A phase II study of retifanlimab (INCMGA00012) in patients with squamous carcinoma of the anal canal who have progressed following platinum-based chemotherapy (POD1UM-202).

BACKGROUND: Locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) has poor prognosis following platinum-based chemotherapy. Retifanlimab (INCMGA00012), a humanized monoclonal antibody targeting programmed death protein-1 (PD-1), demonstrated clinical activity across a range of solid tumors in clinical trials. We present results from POD1UM-202 (NCT03597295), an open-label, single-arm, multicenter, phase II study evaluating retifanlimab in patients with previously treated advanced or metastatic SCAC. PATIENTS AND METHODS: Patients ≥18 years of age had measurable disease and had progressed following, or were ineligible for, platinum-based therapy. Retifanlimab 500 mg was administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Overall, 94 patients were enrolled. At a median follow-up of 7.1 months (range, 0.9-19.4 months), ORR was 13.8% [95% confidence interval (CI) 7.6% to 22.5%], with one complete response (1.1%) and 12 partial responses (12.8%). Responses were observed regardless of human immunodeficiency virus or human papillomavirus status, programmed death ligand 1 (PD-L1) expression, or liver metastases. Stable disease was observed in 33 patients (35.1%) for a DCR of 48.9% (95% CI 38.5% to 59.5%). Median DOR was 9.5 months (range, 5.6 months-not estimable). Median (95% CI) PFS and OS were 2.3 (1.9-3.6) and 10.1 (7.9-not estimable) months, respectively. Retifanlimab safety in this population was consistent with previous experience for the PD-(L)1 inhibitor class. CONCLUSIONS: Retifanlimab demonstrated clinically meaningful and durable antitumor activity, and an acceptable safety profile in patients with previously treated locally advanced or metastatic SCAC who have progressed on or are intolerant to platinum-based chemotherapy.

Relevance of biopsy-derived pancreatic organoids in the development of efficient transcriptomic signatures to predict adjuvant chemosensitivity in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) patients are frequently treated by chemotherapy. Even if personalized therapy based on molecular analysis can be performed for some tumors, PDAC regimens selection is still mainly based on patients' performance status and expected efficacy. Therefore, the establishment of molecular predictors of chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. We have recently developed an RNA-based signature that predicts the efficacy of adjuvant gemcitabine using 38 PDAC primary cell cultures. While demonstrated its efficiency, a significant association with the classical/basal-like PDAC spectrum was observed. We hypothesized that this flaw was due to the basal-like biased phenotype of cellular models used in our strategy. To overcome this limitation, we generated a prospective cohort of 27 consecutive biopsied derived pancreatic organoids (BDPO) and include them in the signature identification strategy. As BDPO's do not have the same biased phenotype as primary cell cultures we expect they can compensate one with each other and cover a broader range of molecular phenotypes. We then obtained an improved signature predicting gemcitabine sensibility that was validated in a cohort of 300 resected PDAC patients that have or have not received adjuvant gemcitabine. We demonstrated a significant association between the improved signature and the overall and disease-free survival in patients predicted as sensitive and treated with adjuvant gemcitabine. We propose then that including BDPO along primary cell cultures represent a powerful strategy that helps to overcome primary cell cultures limitations producing unbiased RNA-based signatures predictive of adjuvant treatments in PDAC.

Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab in metastatic colorectal cancer: a dose-expansion, phase I study.

