Perioperative FOLFOX 4 Versus FOLFOX 4 Plus Cetuximab Versus Immediate Surgery for High-Risk Stage II and III Colon Cancers: A Phase II Multicenter Randomized Controlled Trial (PRODIGE 22).

BACKGROUND: Perioperative chemotherapy has proven valuable in several tumors, but not in colon cancer (CC). OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of perioperative chemotherapy in patients with locally advanced nonmetastatic CC. METHODS: This is a French multicenter randomized phase II trial in patients with resectable high-risk T3, T4, and/or N2 CC on baseline computed tomography (CT) scan. Patients were randomized to receive either 6 months of adjuvant FOLFOX after colectomy (control) or perioperative FOLFOX for 4 cycles before surgery and 8 cycles after (FOLFOX peri-op). In RAS wild-type patients, a third arm testing perioperative FOLFOX-cetuximab was added. Tumor Regression Grade (TRG1) of Ryan et al was the primary endpoint. Secondary endpoints were toxicity, perioperative morbidity, and quality of surgery. RESULTS: A total of 120 patients were enrolled. At interim analysis, the FOLFOX-cetuximab arm was stopped (lack of efficacy). The remaining 104 patients (control, n = 52; FOLFOX preop n = 52) represented our intention-to-treat population. In the FOLFOX perioperative group, 96% received the scheduled 4 cycles before surgery. R0 resection and complete mesocolic excision rate were 94% and 93%, respectively. Overall mortality and morbidity rates were similar in both groups. Perioperative FOLFOX chemotherapy did not improve major pathological response rate (TRG1 = 8%) but was associated with a significant pathological regression (TRG1-2 = 44% vs 8%, P < 0.001) and a trend to tumor downstaging as compared to the control group. CT scan criteria were associated with a 33% rate of overstaging in control group. CONCLUSIONS: Perioperative FOLFOX for locally advanced resectable CC is feasible with an acceptable tolerability but is not associated with an increased major pathological response rate as expected. However, perioperative FOLFOX induces pathological regression and downstaging. Better preoperative staging tools are needed to decrease the risk of overtreating patients.

Development and internal validation of a diagnostic score for gastric linitis plastica.

BACKGROUND: There is no consensual definition for gastric linitis plastica (GLP). We aim to construct a diagnostic score to distinguish this rare tumor from usual gastric adenocarcinomas. METHODS: In this retrospective study, all patients who had gastrectomy for cancer between 2007 and 2017 in French tertiary centers were included. The outcome was a diagnosis of GLP based on pathological review of the surgical specimen. The diagnostic score was created by using variables that were most frequently associated with GLP using penalized logistic regression on multiply imputed datasets. We used discrimination measures to assess the performances of the score. Internal validation was performed using bootstrapping methods to correct for over-optimism. RESULTS: 220 patients including 71 linitis plastica (female 49%, median age 57 years) were analyzed. The six parameters retained in the diagnosis score were the presence of large folds and/or parietal thickening on at least one segment, pangastric infiltration and presence of gastric stenosis on the upper endoscopy, circumferential thickening on at least one segment and thickening of the third hyperechogenic layer on endoscopic ultrasound and the presence of signet ring cells on endoscopic biopsies. The area under the ROC curve (AUC) was 0.967 with a sensitivity of 94% [89.9-97.3] and a specificity of 88.7% [81.7-95.8] for a threshold of 2.75. After internal validation, the corrected AUC was 0.959. CONCLUSION: It is the first study validating a pre-therapeutic diagnostic score (Saint Louis linitis score) with an excellent ability to discriminate GLP from non-GLP adenocarcinomas. An external validation is necessary to confirm our data.

Colorectal cancer (CRC) monitoring by 6-monthly 18FDG-PET/CT: an open-label multicentre randomised trial.

