Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans.

Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.

Prevalence and risk factors for gonococcal infection in Reunion Island.

OBJECTIVE: To determine the prevalence and risk factors for gonococcal infection, and the resistance profile of Neisseria gonorrhoeae (NG) in Reunion Island. PATIENTS AND METHODS: All patients who visited the four sexually transmitted infection (STI) clinics of Reunion Island between January 2017 and December 2018 were screened by multiplex polymerase chain reaction. Data on patient characteristics were collected using a self-administered questionnaire (reason for screening, marital status, risk-taking behaviors, place of birth, employment status, type of health care coverage, sexual orientation, number of sexual partners, occurrence of extra-marital relationships, history of STIs, and symptomatology. Precarity was defined as being unemployed and/or receiving universal health insurance). RESULTS: The prevalence of NG (n=4289) in the screened population was 2.8% (95% CI [2.3-3.3]). Minors were especially at-risk (4.4% (95% CI [2.6-7])) and especially girls (5.6% (95% CI [3.2-8.9])). The prevalence observed in the homosexual population was 4.0% [2.6-5.9]. Gonococcal infection was asymptomatic in 56 (69%) patients. For all infection sites, the main risk factors were male minors (P=0.019), individuals living in conditions of precarity (P=0.023), individuals co-infected with chlamydia (P<0.001) or syphilis (P<0.001), and individuals of foreign origin (P=0.006). No NG strain was resistant to ceftriaxone. Strains were resistant to penicillin G, ciprofloxacin, and azithromycin in 22% (20/91), 38% (35/91), and 1% (1/91) of cases, respectively. CONCLUSION: The prevalence of NG in patients visiting STI clinics in Reunion Island is particularly high among minors. Prevention programs targeting this population should be reinforced and screening should be facilitated in school settings.

Risk factors associated with severe perineal tears: A five-year study.

OBJECTIVE: Our aim was to describe risk factors associated with 34DPT in operative and non-operative vaginal deliveries, over a five-year period. STUDY DESIGN: This was a retrospective cohort study including 39,227 vaginal deliveries from 2013 to 2017 in a single French University Hospital. Annual characteristics of the analyzed population were recorded. Univariate logistic regression was used to evaluate the association between these characteristics and 34DPT. Multivariate analysis was used to identify combinations of risk factors associated with instrumental delivery. RESULTS: The rate of perineal tears was constantly rising but rate of 34DPT was stable, ranging between 0.8 and 1.4% over the study period. Cesarean section rate was stable between 18.8% and 19.6%. Rate of diabetes, preeclampsia and obesity (BMI < 40) was increasing and episiotomy rate decreasing (from 19.8% to 11.8%). Operative deliveries rate remained stable between 11 and 12.8%. Multivariate regression showed that gestational age over 39 weeks (aOR 1.18, 95% CI [1.02; 1.35]), birth weight over 3500 g (aOR 1.62, 95% CI [1.05; 2.49]) were associated with 34DPT in patients without operative vaginal deliveries but not episiotomy. Gestational age (aOR 1.71, 95% CI [1.18; 2.47]), episiotomy (aOR 0.55, 95% CI [0.38; 0.79]) and diabetes (aOR 1.73, 95% CI [1.15; 2.61]) were associated with 34DPT among patients with operative vaginal deliveries. CONCLUSION: In a tertiary medical center model with low cesarean section rate, factors associated with 34DPT were different among patients with or without operative vaginal delivery. The question of the protective effect of mediolateral episiotomy against 34DPT in case of operative delivery deserves further investigations.

EBMT prospective observational study on allogeneic hematopoietic stem cell transplantation in T-prolymphocytic leukemia (T-PLL).