BACKGROUND: In preclinical studies trifluridine/tipiracil (FTD/TPI) plus oxaliplatin (Industriestrasse, Holzkirchen, Germany) sensitised microsatellite stable (MSS) metastatic colorectal cancer (mCRC) to anti-programmed cell death protein-1; the addition of oxaliplatin or bevacizumab (F Hoffmann- la ROCHE AG, Kaiseraugst, Switzerland) enhanced the antitumour effects of FTD/TPI. This study aimed to investigate the safety and efficacy of FTD/TPI plus oxaliplatin and either bevacizumab or nivolumab (Uxbridge business Park, Uxbridge, United Kingdom) in patients with mCRC who had progressed after at least one prior line of treatment. PATIENTS AND METHODS: In 14-day cycles, patients received FTD/TPI 35 mg/m2 (twice daily, days 1-5) plus oxaliplatin 85 mg/m2 (day 1), and, on day 1, either bevacizumab 5 mg/kg (cohort A) or nivolumab 3 mg/kg (cohort B). Patients in Cohort B had confirmed MSS status. RESULTS: In total, 54 patients were enrolled: 37 in cohort A and 17 in cohort B. Recruitment in cohort B was stopped early due to the low response rate (RR) observed at interim analyses of efficacy. The most common adverse events (AEs) in cohort A were neutropenia/decreased neutrophils (75.7%), nausea (59.5%), vomiting (40.5%), diarrhoea (37.8%), peripheral sensory neuropathy (37.8%), fatigue (35.1%) and decreased appetite (35.1%). In cohort B, the most common AEs were neutropenia/decreased neutrophils (70.6%), diarrhoea (58.8%), nausea (47.1%), vomiting (47.1%), fatigue (47.1%), asthenia (41.2%), paraesthesia (41.2%), thrombocytopenia/decreased platelets (35.3%) and decreased appetite (35.3%). Confirmed objective RR was 17.1% in cohort A and 7.1% in cohort B; the corresponding values for median progression-free survival in the two cohorts were 6.3 and 6.0 months. CONCLUSION: FTD/TPI plus oxaliplatin and bevacizumab or nivolumab had an acceptable safety profile and demonstrated antitumour activity in previously treated patients with mCRC.

A transcriptomic signature to predict adjuvant gemcitabine sensitivity in pancreatic adenocarcinoma.

BACKGROUND: Chemotherapy is the only systemic treatment approved for pancreatic ductal adenocarcinoma (PDAC), with a selection of regimens based on patients' performance status and expected efficacy. The establishment of a potent stratification associated with chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. PATIENTS AND METHODS: Concomitant chemosensitivity and genome-wide RNA profiles were carried out on preclinical models (primary cell cultures and patient-derived xenografts) derived from patients with PDAC included in the PaCaOmics program (NCT01692873). The RNA-based stratification was tested in a monocentric cohort and validated in a multicentric cohort, both retrospectively collected from resected PDAC samples (67 and 368 patients, respectively). Forty-three (65%) and 203 (55%) patients received adjuvant gemcitabine in the monocentric and the multicentric cohorts, respectively. The relationships between predicted gemcitabine sensitivity and patients' overall survival (OS) and disease-free survival were investigated. RESULTS: The GemPred RNA signature was derived from preclinical models, defining gemcitabine sensitive PDAC as GemPred+. Among the patients who received gemcitabine in the test and validation cohorts, the GemPred+ patients had a higher OS than GemPred- (P = 0.046 and P = 0.00216). In both cohorts, the GemPred stratification was not associated with OS among patients who did not receive gemcitabine. Among gemcitabine-treated patients, GemPred+ patients had significantly higher OS than the GemPred-: 91.3 months [95% confidence interval (CI): 61.2-not reached] versus 33 months (95% CI: 24-35.2); hazard ratio 0.403 (95% CI: 0.221-0.735, P = 0.00216). The interaction test for gemcitabine and GemPred+ stratification was significant (P = 0.0245). Multivariate analysis in the gemcitabine-treated population retained an independent predictive value. CONCLUSION: The RNA-based GemPred stratification predicts the benefit of adjuvant gemcitabine in PDAC patients.

Continuation versus discontinuation of first-line chemotherapy in patients with metastatic squamous cell oesophageal cancer: A randomised phase II trial (E-DIS).