Background: [18F]2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (18FDG-PET/CT) has high sensitivity for detecting recurrences of colorectal cancer (CRC). Our objective was to determine whether adding routine 6-monthly 18FDG-PET/CT to our usual monitoring strategy improved patient outcomes and to assess the effect on costs. Patients and methods: In this open-label multicentre trial, patients in remission of CRC (stage II perforated, stage III, or stage IV) after curative surgery were randomly assigned (1 : 1) to usual monitoring alone (3-monthly physical and tumour marker assays, 6-monthly liver ultrasound and chest radiograph, and 6-monthly whole-body computed tomography) or with 6-monthly 18FDG-PET/CT, for 3 years. A multidisciplinary committee reviewed each patient's data every 3 months and classified the recurrence status as yes/no/doubtful. Recurrences were treated with curative surgery alone if feasible and with chemotherapy otherwise. The primary end point was treatment failure defined as unresectable recurrence or death. Relative risks were estimated, and survival was analysed using the Kaplan-Meier method, log-rank test, and Cox models. Direct costs were compared. Results: Of the 239 enrolled patients, 120 were in the intervention arm and 119 in the control arm. The failure rate was 29.2% (31 unresectable recurrences and 4 deaths) in the intervention group and 23.7% (27 unresectable recurrences and 1 death) in the control group (relative risk = 1.23; 95% confidence interval, 0.80-1.88; P = 0.34). The multivariate analysis also showed no significant difference (hazards ratio, 1.33; 95% confidence interval, 0.8-2.19; P = 0.27). Median time to diagnosis of unresectable recurrence (months) was significantly shorter in the intervention group [7 (3-20) versus 14.3 (7.3-27), P = 0.016]. Mean cost/patient was higher in the intervention group (18 192 ± 27 679 € versus 11 131 ± 13 €, P < 0.033). Conclusion: 18FDG-PET/CT, when added every 6 months, increased costs without decreasing treatment failure rates in patients in remission of CRC. The control group had very close follow-up, and any additional improvement (if present) would be small and hard to detect. ClinicalTrials.gov identifier: NCT00624260.

Energy expenditure in acute pancreatitis evaluated by the Harris-Benedict equation compared with indirect calorimetry.

OBJECTIVES: Enteral nutrition (EN) is recommended for severe acute pancreatitis (AP) and for biliary AP if cholecystectomy is delayed. Energy expenditure (EE) is calculated using the Harris-Benedict equation (HBE), but indirect calorimetry (IC) can also be employed. We wished to compare EE evaluated by the HBE equation, modified HBE (mHBE) and IC at study inclusion and 1 month after AP resolution. METHODS: We undertook a single-center prospective study in Paris, France. RESULTS: Among 35 patients, 19 had biliary AP and 11 alcoholic-related AP. Eleven cases had severe AP. There was no significant difference between EE calculated by the HBE and that using IC at study inclusion. However, the EE calculated by the mHBE was significantly higher than that calculated using IC. For severe AP, the HBE underestimated EE whereas the mHBE overestimated it. No difference was found based on the cause of AP. There was no difference between methods for EE at 30 days. CONCLUSIONS: The HBE underestimated EE for severe AP, whereas the mHBE overestimated it. IC seems to be the best means of EE evaluation for AP.

Elevated plasma pancreatic enzyme concentrations after Roux-en-Y gastric bypass may indicate closed loop obstruction.

Laparoscopic Roux-en-Y gastric bypass is one of the most commonly performed bariatric procedures and most patients are women of reproductive age. Consequently, general surgeons and obstetricians need to be aware that these patients are at risk of bariatric specific surgical complications during their pregnancy. We report a case involving a 32-year-old woman who had undergone Roux-en-Y gastric bypass surgery 2 years previously. She presented at 25 weeks of gestation with a closed loop obstruction due to a retrograde jejunojejunal intussusception that was initially misdiagnosed as acute pancreatitis.

FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3.

Patients with neuroendocrine carcinomas (NECs) grade 3 have a poor prognosis. Etoposide-platinum combination is the standard chemotherapy but the role of a second-line therapy remains unknown. Irinotecan alone or in combination has shown some efficacy in patients treated for small cell lung cancer which had pathological similarities with neuroendocine tumors. The aim of this study is to determine safety and efficacy of the FOLFIRI regimen in patients with NECs grade 3 after failure of etoposide-platinum combination. This study was retrospective, including patients with NECs grade 3 and treated with the FOLFIRI regimen after progression or toxicity of etoposide-platinum combination in first-line. Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≥3 and/or serum alkaline phosphatase ≥5×upper limit of normal value (ULN) and/or bilirubin ≥1.5×ULN were excluded. Among 39 patients who failed etoposide-platinum combination, 19 (49%; 12 women, median age 53 (29-78) years) received the FOLFIRI regimen with a median number of 6 (1-16) courses. Six patients (31%) had at least one episode of grades 3-4 toxicity (neutropenia, n=3; diarrhea, n=3) without toxic death. Six patients (31%) had objective response, 6 (31%) stable disease, and 7 (38%) tumor progression. Median progression-free survival under FOLFIRI was 4 months. Overall survival was 18 vs 6.8 months in noneligible patients. FOLFIRI regimen is a safe and potentially efficient chemotherapy given as second-line in patients with NECs grade 3 who remain in good condition and with correct liver tests after failure of etoposide-platinum combination. These results should be confirmed in a future prospective study.