Preliminary data suggest that allogeneic stem cell transplantation (allo-SCT) may be effective in T-prolymphocytic leukemia (T-PLL). The purpose of the present observational study was to assess the outcome of allo-SCT in patients aged 65 years or younger with a centrally confirmed diagnosis of T-PLL. Patients were consecutively registered with the EBMT at the time of transplantation and followed by routine EBMT monitoring but with an extended dataset. Between 2007 and 2012, 37 evaluable patients (median age 56 years) were accrued. Pre-treatment contained alemtuzumab in 95% of patients. Sixty-two percent were in complete remission (CR) at the time of allo-SCT. Conditioning contained total body irradiation with 6 Gy or more (TBI6) in 30% of patients. With a median follow-up of 50 months, the 4-year non-relapse mortality, relapse incidence, progression-free (PFS) and overall survival were 32, 38, 30 and 42%, respectively. By univariate analysis, TBI6 in the conditioning was the only significant predictor for a low relapse risk, and an interval between diagnosis and allo-SCT of more than 12 months was associated with a lower NRM. This study confirms for the first time prospectively that allo-SCT can provide long-term disease control in a sizable albeit limited proportion of patients with T-PLL.

A Computer Prescribing Order Entry-Clinical Decision Support system designed for neonatal care: results of the 'preselected prescription' concept at the bedside.

WHAT IS KNOWN: The neonatal intensive care units (NICUs) are at the highest risk of drug dose error of all hospital wards. NICUs also have the most complicated prescription modalities. The computerization of the prescription process is currently recommended to decrease the risk of preventable adverse drug effects (pADEs) in NICUs. However, Computer Prescribing Order Entry-Clinical Decision Support (C.P.O.E./C.D.S.) systems have been poorly studied in NICUs, and their technical compatibility with neonatal specificities has been limited. OBJECTIVES: We set up a performance study of the preselected prescription of drugs for neonates, which limited the role of the prescriber to choosing the drugs and their indications. METHODS: A single 29 bed neonatal ward used this neonatal C.P.O.E./C.D.S. system for all prescriptions of all hospitalized newborns over an 18-month period. The preselected prescription of drugs was based on the indication, gestational age, body weight and post-natal age. The therapeutic protocols were provided by a formulary reference (330 drugs) that had been specifically designed for newborns. The preselected prescription also gave complete information about preparation and administration of drugs by nurses. The prescriber was allowed to modify the preselected prescription but alarms provided warning when the prescription was outside the recommended range. The main clinical characteristics and all items of each line of prescription were stored in a data warehouse, thus enabling this study to take place. RESULTS: Seven hundred and sixty successive newborns (from 24 to 42 weeks' gestation) were prescribed 52 392 lines of prescription corresponding to 65 drugs; About 30·4% of neonates had at least one out of licensed prescription; A prescription out of the recommended range for daily dose was recorded for 1·0% of all drug prescriptions. WHAT IS NEW?: The C.P.O.E./C.D.S. systems can currently provide a complete preselected prescription in NICUs according to dose rules, which are specific to newborns and also comply with local specificities (therapeutic protocols and formulation of drugs). The role of the prescriber is limited to the choice of drugs and their indications. The prescriber still retains the possibility of modifying each item of the prescription, with all other prescription items being calculated by the C.P.O.E. system. In these conditions, the prescribers rarely modified the preselected prescription and the rate of out of range prescription was low. A multicentric study is required to confirm and extend these observations. CONCLUSIONS: This study showed the feasibility of preselected prescription in NICUs and a low rate of out of range prescriptions. The preselected prescription could play a key role in lowering the dose error rate in NICUs.

Allogeneic hematopoietic cell transplantation for multiple myeloma in Europe: trends and outcomes over 25 years. A study by the EBMT Chronic Malignancies Working Party.

We describe the use and outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for multiple myeloma (MM) in Europe between January 1990 and December 2012. We identified 7333 patients, median age at allo-HSCT was 51 years (range: 18-78), of whom 4539 (62%) were males. We distinguished three groups: (1) allo-HSCT upfront (n=1924), (2) tandem auto-allo-HSCT (n=2004) and (3) allo-HSCT as a second line treatment and beyond (n=3405). Overall, there is a steady increase in numbers of allo-HSCT over the years. Upfront allo-HSCT use increased up to year 2000, followed by a decrease thereafter and represented 12% of allo-HSCTs performed in 2012. Tandem auto-allo-HSCT peaked around year 2004 and contributed to 19% of allo-HSCTs in 2012. Allo-HSCT as salvage after one or two or three autografts was steadily increasing over the last years and represented 69% of allo-HSCTs in 2012. Remarkable heterogeneity in using allo-HSCT was observed among the different European countries. The 5-year survival probabilities from time of allo-HSCT for the three groups after year 2004 were 42%, 54% and 32%, respectively. These results show that the use of allo-HSCT is increasing in Europe, especially as second line treatment and beyond. There is an unmet need for well-designed prospective studies investigating allo-HSCT as salvage therapy for MM.