PURPOSE: The role of chemotherapy has not been established in the treatment of metastatic squamous cell oesophageal cancer (mESCC). PATIENTS AND METHODS: E-DIS is a discontinuation trial, aimed at estimating efficacy, quality of life and safety of chemotherapy continuation (CT-CONT) in patients with mESCC who are free from progression after a selection phase of chemotherapy. The primary end-point was overall survival. RESULTS: Sixty-seven patients were randomised. The 9-month survival rate was 50% (85% confidence interval [CI]: 37-62%) and 48% (85% CI: 35-60%) in the CT-CONT arm and in the chemotherapy discontinuation (CT-DISC) arm, respectively. The time until definitive deterioration of the global health status (European Organisation for Research and Treatment of Cancer [EORTC] core quality of life questionnaire) was 6.6 months (95% CI: 3.3-12.4) for the CT-CONT arm and 4.2 months (95% CI: 2.9-6.3) for the CT-DISC arm, with a hazard ratio (HRCT-DISC/CT-CONT) = 1.44 (95% CI: 0.82-2.53). We observed a beneficial trend in favour of CT-CONT (HR > 1) for most dimensions, including an improvement for three dimensions (dysphagia, eating and oesophageal pain) of the EORTC Oesophageal Cancer Module QLQ-OES18. CONCLUSION: CT-CONT provides an overall survival rate that is similar to CT-DISC. E-DIS trial provides valuable data to support shared decision-making between physicians and patients regarding CT-CONT/DISC.

Prognostic factors in patients treated with second-line chemotherapy for advanced gastric cancer: results from the randomized prospective phase III FFCD-0307 trial.

AIM: The aim of this study was to determine prognostic factors in patients treated with second-line therapy (L2) for locally advanced or metastatic gastric and gastro-esophageal junction (GEJ) adenocarcinoma in a randomized phase III study with predefined L2. METHODS: In the FFCD-0307 study, patients were randomly assigned to receive in L1 either epirubicin, cisplatin, and capecitabine (ECX arm) or fluorouracil, leucovorin, and irinotecan (FOLFIRI arm). L2 treatment was predefined (FOLFIRI for the ECX arm and ECX for the FOLFIRI arm). Chi square tests were used to compare the characteristics of patients treated in L2 with those of patients who did not receive L2. Prognostic factors in L2 for progression-free survival (PFS) and overall survival (OS) were analyzed using a Cox model. RESULTS: Among 416 patients included, 101/209 (48.3%) patients in the ECX arm received FOLFIRI in L2, and 81/207 (39.1%) patients in the FOLFIRI arm received ECX in L2. Patients treated in L2, compared with those who only received L1 had : a better ECOG score (0-1: 90.4% versus 79.7%; p = 0.0002), more frequent GEJ localization (40.8% versus 27.6%; p = 0.005), and lower platelet count (median: 298000 versus 335000/mm3; p = 0.02). In multivariate analyses, age < 60 years at diagnosis (HR 1.49, 95% CI 1.09-2.03, p = 0.013) and ECOG score 2 before L2 (HR 2.62, 95% CI 1.41-4.84, p = 0.005) were the only significant poor prognostic factors for OS. CONCLUSION: Age ≥ 60 years at diagnosis and ECOG score 0/1 before L2 were the only favorable prognostic factors for OS.

Risk factors of exocrine and endocrine pancreatic insufficiency after pancreatic resection: A multi-center prospective study.

Management of functional consequences after pancreatic resection has become a new therapeutic challenge. The goal of our study is to evaluate the risk factors for exocrine (ExoPI) and endocrine (EndoPI) pancreatic insufficiency after pancreatic surgery and to establish a predictive model for their onset. PATIENTS AND METHODS: Between January 1, 2014 and June 19, 2015, 91 consecutive patients undergoing pancreatoduodenectomy (PD) or left pancreatectomy (LP) (72% and 28%, respectively) were followed prospectively. ExoPI was defined as fecal elastase content<200µg per gram of feces while EndoPI was defined as fasting glucose>126mg/dL or aggravation of preexisting diabetes. The volume of residual pancreas was measured according to the same principles as liver volumetry. RESULTS: The ExoPI and EndoPI rates at 6 months were 75.9% and 30.8%, respectively. The rate of ExoPI after PD was statistically significantly higher than after LP (98% vs. 21%; P<0.001), while the rate of EndoPI was lower after PD vs. LP, but this difference did not reach statistical significance (28% vs. 38.5%; P=0.412). There was no statistically significant difference in ExoPI found between pancreatico-gastrostomy (PG) and pancreatico-jejunostomy (PJ) (100% vs. 98%; P=1.000). Remnant pancreatic volume less than 39.5% was predictive of ExoPI. CONCLUSION: ExoPI occurs quasi-systematically after PD irrespective of the reconstruction scheme. The rate of EndoPI did not differ between PD and LP.

