteric Gram-negative bacteria including enteric pathogens. Fecal levels of the drug after 3 days' oral therapy exceed 8000 microg/g. Rifaximin is effective in the treatment and prevention of travelers' diarrhea due to Escherichia coli-predominant bacterial pathogens. It shows lower activity against dysenteric forms of bacterial diarrhea. The drug may be useful in other enteric infectious diseases, including Clostridium difficile colitis, pediatric bacterial diarrhea and Helicobacter pylori gastritis and chronic gastrointestinal disorders including hepatic encephalopathy, small bowel bacterial overgrowth, inflammatory-bowel disease, irritable-bowel syndrome and pouchitis. Importantly, rifaximin does not appear to lead to bacterial resistance. Rifaximin has an excellent safety profile and adverse drug reactions have been comparable to those associated with the placebo control agent.