Pre-treatment lymphopenia as a prognostic biomarker in colorectal cancer patients receiving chemotherapy.

BACKGROUND: Lymphopenia is a predictor of the efficacy and hematological toxicity of chemotherapy in various advanced cancers. There is little data about this relationship in colorectal cancer. In this retrospective study, the influence of pretreatment lymphopenia on hematological toxicity and the efficacy of chemotherapy was investigated in colorectal cancer patients. PATIENTS AND METHODS: In total, 260 patients were included in the study. Correlations between pre-treatment lymphopenia (lymphocyte count < 1,000/µl) and the occurrence of hematological toxicity and efficacy of first-line palliative chemotherapy were investigated. RESULTS: Lymphopenia was found in 49/260 (19%) patients. Ten of these patients with lymphopenia (20.4%) experienced severe hematological toxicity compared with 17 of the remaining 211 (8%) patients (P = 0.01). Lymphopenia was identified as an independent factor for hematological toxicity. Among patients who received palliative chemotherapy, the objective response rate was significantly lower in lymphopenic patients than in the other patients (12.5% vs. 40.2%; P = 0.004). Lymphopenia was strongly associated with shorter progression-free survival (median 4 vs. 7 months; P = 0.033) and shorter overall survival (median 16 vs. 24 months, P = 0.024). Multivariate analysis revealed that lymphopenia had an independent effect on survival. CONCLUSIONS: Our findings show that lymphopenia is an independent predictive factor for both hematological toxicity and efficacy of chemotherapy in colorectal cancer. Pre-treatment lymphocyte count may represent a simple and new predictive biomarker of chemotherapy effects in colorectal cancer patients.

Element-selective X-ray detected magnetic resonance: a novel application of synchrotron radiation.

X-ray detected magnetic resonance (XDMR) is a new element-selective spectroscopy in which X-ray magnetic circular dichroism is used to probe the resonant precession of spin and orbital magnetization components when a strong microwave pump field is applied perpendicularly to the static bias field. Experimental configurations suitable for detecting the very weak XDMR signal are compared. XDMR signatures were measured in yttrium iron garnet and related thin films on exciting not only the iron K-edge but also the yttrium at diamagnetic sites. These measurements are shown to yield unique information regarding the wide-angle precession of induced magnetization components involving either orbital p-projected densities of states at the iron sites, or spin polarized d-projected densities of states at the yttrium sites. Extending XDMR measurements into the millimeter wave range would make it possible to study paramagnetic systems routinely and investigate optical modes as well as acoustic modes in ferrimagnetic/antiferromagnetic systems.

Advanced detection systems for X-ray fluorescence excitation spectroscopy.

This paper accounts for selected detector developments carried out over the past 15 years within the ESRF X-ray Absorption Spectroscopy group. This includes various types of photodiodes used as integrated current detectors. Special emphasis is put on the long-standing development of a Si drift-diode array suitable for energy-dispersive detection of X-ray fluorescence. This detector, which is now operational, was used to record high-quality XMCD/XAFS spectra on [Fe70Pt30] nanoparticles highly dispersed on a Si wafer. Using numerically deconvoluted spectra, energy resolution was decreased to 82 eV for the Si Kalphabeta line, 126 eV for the Fe Kalpha line and 176 eV for the Pt Lalpha line. A high-vacuum-compatible high-energy-resolution crystal analyzer was also installed on ID12, making it possible to record X-ray fluorescence excitation spectra in the photon-in/photon-out mode over a wide spectral range. Prospects of adapting these methods in order to investigate biological samples are briefly discussed.

Development of 32-channel silicon drift detectors and digital electronics for X-ray spectroscopy.

The performance of silicon-drift-detector (SDD) arrays and digital electronics designed for X-ray absorption spectroscopy in the fluorescence excitation mode is reported. Different detectors have been manufactured and tested: two single-channel SDDs with different active areas (10 mm(2) and 1 cm(2)) and a monolithic 2 cm(2) SDD with eight readout anodes. The energy resolution varies between 160 and 170 eV FWHM. A new digital multichannel shaping amplifier has been produced. Its performance is presented in comparison with that of a standard commercial shaper.