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

BACKGROUND: Diagnosis 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. PATIENTS AND METHODS: All 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. RESULTS: 253 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 survival was 15.6 (13.6-17.0) months. Significant adverse prognostic factors in univariate analysis were PS > 1 (hazard ratio [HR] = 2.5), metastatic disease (HR = 1.6), NSE>2 upper limit of normal [ULN]; HR = 3.2), CgA>2 ULN (HR = 1.7) and lactate dehydrogenase >2 ULN (HR = 2.1). After first-line palliative chemotherapy (CT1) with platinum-etoposide (n = 152), objective response, progression-free survival and overall survival were 50%, 6.2 and 11.6 months; they were 24%, 2.9 and 5.9, respectively, after post-CT1 FOLFIRI regimen (n = 72). CONCLUSIONS: We 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.

Patterns of recurrence in early-stage oesophageal cancer after chemoradiotherapy and surgery compared with surgery alone.

BACKGROUND: Patterns of disease recurrence in patients with oesophageal cancer following treatment with neoadjuvant chemoradiotherapy and surgery (nCRTS) or surgery alone are poorly reported. An understanding of patterns of disease recurrence is important for subsequent treatment planning. METHODS: An analysis was undertaken of patterns of disease recurrence from a phase III multicentre randomized trial (FFCD9901) comparing nCRTS with surgery alone in patients with stage I and II oesophageal cancer. RESULTS: Some 170 patients undergoing surgical resection were included in the study. R0 resection rates were similar in the two groups: 94 per cent following nCRTS versus 92 per cent after surgery alone (P = 0·749). After a median follow-up of 94·2 months, recurrent disease was found in 39·4 per cent of the overall cohort (31 per cent after nCRTS versus 47 per cent following surgery alone; P = 0·030). Locoregional recurrence was diagnosed in 41 patients (17 versus 30 per cent respectively; P = 0·047) and distant metastatic recurrence in 47 (23 versus 31 per cent respectively; P = 0·244). Metastatic recurrence was more frequent in patients with adenocarcinoma than in those with squamous cell cancer (40 versus 23·1 per cent respectively; P = 0·032). ypT0 N0 category was associated with prolonged time to mixed locoregional and metastatic recurrence (P = 0·009), and time to locoregional (P = 0·044) and metastatic (P = 0·055) recurrence. In multivariable analysis, node-positive disease predicted both locoregional (P = 0·001) and metastatic (P < 0·001) recurrence. CONCLUSION: Locoregional disease control following nCRTS indicated a local field effect not related solely to completeness of resection. pN+ disease was strongly predictive of time to locoregional and metastatic disease recurrence.

Parylene-based flexible neural probes with PEDOT coated surface for brain stimulation and recording.

Implantable neural prosthetics devices offer a promising opportunity for the restoration of lost functions in patients affected by brain or spinal cord injury, by providing the brain with a non-muscular channel able to link machines to the nervous system. Nevertheless current neural microelectrodes suffer from high initial impedance and low charge-transfer capacity because of their small-feature geometry (Abidian et al., 2010; Cui and Zhou, 2007). In this work we have developed PEDOT-modified neural probes based on flexible substrate capable to answer to the three critical requirements for neuroprosthetic device: efficiency, lifetime and biocompatibility. We propose a simple procedure for the fabrication of neural electrodes fully made of Parylene-C, followed by an electropolymerization of the active area with the conductive polymer PEDOT that is shown to greatly enhance the electrical performances of the device. In addition, the biocompatibility and the very high SNR exhibited during signal recording make our device suitable for long-term implantation.

