Prognostic and predictive value of the Immunoscore in stage III colon cancer patients treated with oxaliplatin in the prospective IDEA France PRODIGE-GERCOR cohort study.

BACKGROUND: The Immunoscore (IS), which prognostically classifies stage I-III colon cancer (CC) patients, was evaluated in the International Duration Evaluation of Adjuvant Therapy (IDEA) France cohort study investigating 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy in stage III CC patients. PATIENTS AND METHODS: Densities of CD3+ and CD8+ T cells in the tumor and invasive margin were determined by immunohistochemistry, quantified by digital pathology, and converted to IS. Mismatch repair status was determined by immunohistochemistry or by pentaplex PCR. Prediction of disease-free survival (DFS) by IS was analyzed by a multivariable Cox regression model in each study arm. Harrell's C-statistics were used to investigate the IS performance. RESULTS: Samples of 1322 patients were available. IS Low, Intermediate (Int), and High were observed in 43.6%, 47.0%, and 9.4% of patients, respectively. IS Low identified patients at higher risk of relapse or death compared with Int + High [hazard ratio (HR) = 1.54; 95% confidence interval (CI) 1.24-1.93, P = 0.0001]. The 3-year DFS was 66.80% (95% CI 62.23-70.94) for IS Low and 77.14% (95% CI 73.50-80.35) for IS Int + High. In multivariable analysis, IS remained significantly independently associated with DFS (P = 0.003) when adjusted for sex, histological grade, T/N stage, and microsatellite instability. For mFOLFOX6-treated patients (91.6% of the cohort), a statistical significant interaction was observed for the predictive value of IS for treatment duration (3 versus 6 months) in terms of DFS (P = 0.057). IS Int + High significantly predicted benefit of 6 months of treatment (HR = 0.53; 95% CI 0.37-0.75; P = 0.0004), including clinically low- and high-risk stage III CC (all P < 0.001). Conversely, patients with IS Low (46.4%) did not significantly benefit from the 6-month mFOLFOX6 versus the 3-month mFOLFOX6. CONCLUSIONS: The prognostic value of IS for DFS was confirmed in patients with stage III CC treated with oxaliplatin-based chemotherapy. Its predictive value for DFS benefit of longer duration of mFOLFOX6 adjuvant treatment was found in IS Int + High. These results will be validated in an external independent cohort. CLINICALTRIALS. GOV REGISTRATION: NCT03422601; EudraCT Number: 2009-010384-16.

Semantic memory assessment in 15 patients with amyotrophic lateral sclerosis.

INTRODUCTION: A total of 30 to 50% of amyotrophic lateral sclerosis patients suffer from cognitive disorders. The aim of the study is to characterize these disorders and to assess semantic memory in non-demented ALS patients. The secondary aim is to look for a link between disease type and neuropsychological characteristics. METHOD: Patients were followed in an ALS center in Dijon. The following neuropsychological tests were used in this study: Folstein test, BREF test, verbal fluency, Isaac test, GRESEM test and TOP 30 test. RESULTS: Fifteen ALS patients were included. Nine of them (60%) were suffering from a semantic memory disorder. There was no correlation between ALS characteristics and the semantic memory disorder. DISCUSSION: This is the first study to reveal a semantic memory disorder in ALS. This result accentuates the hypothesis that ALS and semantic dementia are two phenotypes of the same degenerative process linked to TDP 43 proteinopathy.

Genomic grade adds prognostic value in invasive lobular carcinoma.

BACKGROUND: The prognostic value of histologic grade (HG) in invasive lobular carcinoma (ILC) remains uncertain, and most ILC tumors are graded as HG2. Genomic grade (GG) is a 97-gene signature that improves the prognostic value of HG. This study evaluates whether GG may overcome the limitations of HG in ILC. METHODS: Gene expression data were generated from frozen tumor samples, and GG calculated according to the expression of 97 genes. The prognostic value of GG was assessed in a stratified Cox regression model for invasive disease-free survival (IDFS) and overall survival (OS). RESULTS: A total of 166 patients were classified by GG. HG classified 33 (20%) tumors as HG1, 120 (73%) as HG2 and 12 (7%) as HG3. GG classified 106 (64%) tumors as GG low (GG1), 29 (17%) as GG high (GG3) and 31 (19%) as equivocal (cases not classified as GG1 or GG3). The median follow-up time was 6.5 years. In multivariate analyses, GG was associated with IDFS [HR(GG3 vs GG1) 5.6 (2.1-15.3); P < 0.001] and OS [HR(GG3 vs GG1) 7.2, 95% CI (1.6-32.2); P = 0.01]. CONCLUSIONS: GG outperformed HG in ILC and added prognostic value to classic clinicopathologic variables, including nodal status.