Influence of pre-existing invasive aspergillosis on allo-HSCT outcome: a retrospective EBMT analysis by the Infectious Diseases and Acute Leukemia Working Parties.

Historically, invasive aspergillosis (IA) has been a major barrier for allogeneic hematopoietic stem cell transplantation (allo-HSCT). The influence of invasive IA on long-term survival and on transplant-related complications has not been investigated in a larger patient cohort under current conditions. Our aim was to analyze the long-term outcome of patients undergoing allo-HSCT with a history of prior IA. We used European Society for Blood and Marrow Transplantation database data of first allo-HSCTs performed between 2005 and 2010 in patients with acute leukemia. One thousand one hundred and fifty patients with data on IA before allo-HSCT were included in the analysis. The median follow-up time was 52.1 months. We found no significant impact of IA on major transplant outcome variables such as overall survival, relapse-free survival, non-relapse mortality, cumulative incidence of acute GvHD grade II-IV, chronic GvHD, pulmonary complications and leukemia relapse. However, we found a trend toward lower overall survival (P=0.078, hazard ratio (HR) (95% confidence interval (CI)): 1.16 (0.98, 1.36)) and higher non-relapse mortality (P=0.150, HR (95% CI): 1.19 (0.94, 1.50)) in allo-HSCT recipients with pre-existing IA. Our data suggest that a history of IA should not generally be a contraindication when considering the performance of allo-HSCT in patients with acute leukemia.

Original technique for preoperative preparation of patients and intraoperative localization of parathyroid adenomas.

Surgical approach of single parathyroid adenoma treatment is turning to a less invasive surgery, allowing us to obtain better aesthetic results, reduction of duration of surgical operation, reduction of post-operative morbidity and hospital stay. Tc99m-sestaMIBI scintigraphy is mainly performed for preoperative localization of parathyroid adenomas. Our technique is instead based on the possibility to inhibit the interference of Tc99m-sestaMIBI uptake of the thyroid gland by means of the administration of Lugol's solution. Indeed, to confirm the identification and removal of the hyperfunctional parathyroid, it is accepted as adequate an ex vivo radioactivity count of the adenoma 20% or 40% greater than the value of the post-excisional background radioactivity, in association or not with intraoperative measurement of PTH. This method allows us to perform surgery with no timetable restriction, and to clearly distinguish the radioactivity of parathyroid adenoma from that of the surrounding tissues and thyroid gland.

Current practices used for the prevention of central venous catheter-associated infection in hematopoietic stem cell transplantation recipients: a survey from the Infectious Diseases Working Party and Nurses' Group of EBMT.

BACKGROUND: Central line-associated bloodstream infection (CLABSI) is one of the most common infectious complications after hematopoietic stem cell transplantation. To prevent this complication, international guidelines recommend the implementation of the CLABSI 'prevention bundle' consisting of hand hygiene, full barrier precautions, cleaning the insertion site with chlorhexidine, avoiding femoral sites for insertion, and removing unnecessary catheters. The aim of this survey was to analyze to what extent European Group for Blood and Marrow Transplantation (EBMT) centers have included the CLABSI prevention bundle in practice. METHODS: A questionnaire used for data collection was sent to the 545 EBMT centers worldwide, 103 of which responded. RESULTS: All 5 components of the CLABSI prevention bundle were recorded in 28% of the centers' standard operating procedures (SOP), and 21% of the centers answered that they used all of the bundle components in clinical practice. The most common recommendation absent from the SOP was specification of all the components of full barrier precautions (43% of the centers did not include at least 1 component). Skin disinfection with chlorhexidine before catheter insertion was reported by 66% centers. CLABSI rates were monitored in 21% of centers. CONCLUSIONS: Although most of the centers lacked 1 or more of the CLABSI prevention bundle components in their SOP, improvements could easily be made by updating the centers' SOP. The first important step is introduction of CLABSI rate monitoring in this high-risk patient population.