Cortical regulation of dopaminergic neurons: role of the midbrain superior colliculus.

Dopaminergic (DA) neurons respond to stimuli in a wide range of modalities, although the origin of the afferent sensory signals has only recently begun to emerge. In the case of vision, an important source of short-latency sensory information seems to be the midbrain superior colliculus (SC). However, longer-latency responses have been identified that are less compatible with the primitive perceptual capacities of the colliculus. Rather, they seem more in keeping with the processing capabilities of the cortex. Given that there are robust projections from the cortex to the SC, we examined whether cortical information could reach DA neurons via a relay in the colliculus. The somatosensory barrel cortex was stimulated electrically in the anesthetized rat with either single pulses or pulse trains. Although single pulses produced small phasic activations in the colliculus, they did not elicit responses in the majority of DA neurons. However, after disinhibitory intracollicular injections of the GABAA antagonist bicuculline, collicular responses were substantially enhanced and previously unresponsive DA neurons now exhibited phasic excitations or inhibitions. Pulse trains applied to the cortex led to phasic changes (excitations to inhibitions) in the activity of DA neurons at baseline. These were blocked or attenuated by intracollicular administration of the GABAA agonist muscimol. Taken together, the results indicate that the cortex can communicate with DA neurons via a relay in the SC. As a consequence, DA neuronal activity reflecting the unexpected occurrence of salient events and that signaling more complex stimulus properties may have a common origin.

BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer.

BACKGROUND: Sorafenib is an oral anticancer agent targeting Ras-dependent signaling and angiogenic pathways. A phase I trial demonstrated that the combination of gemcitabine and sorafenib was well tolerated and had activity in advanced pancreatic cancer (APC) patients. The BAYPAN study was a multicentric, placebo-controlled, double-blind, randomized phase III trial comparing gemcitabine/sorafenib and gemcitabine/placebo in the treatment of APC. PATIENTS AND METHODS: The patient eligibility criteria were locally advanced or metastatic pancreatic adenocarcinoma, no prior therapy for advanced disease and a performance status of zero to two. The primary end point was progression-free survival (PFS). The patients received gemcitabine 1000 mg/m(2) i.v., weekly seven times followed by 1 rest week, then weekly three times every 4 weeks plus sorafenib 200 mg or placebo, two tablets p.o., twice daily continuously. RESULTS: Between December 2006 and September 2009, 104 patients were enrolled on the study (52 pts in each arm) and 102 patients were treated. The median and the 6-month PFS were 5.7 months and 48% for gemcitabine/placebo and 3.8 months and 33% for gemcitabine/sorafenib (P = 0.902, stratified log-rank test), respectively. The median overall survivals were 9.2 and 8 months, respectively (P = 0.231, log-rank test). The overall response rates were similar (19 and 23%, respectively). CONCLUSION: The addition of sorafenib to gemcitabine does not improve PFS in APC patients.

Prognostic impact of weight loss in 1-year survivors after transthoracic esophagectomy for cancer.