Phase I safety, pharmacokinetic and pharmacodynamic trial of BMS-599626 (AC480), an oral pan-HER receptor tyrosine kinase inhibitor, in patients with advanced solid tumors.

PURPOSE: We studied the safety, tolerability, and recommended dose of BMS-599626, an orally bioavailable inhibitor of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. PATIENTS AND METHODS: Patients with advanced solid tumors that expressed epidermal growth factor receptor (EGFR) and/or HER-2 were recruited and enrolled in a phase I, open-label, dose escalation trial of oral BMS-599626 starting at 100 mg/day given once daily for at least 28 days. RESULTS: Forty-five patients received BMS-599626 (100-660 mg/day). Dose-limiting toxic effects were reported at 660 mg/day (grade 3 elevation of hepatic transaminases [two patients] and QTc interval prolongation [one patient]), therefore the recommended maximum tolerated dose was 600 mg/day. The most frequent drug-related toxic effects were diarrhea (30% of patients), anorexia (13%), asthenia (30%), and cutaneous toxic effects, including skin rash (30%). Pharmacokinetic analysis demonstrated C(max) and exposure to BMS-599626 in patients increased with dose. Eleven patients had stable disease and received BMS-599626 for ≥ 4 months. Serial skin and tumor biopsies taken before and after treatment revealed expected changes in pharmacodynamic biomarkers, indicating that the EGFR and HER-2 pathways were affected. Positron emission tomography imaging showed a metabolic response in 2 of 10 patients evaluated. CONCLUSION: BMS-599626 was generally well tolerated, with disease stabilization across a range of tumor types and doses.

Review: Why screen for severe combined immunodeficiency disease?

Newborn screening for severe combined immunodeficiency (SCID) is now routinely performed in many countries across Europe and around the world. The number of T-cell receptor excision circles (TRECs) reflects T cell levels. TREC quantification is possible using dried blood spot (DBS) samples already collected from newborns to screen for other conditions. This method is very sensitive and highly specific. Data in the literature show that the survival rate for children with SCID is much higher when the disease is detected through early screening, as opposed to a later diagnosis. Newborns diagnosed with SCID may receive the appropriate care quickly, before the onset of serious infectious complications, which raises survival rates, improves quality of life, and limits side effects and treatment costs. At the request of the French Ministry of Health, France's National Authority for Health (Haute Autorité de Santé) is expected to issue recommendations on this topic soon. The nationwide DEPISTREC study, involving 48 maternity units across France, showed that routine SCID screening is feasible and effective. Such screening offers the additional benefit of also diagnosing non-SCID lymphopenia within the infant population.

[Leptomeningeal dissemination after ethmoidal sinus adenocarcinoma surgery: a rare complication]. / Dissémination leptoméningée après chirurgie d'un adénocarcinome de l'ethmoïde.

INTRODUCTION: Although rare, adenocarcinoma is the most frequent neoplasm of the ethmoid sinus and must be regarded as an occupational disease secondary to chronic wood dust exposure. Few cases with neurological metastasis have been reported. CASE REPORT: We report the cases of two patients who developed a multiple cranial nerve disorder for the first case and a cauda equina syndrome for the second, after ethmoid adenocarcinoma surgery. CONCLUSION: Diagnosis of carcinomatous meningitis is difficult and is based on clinical data, CSF analysis and gadolinium-enhanced T1-weighted brain and spinal cord MRI. The implication of surgery is discussed. Prognosis of such a disorder is poor.

Leptin and its potential interest in assisted reproduction cycles.

