Association between hereditary predisposition to common cancers and congenital multimalformations

In a previous article we reported that mutations favoring cancer at adulthood seemed to improve fertility and limit miscarriages. Because spontaneous abortion may result from anomalies in embryo, we questioned if an increased frequency of congenital malformation could be evidenced among cancer-prone families. Oncogenetics database (≈193 000 members) of the comprehensive cancer center Jean Perrin was crossed with regional registry of congenital malformations (≈10 000). Among children born between 1986 and 2011, 176 children with malformation matched in both databases. In breast/ovaries cancer-prone families, the risk for malformations was multiplied by 2.4 [1.2-4.5] in case of a BRCA1 mutation. Frequencies of malformation in BRCA2 and MMR mutated families were similar to families without a cancer syndrome. In comparison to malformations concerning a unique anatomical system, multimalformations were significantly more frequent in case of BRCA or MMR mutations: compared to families without cancer syndrome, the risk of multimalformations was multiplied by 4.1 [0.8-21.7] for cancer-prone families but with no known deleterious mutation, by 6.9 [1.2-38.6] in families with a known mutation but an unknown parental mutational status and by 10.4 [2.3-46.0] when one parent carried the familial mutation. No association with the type of anatomical system was found, nor with multiple births. These results suggest that BRCA and MMR genes play an important role in human embryogenesis and that if their function is lowered because of heterozygote mutations, congenital malformations are either more likely (BRCA1 mutations) and/or more susceptible to concern several anatomical systems.     

Health-Related Quality of Life in KEYNOTE-010: a Phase II/III Study of Pembrolizumab Versus Docetaxel in Patients With Previously Treated Advanced,Programmed Death Ligand 1–Expressing NSCLC

Introduction

In the phase II/III KEYNOTE-010 study (ClinicalTrials.gov, NCT01905657), pembrolizumab significantly prolonged overall survival over docetaxel in patients with previously treated, programmed death ligand 1–expressing (tumor proportion score ≥ 1%), advanced NSCLC. Health-related quality of life (HRQoL) results are reported here.

Influence of Genetic Variation in the C-Reactive Protein Gene on the Inflammatory Response During and After Acute Coronary Ischemia

The aim of this research was to assess whether common genetic variants within the C-reactive protein gene ( CRP ) are related to the degree of acute rise in plasma C-reactive protein (CRP) levels following an acute coronary syndrome (ACS). While polymorphisms within CRP are associated with basal CRP levels in healthy men and women, less is known about the relationship of such genetic variants and the degree of CRP rise during and after acute ischemia. Plasma CRP is associated with increased rates of recurrent coronary events. We evaluated seven common genetic variants within CRP and assessed their relationship to the degree of rise in CRP levels immediately following an acute coronary syndrome in 1827 European American patients. Variants in the putative promoter region, −757T > C and −286C > T > A, were associated with the highest CRP elevations after ACS. Patients with two copies of the A allele of SNP −286C > T > A had median CRP values of 76.6 mg/L, compared to 11.1 mg/L in patients with no copies of the rare variant (p-value <0.0001), post ACS. The lowest CRP values were found for patients with minor alleles of the exonic 1059G > C and the 3'untranslated region 1846G > A SNPs. For example, patients homozygous for the minor allele of 1059G > C had 71% lower median CRP values than those homozygous for the major allele [3.5 vs 12.0 mg/L, p < 0.0001]. These trends persisted in the chronic stable phase after ischemia had resolved, and after adjustment for infarct size by peak creatinine kinase levels and clinical status by Killip class. Assessment of CRP genetic variants identified patients with higher and lower CRP elevation after acute coronary syndrome.     

Early experience with robotic aortic valve replacement.