Malnutrition is common 1 year after esophageal cancer surgery. However, the prognostic impact of this malnutrition on long-term outcome has been poorly reported. This study aims at determining the potential effect on disease-free survival (DFS) of weight loss observed at 1 year in disease-free survivors after curative esophageal resection. From a prospective single-institution database, 304 patients having undergone a transthoracic esophagectomy with two-field lymphadenectomy and gastric reconstruction between 1996 to 2008 were identified. Patients who died during the postoperative course (n= 24), patients who died within the first postoperative year (n= 12), patients who presented with an early recurrence within the first postoperative year (n= 20), and those who were lost to follow-up (n= 22) were excluded from the study, as well as those for whom the follow-up was shorter than 1 year (n= 21). The remaining 205 patients constituted a homogeneous group of 1-year disease-free survivors after full postoperative work-up and formed the material of the present study. Body weight (BW) values were collected before any treatment at the onset of symptoms (initial BW) and 1 year after esophagectomy. A 1-year weight loss (1-YWL) exceeding 10% of the initial BW defined an important malnutrition. Impact of the 1-YWL ≥ or <10% of the initial BW on DFS was investigated. Logistic regression was performed to identify factors affecting DFS. The mean initial BW was 69.1 ± 12 kg, corresponding to a mean body mass index (BMI) of 23.8 ± 3 kg/m(2) . Preoperatively, 32 (15%) patients were in the underweight category (BMI < 20 kg/m2), 110 (54%) were in normal (BMI = 20-24 kg/m2), and 63 (31%) were in the overweight category (BMI ≥ 25 kg/m2). Mean 1-year BW was 63.5 ± 12 kg. 1-YWL was <10% of the initial BW in 92 patients (45%) and ≥ 10% in 113 patients (55%). Accordingly, 5-year DFS rates were 66% (median: 80 months) and 48% (median: 51 months), respectively (P= 0.005). On multivariate analysis, only three independent variables affected the DFS significantly: clinical N stage (cN) status (P= 0.007; odds ratio: 1.99, 1.2-3.3), incomplete resection (P= 0.008, OR: 3.6, 1.3-9.3), and 1-YWL ≥ 10% (P= 0.004, OR: 2.1: 1.2-3.4). 1-YWL of or exceeding 10% of the initial BW in 1-year disease-free survivors has a negative prognostic impact on DFS after esophagectomy for cancer. This information offers another view on the objectives of the perioperative nutritional care of these patients. Special vigilance program on the nutritional status in post-esophagectomy patients should be the rule.

Effects of bifeprunox and aripiprazole on rat serotonin and dopamine neuronal activity and anxiolytic behaviour.

The atypical antipsychotic bifeprunox is a partial dopamine D(2) and 5-HT(1A) receptor agonist. Using in-vivo electrophysiological and behavioural paradigms in the rat, the effects of bifeprunox and aripiprazole were assessed on ventral tegmental area (VTA) dopamine and dorsal raphe serotonin (5-HT) cell activity and on foot shock-induced ultrasonic vocalisation (USV). In VTA, bifeprunox and aripiprazole decreased (by 20-50%) firing of dopamine neurons. Interestingly, bursting activity was markedly reduced (by 70-100%), bursting being associated with a larger synaptic dopamine release than single spike firing. Both ligands reduced inhibition of firing rate induced by the full dopamine receptor agonist apomorphine, whereas the D(2) receptor antagonist haloperidol prevented these inhibitory effects, confirming partial D(2)-like agonistic properties. On 5-HT neurons, bifeprunox was more potent than aripiprazole to suppress firing activity. The 5-HT(1A) receptor antagonist WAY-100,635 prevented their effects. In the USV test of anxiolytic-like activity, bifeprunox had higher potency than aripiprazole to reduce vocalisations. Both WAY-100,635 and haloperidol reversed the effects of both agonists. The present in-vivo study shows that bifeprunox is a potent partial D(2)-like and 5-HT(1A) receptor agonist reducing preferentially the phasic activity of dopamine neurons. Thus, bifeprunox would be expected to be an effective compound against positive and negative symptoms of schizophrenia.

[Postoperative follow-up in patients with colorectal cancers who have undergone curative resection: intensive or conventional follow-up?]. / Surveillance des cancers coliques opérés à visée curative: faut-il revoir les recommandations de la conférence de consensus?

Colorectal cancer is one of the most common human malignancies. Surgical resection remains the primary treatment but cancer recurrences (locoregional or distant) are associated with a poor prognosis. Follow-up is of particular importance in the three-years after surgery and various strategies have been purposed in the surveillance of patients after curative resection for colorectal cancer. The objective is to diagnose a recurrence at the earliest possible stage, enabling a second curative treatment. Optimal strategy for follow-up remains controversial. Results from randomized trials comparing low intensity programs and intensive programs of colorectal cancer surveillance are insufficient to recommend a follow-up strategy. To update recommendations for surveillance of colorectal cancer, larger prospective randomized studies are required.

