This document is a summary of the French Intergroup guidelines regarding the management of digestive neuroendocrine neoplasms (NEN) published in February 2020 (www.tncd.org).
All French medical ...societies involved in the management of NEN took part in this work. Recommendations were graded into four categories (A, B, C or D), according to the level of evidence found in the literature until May 2019.
The management of NEN is challenging because of their heterogeneity and the increasing complexity of diagnostic and therapeutic procedures. Pathological analysis is required for their diagnostic and prognostic characterization, which mainly relies on differentiation, grade and stage. The two main emergency situations are functioning syndromes and poorly-differentiated carcinoma. Chromogranin A is the main biochemical marker of NET, although of limited clinical interest. Initial characterization relies on morphological and isotopic imaging. The treatment of localized NET relies on watchful follow-up and local or surgical resection depending on its supposed aggressiveness. Treatment options for metastatic disease include surgery, somatostatin analogues, chemotherapy, targeted therapies, organ-driven locoregional therapies and peptide-receptor radionuclide therapy. As specific predictive factors of treatment efficacy are yet to be identified and head-to-head comparisons have not or only rarely been performed, the therapeutic strategy currently depends on prognostic factors. Cumulative toxicity and the impact of treatment on quality of life must be considered since survival is relatively long in most patients with NET.
These guidelines are proposed to achieve the most beneficial therapeutic strategy in clinical practice as the therapeutic landscape of NEN is becoming ever more complex. These recommendations are permanently being reviewed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
There is currently no standard second-line treatment for metastatic pancreatic adenocarcinoma (MPA), and progression-free survival is consistently <4 months in this setting. The aim of this study was ...to evaluate the efficacy and tolerability of Nab-paclitaxel plus gemcitabine (A+G) after Folfirinox failure in MPA.
From February 2013 to July 2014, all consecutive patients treated with A+G for histologically proven MPA after Folfirinox failure were prospectively enrolled in 12 French centres. A+G was delivered as described in the MPACT trial, until disease progression, patient refusal or unacceptable toxicity.
Fifty-seven patients were treated with Nab-paclitaxel plus gemcitabine, for a median of 4 cycles (range 1-12). The disease control rate was 58%, with a 17.5% objective response rate. Median overall survival (OS) was 8.8 months (95% CI: 6.2-9.7) and median progression-free survival was 5.1 months (95% CI: 3.2-6.2). Since the start of first-line chemotherapy, median OS was 18 months (95% CI: 16-21). No toxic deaths occurred. Grade 3-4 toxicities were reported in 40% of patients, consisting of neutropenia (12.5%), neurotoxicity (12.5%), asthenia (9%) and thrombocytopenia (6.5%).
A+G seems to be effective, with a manageable toxicity profile, after Folfirinox failure in patients with MPA.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The occurrence of KRAS mutation is predictive of nonresponse and shorter survival in patients treated by anti-epidermal growth factor receptor (anti-EGFR) antibody for metastatic colorectal cancer ...(mCRC), leading the European Medicine Agency to limit its use to patients with wild-type KRAS tumors. However, only half of these patients will benefit from treatment, suggesting the need to identify additional biomarkers for cetuximab-based treatment efficacy.
We retrospectively collected tumors from 173 patients with mCRC. All but one patient received a cetuximab-based regimen as second-line or greater therapy. KRAS and BRAF status were assessed by allelic discrimination. EGFR amplification was assessed by chromogenic in situ hybridization and fluorescent in situ hybridization, and the expression of PTEN was assessed by immunochemistry.
In patients with KRAS wild-type tumors (n = 116), BRAF mutations (n = 5) were weakly associated with lack of response (P = .063) but were strongly associated with shorter progression-free survival (P < .001) and shorter overall survival (OS; P < .001). A high EGFR polysomy or an EGFR amplification was found in 17.7% of the patients and was associated with response (P = .015). PTEN null expression was found in 19.9% of the patients and was associated with shorter OS (P = .013). In multivariate analysis, BRAF mutation and PTEN expression status were associated with OS.
BRAF status, EGFR amplification, and cytoplasmic expression of PTEN were associated with outcome measures in KRAS wild-type patients treated with a cetuximab-based regimen. Subsequent studies in clinical trial cohorts will be required to confirm the clinical utility of these markers.
Background
Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is increasingly used to manage gastric cancer peritoneal metastasis (GCPM).