BACKGROUND: Leptin, an adipose hormone, has been shown to control energy homeostasis and food intake, and exert many actions on female reproductive function. Consequently, this adipokine is a pivotal factor in studies conducted on animal models and humans to decipher the mechanisms behind the infertility often observed in obese women. METHODS: A systematic PubMed search was conducted on all articles, published up to January 2015 and related to leptin and its actions on energy balance and reproduction, using the following key words: leptin, reproduction, infertility, IVF and controlled ovarian stimulation. The available literature was reviewed in order to provide an overview of the current knowledge on the physiological roles of leptin, its involvement in female reproductive function and its potential interest as a prognostic marker in IVF cycles. RESULTS: Animal and human studies show that leptin communicates nutritional status to the central nervous system and emerging evidence has demonstrated that leptin is involved in the control of reproductive functions by acting both directly on the ovaries and indirectly on the central nervous system. With respect to the clinical use of leptin as a biomarker in IVF cycles, a systematic review of the literature suggested its potential interest as a predictor of IVF outcome, as high serum and/or follicular fluid leptin concentrations have correlated negatively with cycle outcome. However, these preliminary results remain to be confirmed. CONCLUSION: Leptin regulates energy balance and female reproductive function, mainly through its action on hypothalamic-pituitary-ovarian function, whose molecular and cellular aspects are progressively being deciphered. Preliminary studies evaluating leptin as a biomarker in human IVF seem promising but need further confirmation.

Methylation of the BRCA1 promoter region in sporadic breast and ovarian cancer: correlation with disease characteristics.

Reduced expression of BRCA1 has been reported in sporadic breast cancer, although the mechanisms underlying this phenomenon remain unclear. Abnormal methylation leading to silencing of tumour suppressor genes has been implicated in tumorigenesis in a wide range of sporadic cancers. Therefore, we sought to determine the frequency of methylation within the BRCA1 promoter region in a large group of sporadic invasive breast (n =96) and ovarian (n = 43) carcinomas using Southern analyses. Overall, methylation was detected in 11% of breast cancer cases and in 5% of ovarian tumours. Methylation of the BRCA1 promoter region was strongly correlated with lack of estrogen and progesterone receptor expression. It is clear from the frequency of abnormal methylation of the BRCA1 promoter region, that this cannot be the sole mechanism mediating the reduced expression of BRCA1 that has previously been reported to occur in the majority of invasive sporadic breast tumours. Nevertheless this study suggests that abnormal methylation of the BRCA1 promoter may be important in tumorigenesis in a subset of sporadic breast and ovarian cancers.

Genetic polymorphism of induction of CYP1A1 (EROD) activity.

CYP1A1 is a cytochrome P450 which is inducible by polycyclic aromatic hydrocarbons (PAH). This induction is mediated via the Ahr locus which encodes the cytosolic Aryl hydrocarbon receptor. The induced activity of CYP1A1 can be measured in vitro by the ethoxyresorufin-O-deethylase (EROD) activity in lymphocytes after induction by benz(a)anthracene (B(a)A). Our purpose was to determine, using this assay, the genetic polymorphism of CYP1A1 induction. With this aim, a population and family study was undertaken. Using the statistical SKUMIX method, a bimodal distribution (two peaks) of the induced EROD activity among 102 unrelated individuals was obtained. We were unable to discriminate three classes of CYP1A1 induction phenotype since a trimodal distribution did not significantly improve the fit to the data (chi 2(1) = 0.37, p > 0.9). Segregation analysis performed on 57 nuclear families gave evidence of a major gene effect together with a polygenic component. The frequency of the high induction allele is equal to 0.11 with dominance on the low induction allele. This is an accordance with two distributions, with individuals showing low and high CYP1A1 induction phenotypes in proportions of 89% and 21% respectively. However, some degree of overlap between the two distributions prevented a clear genotype classification on the basis of the phenotype measured with the EROD assay. Further analyses should not be made with a dichotomized phenotype (low and high inducers) but should use quantitative measurements.

[Obstruction of the sigmoid colon due to an ovarian metastasis of colonic origin]. / Obstruction du côlon sigmoïde par une métastase ovarienne d'origine colique.

The authors present a case of left ovarian metastasis from colon carcinoma causing sigmoid obstruction. On US and CT the ovarian mass appears as a primary malignant lesion. The lesion caused a regular sigmoid stenosis which mimicked, on barium enema, a volvulus and screened the primary lesion.