Comparison of upfront tandem autologous-allogeneic transplantation versus reduced intensity allogeneic transplantation for multiple myeloma.

We performed a retrospective analysis of the European Group for Blood and Marrow Transplantation database comparing the outcomes of multiple myeloma patients who received tandem autologous followed by allogeneic PSCT (auto-allo) with the outcomes of patients who underwent a reduced intensity conditioning allograft (early RIC) without prior autologous transplant. From 1996 to 2013, we identified a total of 690 patients: 517 patients were planned to receive auto-allo and 173 received an early RIC allograft without prior autologous transplant. With a median follow-up of 93 months, 5-year PFS survival was significantly better in the auto-allo group, 34% compared with 22% in the early RIC group (P<0.001). OS was also significantly improved in the auto-allo group with a 5-year rate of 59% vs 42% in the early RIC group (P=0.001). The non-relapse mortality rate was lower in the auto-allo group than in the early RIC group, with 1- and 3-year rates of 8% and 13% vs 20% and 28%, respectively (P<0.001). The relapse/progression rate was similar in the two groups, with 5-year rates of 50% for auto-allo and 46% for early RIC (P=0.42). These data suggest that planned tandem autologous allograft can improve overall survival compared with upfront RIC allograft alone in patients with multiple myeloma.

Impact of CR before and after allogeneic and autologous transplantation in multiple myeloma: results from the EBMT NMAM2000 prospective trial.

Previous studies have shown that obtaining complete hematologic remission (CR) in multiple myeloma is an important predictor of PFS and OS. This applies both to autologous and allogeneic transplantation. However, the importance of CR obtained before vs after second transplant or following allogeneic vs autologous transplantation is not clear. We investigated the role of CR analyzing data from the EBMT-NMAM2000 interventional prospective study comparing tandem autologous/reduced intensity conditioning allogeneic transplantation (auto/RICallo) to autologous transplantation-single or double (auto/auto). Allocation to treatment was performed according to availability of a matched sibling donor. Cox regression and multi-state models were applied. The long-term probability of survival in CR was superior in auto/RICallo, both comparing groups according to treatment allocated at start (28.8 vs 11.4% at 60 months, P=0.0004) and according to actual administration of second transplant (25.6 vs 9.6% at 60 months, P=0.008). CR achieved before the second transplant was predictive for PFS (hazard ratio (HR)=0.44, P= 0.003) and OS (HR 0.51, P=0.047) irrespective of the type of second transplant. CR achieved after auto/RICallo was more beneficial for PFS (HR=0.53, P=0.027) than CR after auto/auto (HR=0.81, P=0.390), indicating a better durability of CR obtained after an allotransplant procedure.

LGALS3BP, lectin galactoside-binding soluble 3 binding protein, promotes oncogenic cellular events impeded by antibody intervention.

The extracellular matrix protein lectin galactoside-binding soluble 3 binding protein (LGALS3BP) constitutes a negative prognostic marker of cancer onset and progression with increasing value in clinical application. Since its discovery, however, although the glycoprotein has been implicated in a growing number of disease-related processes, its actual role and mechanism of action have remained ambiguous, thus hindering opportunities for therapeutic development. In this study, we have determined that LGALS3BP constitutes a novel ligand for integrins α1ß1, α5ß1, αvß1 and α6ß1 and have identified that these newly established partnerships at the membrane level are responsible for exerting the molecule's involvement in cancer through manipulation of multiple canonical 'outside-in' integrin signalling events. We demonstrate that LGALS3BP-mediated integrin activation results into signal transmission via Akt, JNK and the Ras cascade via the Raf-ERK axis while p38 activity is kept at baseline levels. Transient cellular adherence to LGALS3BP favours survival and proliferation signalling while apoptosis is kept at bay. Sustained cellular exposure to LGALS3BP significantly supports viability, motility and migration. Importantly, an anti-LGALS3BP antibody, SP2 is capable of impeding these newly defined LGALS3BP-driven processes without, however, compromising cell viability. These novel findings reveal the mechanism of action of LGALS3BP during cellular adherence and warrant its further validation as a potential pharmacological target for anticancer therapies.