Epidermal growth factor receptor (EGFR) status and K-Ras mutations in colorectal cancer.

BACKGROUND: In advanced colorectal cancer, K-Ras somatic mutations predict resistance to mAbs targeting epidermal growth factor receptor (EGFR). Relationships between K-Ras mutations and EGFR status have not been examined so far. We analyzed relationships between K-Ras mutations and EGFR tumoral status based on EGFR germinal polymorphisms, gene copy number and expression. METHODS: Eighty colorectal tumors (stage 0-IV) and 39 normal mucosas were analyzed. K-Ras mutations at codons 12 and 13 were detected by a sensitive enrichment double PCR-restriction fragment length polymorphism (RFLP) assay. EGFR gene polymorphisms at positions -216G>T, -191C>A and 497Arg>Lys were analyzed (PCR-RFLP), along with CA repeat polymorphism in intron 1 (fluorescent genotyping) and EGFR gene copy number (PCR amplification). EGFR expression was quantified by Scatchard binding assay. RESULTS: The number of EGFR high-affinity sites, dissociation constant (Kd), gene copy number, intron 1, -216G>T, -191C>A or 497Lys>Arg genotypes was not different between K-Ras-mutated or K-Ras-non-mutated tumors. No relationship was observed between any of the analyzed EGFR genotypes and EGFR expression. EGFR expression was not related to gene copy number. EGFR gene copy number in tumor and normal tissue was not correlated. The mean value of the tumor/normal mucosa gene copy number ratio was 1.16. CONCLUSIONS: Present data clearly show that EGFR status is independent of K-Ras mutations in colorectal tumors.

Predictive factors of the response to chemoradiotherapy in esophageal cancer.

BACKGROUND: The aim of this study was to identify factors predictive of a complete endoscopic/histopathological response to chemoradiotherapy in patients with esophageal cancer. PATIENTS: Clinical and histopathological factors (Ki67, p53 and EGFR expression) were studied in 56 patients presenting with esophageal cancer between September 2000 and March 2006 (35 squamous cell carcinomas, 20 adenocarcinomas, one undifferentiated carcinoma). The response to chemoradiotherapy was evaluated endoscopically and by histological examination in 16 patients who underwent surgical resection. RESULTS: Independent factors predictive of a complete endoscopic response were good performance status (RR=15.75; CI: 1.74-142.58; P=0.01) and overexpression of Ki67 (RR=4.46; CI: 1.08-18.31; P=0.04). In patients who underwent surgery, a major histopathological response was associated with complete endoscopic response (P<0.01), complete CT-scan response (P=0.04) and good performance status (WHO=0) (P=0.04). The mean survival was 40 months. Adenocarcinoma histology (RR=3.18, CI: 1.13-8.54; P=0.02) and an impaired performance status (RR=4.79; CI: 1.07-21.41; P=0.04) were independently associated with poor survival. CONCLUSION: In the present study, good performance status and overexpression of Ki67 were two independent factors for complete endoscopic response after chemoradiotherapy for esophageal cancer. Independent risk factors for poor survival were adenocarcinoma histological type and impaired performance status. Further prospective studies are necessary to complete the present results.

Multicentre phase II trial of capecitabine plus oxaliplatin (XELOX) in patients with advanced hepatocellular carcinoma: FFCD 03-03 trial.