Methods
This study analyzed a prospective database of ...GCPM patients treated with cisplatin and doxorubicin PIPAC (PIPAC-C/D). The outcome criteria were adverse events, pathologic response peritoneal regression grading score (PRGS), and overall survival (OS).
Results
The PIPAC-C/D procedure was scheduled for 144 patients with a median age of 57 years (range 22–88 years). Access to the abdominal cavity for the first PIPAC failed in 11 patients (7.7 %). A total of 296 procedures were performed for 131 patients. Of the 144 patients, 52 (36.1%) underwent one PIPAC, 32 (22.2%) underwent two PIPACs, 24 (16.7%) underwent three PIPACs, and 21 (14.6%) underwent four or more PIPACs. The overall morbidity/mortality was grade 1 for 22 patients (15.3%), grade 2 for 32 patients (22.2%), grade 3 for 7 patients (4.9%), grade 4 for no patients (0%), and grade 5 for 2 patients (1.4%). Of the 37 patients who had three or more PIPACs eligible for histopathologic response analysis, 27 (73%) had major or complete regression (PRGS 1/2). A median OS of 11 months (range 0–61 months) for the total study population and 16 months (range 2–61 months) for the patients with three or more PIPACs was observed. For 10 patients (7%) who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, the median OS was 15 months (minimum, 4 months; maximum, 27 months). Multivariate analysis showed three or more PIPACs to be an independent prognostic factor for improved OS (hazard ratio, 0.36;
p
< 0.0001).
Conclusions
Repetitive PIPAC-C/D ± systemic chemotherapy is associated with low morbidity and mortality rates. Prospective randomized trials are needed to confirm whether three or more PIPAC-C/Ds improve clinical outcome.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Elderly patients form a heterogeneous population. Evaluation of geriatric factors may help evaluate a patient's health status to better adapt treatment.
Elderly patients with previously untreated ...metastatic colorectal cancer (mCRC) were randomly assigned to receive fluorouracil (FU) -based chemotherapy either alone or in combination with irinotecan (IRI) in the Fédération Francophone de Cancérologie Digestive (FFCD) 2001-02 study. Sites participating in the geriatric substudy completed geriatric screening tools to perform prognostic factor analyses for treatment safety during the first 4 months after treatment initiation.
The geriatric score was calculated in 123 patients (44%). Median age was 80 years (range, 75 to 91 years). The Charlson comorbidity index was ≤ 1 in 75%, Mini-Mental State Examination (MMSE) score was ≤ 27/30 in 31%, and Instrumental Activities of Daily Living (IADL) showed impairment in 34% of the patients. Seventy-one patients (58%) had grade 3 to 4 toxicity, 41 (33%) had a dose-intensity reduction of more than 33%, and 54 (44%) had at least one unexpected hospitalization during the first 4 months after starting treatment. In multivariate analysis, significant predictive factors for grade 3-4 toxicity were IRI arm (odds ratio OR, 5.03), MMSE ≤ 27/30 (OR, 3.84), and impaired IADL (OR, 4.67); for dose-intensity reduction of > 33%, the significant predictive factors were alkaline phosphates > 2 × upper limit of normal (OR, 4.16) and IRI arm (OR, 6.85); and for unexpected hospitalization, significant predictive factors were MMSE ≤ 27/30 (OR, 4.56) and Geriatric Depression Scale ≤ 2 (OR, 5.52).
Geriatric factors (MMSE and IADL) are predictive of severe toxicity or unexpected hospitalization (MMSE) in a randomized prospective phase III study in mCRC. These results suggest that cognitive function and autonomy impairment should be taken into account when choosing a regimen for chemotherapy.
Background
The benefit of repetitive PIPAC specifically in CPM patients has yet to be demonstrated in terms of oncological and functional outcomes.
Objective
The aim of this study was to evaluate the ...outcome of patients with non-resectable colorectal peritoneal metastases (CPM) treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC).
Methods
We conducted an analysis of a prospective single-center database of all CPM patients who underwent PIPAC with oxaliplatin 92 mg/m
2
body surface (PIPAC-Ox). The outcome criteria were adverse events (Common Terminology Criteria for Adverse Events version 4.0), Peritoneal Regression Grading Score (PRGS), and survival.