We report our initial experience with aortic valve replacement using robotic assistance. All procedures were performed with peripheral cardiopulmonary bypass, transthoracic aortic cross-clamp, and antegrade cold crystalloid cardioplegia. One or two ports and a 5-cm intercostal incision in the right chest were used for access. All patients had aortic valve replacement performed robotically. Between February and September 2004, five patients underwent robotic aortic valve replacement. The mean age was 59 years (range 35-82 years). There were no incisional conversions, death, stokes, or reoperations for bleeding. Overall mean study times were as follows: procedure, 231.2 min (range 180-315 min); cardiopulmonary bypass, 121.5 min (range 83-173 min), and cross-clamp, 98.2 min (range 67-140 min). One patient developed postoperative pneumonia. Aortic valve replacement can be successfully performed with the da Vinci robotic system.     

Does the extent of lymph node dissection influence outcome in patients with stage I non-small-cell lung cancer?

OBJECTIVE: To assess the therapeutic effect of the extent of lymph node dissection performed in patients with a stage pI non-small-cell lung cancer (NSCLC). METHODS: We analysed data on 465 patients with stage I NSCLC who were treated with surgical resection and some form of lymph node sampling. The median number of lymph node sampled was 10 and the median number of ipsilateral mediastinal lymph node stations sampled was two. We chose to define a procedure that harvested 10 or more lymph nodes and sampled two or more ipsilateral mediastinal stations as a lymphadenectomy, by contrast with sampling when one or both criteria were not satisfied. The effect of the surgical techniques: lymph node sampling (LS; n=207) vs. lymphadenectomy (LA; n=258) on 30-day mortality and overall survival were investigated. RESULTS: A total of 6244 lymph nodes was examined, including 4306 mediastinal lymph nodes. The mean (+/-SD) numbers of removed lymph nodes were 7+/-6.1 per patient following LS vs.18.6+/-9.3 following LA (P=0.001). An average mean of 1+/-0.90 mediastinal lymph node station per patient was sampled following LS vs. 2.7+/-0.8 following LA (P<10(-6)). Overall 30-day mortality rates were 2.4 and 3.1%, respectively. LA was disclosed as a favourable prognosticator at multivariate analysis (Hazard Risk: 1.43; 95% Confidence Interval: 1.00-2.04; P=0.048), together with younger patient age, absence of blood vessels invasion, and smaller tumour size. CONCLUSIONS: Importance of lymph node dissection affects patients outcome, while it does not enhance the operative mortality. A minimum of 10 lymph nodes assessed, and two mediastinal stations sampled are suggested as possible pragmatic markers of the quality of lymphadenectomy.     

Major vascular injuries during gynecologic laparoscopy

Background:This study was undertaken to report our experience with major vascular injuries in gynecologic laparoscopy in order to specify the circumstances under which they occurred, the means of diagnosis, the risk factors, and the means for prevention.Study Design:Retrospective case review study.Results:Seventeen patients with 21 major vascular injuries were identified. The average age of the patients was 33.8 ± 11.6 years, and the mean body index mass was 21.6 ± 3.08 kg/m². Three of four of the accidents occurred during the set-up phase of laparoscopy (13 cases; 76.5%), and in 4 cases (23.5%) the accident occurred during the laparoscopic surgery procedure. Eleven (84.6%) of the complications occurring during the set-up phase were secondary to insertion of the umbilical trocar and 2 (15.4%) to insertion of the needle used to create the pneumoperitoneum (P-needle). Half (6 cases; 54.5%) of the major vascular injuries secondary to insertion of the umbilical trocar were observed when reusable trocars were used. In every case, the diagnosis was made during the operation. Two patients died, and two others presented a serious complication (phlebitis; acute ischemia requiring reoperation).Conclusions:Major vascular injuries are rare but serious complications of laparoscopic surgery. Prevention of these accidents relies on the surgeon’s experience and scrupulous respect of the safety rules. In the vast majority of cases, it is necessary to convert to laparotomy immediately, calling in a vascular surgeon.     

The activity of erythrocyte sodium-proton exchanger in women with pregnancy- induced hypertension.