Evaluation of new drug combinations is needed to improve patients' prognosis in advanced hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the safety and efficacy of the capecitabine-oxaliplatine combination (XELOX) in HCC patients. First-line chemotherapy with XELOX regimen consisting of a 3-week cycle of intravenous oxaliplatin (130 mg m(-2)) on Day 1, and oral capecitabine twice daily from Days 1-14 (1000 mg m(-2)) was administered in patients with measurable, unresectable HCC. Fifty patients (male, 88%; median age, 68 years) received a total of 295 cycles (median, 6) of treatment. Disease control (three partial responses, 29 stable diseases) rate was 72% (95% CI 57-83%). Median overall and median progression-free (PFS) survival was 9.3 months and 4.1 months, respectively. Progression-free survival rates at 6 and 12 months were 38% (95% CI 26-52%) and 14% (95% CI 7-26%), respectively. Main grade 3-4 drug-related toxicities included diarrhoea (16%), elevation of aminotransferases and/or bilirubin (16%), thrombocytopenia (12%), and neurotoxicity (6%). Capecitabine plus oxaliplatin regimen showed modest anti-tumour activity with tolerable toxicities in patients with advanced HCC. However, the manageable toxicity profile and the encouraging disease control rate deserve further attention for this convenient, outpatient-based chemotherapy regimen.

Induction cisplatin-irinotecan followed by concurrent cisplatin-irinotecan and radiotherapy without surgery in oesophageal cancer: multicenter phase II FFCD trial.

A recent phase I study showed that weekly cisplatin, irinotecan and concurrent radiotherapy can be administered with moderate toxicity in patients with oesophageal cancer. Patients with no prior treatment and oesophageal cancer stage I to III, performance status <3, caloric intake >1,500 kcal day(-1) were included. Chemotherapy, with cisplatin 30 mg m(-2) and irinotecan 60 mg m(-2), was administered at days 1, 8, 22, 29, and concurrently with radiotherapy at days 43, 50, 64 and 71. Radiotherapy was delivered with 50 or 50.4 Gy in 25 fractions/5 weeks. Forty-three patients were included, 10 stage I, 19 stage II and 14 stage III. Mean age was 59.2 years (range 44-79). A total of 30 out of 43 (69.8%) patients underwent all planned treatment. During induction chemotherapy, 14 severe toxicities of grade 3 or 4 in 10 patients (23.3%) were reported with 57.1% due to haematoxicity. During chemoradiotherapy, 31 severe toxicities of grade 3 or 4 with 64.5% due to haematotoxicity were reported in 18 patients. One toxic death occurred (diarrhoea grade 4). The complete clinical response rate was 58.1% (95% CI: 43.4-72.8%). Overall survival rate at 1 and 2 years was 62.8%, (95% CI, 58.3-77.3%) and 27.9% (95% CI, 13.4-41.3%), respectively. In conclusion, cisplatin-irinotecan-radiotherapy is an active and well-tolerated regimen feasible in out-patients.

[Wakefulness and central basal nuclei: experimental observations and possible implications in Parkinson's disease]. / Vigilance et noyaux gris centraux: observations expérimentales et possibles implications dans la maladie de Parkinson.

Movement disorders in Parkinson disease, notably dampened during sleep, are associated with hyperactivity of the subthalamic nucleus (STN), whose origin is controversial. We have studied, on non-anaesthetized head-restrained rats, the STN spontaneous unit activity and the one of its principal GABAergic afferents, the globus pallidus (GP). In normal rats, STN neurons shifted from a random discharge in wakefulness (W) to a bursting pattern in slow wave sleep (SWS), without any change in their mean firing rate. In contrast GP neurons, with a mean firing rate higher in W than in SWS, exhibited a relatively regular discharge rate whatever the vigilance state. During paradoxical sleep, both STN and GP neurons increased markedly their firing rate. When applied during W, GABA-A antagonists increased the STN firing rate but did not change the typical W random pattern. When applied during SWS, they strongly reinforced the spontaneous burst pattern into a particularly marked one with instantaneous frequencies reaching 500Hz. SWS-W transitions occurring during ongoing antagonist iontophoresis invariably disrupted this burst pattern into a random one. On 6-OHDA unilaterally treated rats, the ipsilateral STN was hyperactive whatever the vigilance state (with an abnormal burst pattern during W on some neurons), but this hyperactivity did not seem to be associated with a GP hypoactivity. These results show that STN activity is not inversely correlated with GP activity, that its discharge pattern is strongly dependent on vigilance states, that GABA receptors do not play an exclusive role in regulating its firing pattern, and question the depolarization block hypothesis during STN high frequency stimulation.