[Computed tomography aspects of cerebral toxoplasmosis in AIDS]. / Aspects tomodensitométriques de la toxoplasmose cérébrale dans le SIDA.

We followed by CT 19 AIDS patients with cerebral toxoplasmosis. Diagnosis of cerebral toxoplasmosis was assessed on radiological and clinical basis, including the therapeutic response. CT allowed to confirm brain lesions (40 lesions in 19 patients) and to follow the evolution with treatment. Analysis of the CT features of these brain lesions permits to define some characteristic findings, though not pathognomonic. These lesions share common characteristics with other granulomatous diseases or with brain abscesses. The most frequently observed features are: target lesions (74%) with contrast enhancement (95%), frequently multiple (53%), associated with a hypodense area of oedema (100%), and responsible for a mass effect (79%). Under treatment, we observed improvement in 89%, resulting either in complete disappearance of the lesions (16%), disappearance of one or more contrast enhancing (46%) or hypodense (6%) areas, or volumetric regression of the hypodensities (50%). We conclude that CT is a good first-step examination for the detection and follow-up of cerebral toxoplasmosis in AIDS patients. MRI, a method with a higher sensitivity but still less accessible, may be considered at the present time as a second-step examination for those patients with solitary lesions on CT, or for symptomatic patients with normal CT.

A population and family study of CYP1A2 using caffeine urinary metabolites.

CYP1A2 is a cytochrome P450 which is inducible by polycyclic aromatic hydrocarbons. This induction could be mediated via the Ah locus, which encodes a cytosolic receptor responsible for the regulation of the CYP1A1 gene. Enzyme activity in vivo can be measured by the urinary caffeine metabolite ratio (AFMU + 1X + 1U)/17U. Our goal was to determine, using this ratio, the possible existence of a genetic polymorphism in CYP1A2 induction. For this purpose, a population and family study, including smokers, were undertaken. In a first step, we investigated factors influencing enzyme activity in a population of 245 unrelated individuals. The induction effect of smoking and inhibiting effect of oral contraceptive use were confirmed. None of the other factors examined (age, sex, level of cigarette consumption, nicotine or tar amounts, filter, inhalation) accounted for the interindividual variability in the metabolic ratio. Using the statistical SKUMIX method, a unimodal (one peak) distribution of the ratio was concluded in 164 unrelated smokers, since a second distribution did not significantly improve the fit to the data (chi 2(1) = 1.39, P > 0.2). Segregation analysis was performed on 68 nuclear families and no major gene effect could be shown. Furthermore, the polygenic model did not provide a higher likelihood than the sporadic one, which argues against the existence of any familial resemblance. Although we cannot rule out the possibility that some environmental factors could obscure the phenotypes and occult a genetic determinism, we conclude that genetic factors are probably negligible in the determination of CYP1A2 activity measured by this method.(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of a C/G polymorphism in the promoter region of the BRCA1 gene and its use as a marker for rapid detection of promoter deletions.

Reduced expression of BRCA1 has been implicated in sporadic breast cancer, although the mechanisms underlying this phenomenon remain unclear. To determine whether regulatory mutations could account for the reduced expression, we screened the promoter region by sequencing in 20 patients with sporadic disease. No mutations were detected; however, a new polymorphism consisting of a C-to-G base change within the beta-promoter was identified, with the frequency of the G allele being 0.34. Close to complete linkage disequilibrium was found between this marker and the Pro871 Leu polymorphism, situated in exon 11, which has previously been shown not to be associated with breast or ovarian cancer. This indicates that the C/G polymorphism is also unlikely to play a role in either disease. However, the strength of linkage disequilibrium between these markers permitted their use for rapid screening for genomic deletions within BRCA1. A series of 214 cases with familial breast cancer were analysed using this approach; 88/214 were heterozygous for the promoter polymorphism, thereby excluding a deletion in this region. Among the remaining patients, one hemizygous case reflecting a promoter deletion was successfully identified. Therefore, this study indicates that deletions within the beta-promoter region of BRCA1 are an uncommon event in familial breast cancer. Furthermore, it suggests that mutations within the BRCA1 promoter are unlikely to account for the reported decreased expression of BRCA1 in sporadic disease.