BACKGROUND: Hypertension that develops after 20 gestational weeks and is defined as pregnancy-induced hypertension (PIH). The main cause of PIH is vasoconstriction and the thickening of vascular media, which decreases vascular capacity and increases peripheral resistance. One of the theories postulated to explain this phenomenon is that a transmembrane sodium transport disorder causes an increase in intracellular sodium concentration. In the latest literature, special attention is paid to the role of the increased intracellular sodium concentration in the pathogenesis of essential hypertension (EH). One of the best documented phenotypes for EH is the increased activity of the sodium-proton exchanger (NHE). The aim of this study was to assess if increased NHE activity could be the mechanism responsible for the development of PIH. SUBJECTS AND METHODS: The study included 30 women: 10 pregnant women with PIH after gestational week 30, 10 women with physiological pregnancy after 30 gestational weeks, and 10 healthy non-pregnant women. NHE activity was determined according to Orlov's method as amiloride-sensitive H(+) efflux from acid-loaded cells. RESULTS: The NHE activity in the group of women with PIH was significantly higher than that in women with physiological pregnancy: 10.09 +/- 1.65 vs. 6.81 +/- 2.3 mmol/L RBC/h (p < 0.049) and in the group of non-pregnant women: 10.09 +/- 1.65 vs. 7.56 +/- 1.66 mmol/L RBC/h (p < 0.029). Erythrocyte NHE activity did not differ in the group of women with physiological pregnancy and in the group of non-pregnant women. CONCLUSION: These results seem to suggest that erythrocyte NHE activity is elevated in PIH pregnancies.     

Pharmacokinetics of phenazone after bilateral ovariectomy in female rabbits]

The aim of this study was to evaluate the influence of female sex hormones on phenazone pharmacokinetics using as an experimental model female rabbits after a bilateral ovariectomy. Eighteen female rabbits divided into two groups: control animals and experimental rabbits, that underwent ovariectomy, were used in the study. Pharmacokinetic assays were performed in all animals: prior to the study, after 1 month and after 2 months. Blood was sampled within 24 hours after intragastric administration of phenazone at a dose 50 mg/kg b.w. Two compartment open model was used for calculations. Significant increase in AUC and prolongation of phenazone halflife as well as a decrease in the total body clearance were noted. The study demonstrated the possible inhibition of the microsomal mixed-function oxidase system by oestrogens.     

Risk factors of influenza transmission in households.

BACKGROUND: Influenza transmission in households is a subject of renewed interest, as the vaccination of children is currently under debate and antiviral treatments have been approved for prophylactic use. AIMS: To quantify the risk factors of influenza transmission in households. DESIGN OF STUDY: A prospective study conducted during the 1999 to 2000 winter season in France. SETTING: Nine hundred and forty-six households where a member, the index patient, had visited their general practitioner (GP) because of an influenza-like illness were enrolled in the study. Five hundred and ten of the index patients tested positive for influenza A (subtype H3N2). A standardised daily questionnaire allowed for identification of secondary cases of influenza among their household contacts, who were followed-up for 15 days. Of the 395 (77%) households that completed the questionnaire, we selected 279 where no additional cases had occurred on the day of the index patient's visit to the GP. METHODS: Secondary cases of influenza were those household contacts who had developed clinical influenza within 5 days of the disease onset in the index patient. Hazard ratios for individual clinical and demographic characteristics of the contact and their index patient were derived from a Cox regression model. RESULTS: Overall in the 279 households, 131 (24.1%) secondary cases occurred among the 543 household contacts. There was an increased risk of influenza transmission in preschool contacts (hazard ratio [HR] = 1.85, 95% confidence interval [CI] = 1.09 to 3.26) as compared with school-age and adult contacts. There was also an increased risk in contacts exposed to preschool index patients (HR = 1.93, 95% CI = 1.09 to 3.42) and school-age index patients (HR = 1.68, 95% CI = 1.07 to 2.65), compared with those exposed to adult index cases. No other factor was associated with transmission of the disease. CONCLUSION: Our results support the major role of children in the dissemination of influenza in households. Vaccination of children or prophylaxis with neuraminidase inhibitors would prevent, respectively, 32-38% and 21-41% of secondary cases caused by exposure to a sick child in the household.