Results
Overall, 102 patients with a median age of 64 years (33–88) were scheduled for PIPAC-Ox. Access to the abdominal cavity for the first application failed in 22/102 (21.6%) patients. A total of 185 PIPACs were performed, with 26/102 (25.5%), 20/102 (19.6%), 17/102 (16.7%), and 17/102 (16.7%) patients undergoing one, two, three, and four or more PIPACs, respectively. Perioperative overall morbidity/mortality Grade I–V occurred in 14 (7.6%), 29 (15.8%), 6 (3.2%), 1 (0.5%), and 1 (0.5%) patient without significant differences between each cycle. Of 27 patients who underwent three or more PIPACs, 20/102 (19.6%) had major/complete CPM regression (PRGS 1–2). In a multivariate analysis, independent predictive factors for > 12 months’ survival following the first PIPAC-Ox administration were three or more PIPACs (odds ratio OR 4.5, 95% confidence interval CI 1.35–15.2;
p
= 0.014) and younger patient age (OR 1.058, 95% CI 1.00–1.12;
p
= 0.039).
Conclusions
Repetitive PIPAC-Ox for CPM patients, alone or combined with perioperative systemic chemotherapy, is feasible. Our data suggest that three or more consecutive PIPAC-Ox cycles for advanced CPM can improve survival.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
: Colorectal cancer (CRC) is a highly devastating cancer. Ca
-dependent channels are now considered key regulators of tumor progression. In this study, we aimed to investigate the association of ...non-voltage gated Ca
channels and Ca
-dependent potassium channels (KCa) with CRC using the transcriptional profile of their genes.
: We selected a total of 35 genes covering KCa channels
-
,
and their subunits
-
, endoplasmic reticulum (ER) calcium sensors
and
, Ca
channels
and the family of cation channels TRP (
-
and
). We analyzed their expression in two public CRC datasets from The Cancer Genome Atlas (TCGA) and GSE39582.
:
and
were induced while
and
were downregulated in tumor tissues comparing to normal tissues. In proximal tumors,
and
were upregulated while
and
were downregulated.
decreased in lymph node metastatic tumors.
and
predicted poor prognosis in CRC patients. Moreover, we found that
ratio is increased in CRC progression and predicted poor prognosis.
KCa and Ca
channels could be important contributors to CRC initiation and progression. Our results provide new insights on KCa and Ca
channels remodeling in CRC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•Smart combination of B formal method and diverse electronics.•Safety critical systems do not require high profiles anymore.•Connection with DSLs to seamlessly integrate existing development ...cycle.•Connection with proved system-level model, to derive software specification.
The CLEARSY Safety Platform (CSSP) was designed to ease the development of safety critical systems and to reduce the overall costs (development, deployment, and certification) under the pressure of the worldwide market. A smart combination of hardware features (double processor) and formal method (B method and code generators) was used to produce a SIL4-ready platform where safety principles are built-in and cannot be altered by the developer. Summarizing a 5-year return of experience in the effective application in the railways, this article explains how this approach is a game-changer and tries to anticipate the future of this platform for safety critical systems. In particular, the education of future engineers and the seamless integration in existing engineering processes with the support of Domain Specific Languages are key topics for a successful deployment in other domains. DSL like Robosim to program mobile robots and relay circuits to design railway signaling systems are connected to the platform.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hepatocholangiocarcinoma (cHCC-ICC) is a rare liver tumour for which no data on chemosensitivity exist. The aims of this multicentre study were to evaluate overall survival (OS), progression-free ...survival (PFS), and prognostic factors in cHCC-ICC treated by gemcitabine plus platinum as first-line.
Unresectable cHCC-ICC treated by gemcitabine plus platinum-based chemotherapy between 2008 and 2017 were retrospectively analysed. Diagnosis was based on histology or, in case of ICC or HCC histology, on discordant computerised tomography scan enhancement patterns associated with discordant serum tumour marker elevation suggesting the alternative tumour. OS and PFS were evaluated by Kaplan-Meier method and prognostic factors by Log-rank test and Cox model.
Among 30 patients included, cHCC-ICC was histologically proven in 22 (73.3%). 18 (60%) received gemcitabine plus oxaliplatin (GEMOX), 9 (30%) GEMOX plus bevacizumab, and 3 (10%) gemcitabine plus cisplatin. RECIST criteria were reported in 28 patients: 8 (28.6%) showed partial response, 14 (50%) stable disease, and 6 (21.4%) tumour progression at first evaluation. Median PFS and OS were 9.0 and 16.2 months, respectively. Serum bilirubin ⩾30 μmol l
(P=0.001) and positive serology for HBV and/or HCV (P=0.014) were independent poor prognostic factors for OS.
Gemcitabine plus platinum-based chemotherapy is effective as first-line for advanced cHCC-ICC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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