Membranous Nectin-4 expression is a risk factor for distant relapse of T1-T2, N0 luminal-A early breast cancer.

Nectins are Ca(2+)-independent immunoglobulin-like cell adhesion molecules that compose a family of four members that regulate several cellular activities such as movement, proliferation, survival, differentiation, polarization, and the entry of viruses. Nectin-4 has recently emerged as a metastatis-associated protein in several cancers. Here, we have evaluated the association between the expression of Nectin-4 and the clinical outcome of patients with node-negative, T1/T2 breast cancers.The study group consisted of 197 patients presenting with primary unilateral breast carcinoma (T1/T2), with no evidence of nodal involvement and distant metastases. Nectin-4 protein expression was assessed by immunohistochemistry on tissue microarrays, and the results correlated with the clinical data using Kaplan-Meier curves and multivariate Cox regression analysis. Thirty-four out of 197 tumors (17.3%) exhibited Nectin-4 expression on cell membrane (m-Nectin-4) and 122 out of the 163m-Nectin-4 negative tumors (74.8%) showed high cytoplasmic expression of Nectin-4 (c-Nectin-4(High)). At Kaplan-Meier analysis, m-Nectin-4 positivity was significantly associated with a lower disease-free survival (DFS) and distant relapse-free survival (DRFS) rate in patients with a luminal-A phenotype (P=0.030 and P=0.002, respectively). Multivariate analysis showed that in luminal-A tumors m-Nectin-4 positivity is an independent prognostic factor for DFS (P=0.018) and DRFS (P=0.004), but not for local relapse-free survival (LRFS). On the other hand, c-Nectin-4(High) was significantly associated with higher rates of DFS and LRFS, but not DRFS, in the whole population (P=0.008 and P=0.004, respectively) and in patients with luminal-A tumors (P=0.022 and P=0.018, respectively). In patients with luminal-A tumors, multivariate analysis showed that the prognostic value of c-Nectin-4(Low/Negative) is limited to DFS (P=0.012) and LRFS (P=0.022). We suggest that Nectin-4 represents a prognostic factor and a therapeutic target in luminal-A early stage breast cancer.

Dual targeting of ErbB-2/ErbB-3 results in enhanced antitumor activity in preclinical models of pancreatic cancer.

ErbB-3 and its ligand NRG-1ß are key players in driving oncogenic signaling and resistance to therapy through the activation of the PI3K/Akt pathway. We have recently reported that EV20, a humanized anti-ErbB3 antibody, possesses a marked antitumor activity in a variety of human tumor models, including pancreatic cancer (PC). Here, we report that despite epidermal growth factor receptor overexpression, PC cells are more sensitive to NRG-1ß than EGF in terms of Akt activation and cell proliferation. Using stable ErbB-3-knocked down cells and EV20 in combination with trastuzumab, we showed that dual targeting of ErbB-2 and ErbB-3 was necessary to completely abrogate ErbB-3 signaling and to impair cell proliferation. Similarly, enhanced therapeutic efficacy of the antibody combination was seen in xenografts originating from K-Ras-mutated HPAF-II and SW1990 cells, without increasing the toxicity. These results indicate that dual targeting of ErbB-2 and ErbB-3 could represent a new therapeutic approach in PC.Oncogenesis (2014) 3, e117; doi:10.1038/oncsis.2014.31; published online 18 August 2014.

Frequency of dosage prescribing medication errors associated with manual prescriptions for very preterm infants.

WHAT IS KNOWN AND OBJECTIVE: The risk of dosage Prescription Medication Error (PME) among manually written prescriptions within 'mixed' prescribing system (computerized physician order entry (CPOE) + manual prescriptions) has not been previously assessed in neonatology. This study aimed to evaluate the rate of dosage PME related to manual prescriptions in the high-risk population of very preterm infants (GA < 33 weeks) in a mixed prescription system. METHODS: The study was based on a retrospective review of a random sample of manual daily prescriptions in two neonatal intensive care units (NICU) A and B, located in different French University hospitals (Dijon and La Reunion island). Daily prescription was defined as the set of all drugs manually prescribed on a single day for one patient. Dosage error was defined as a deviation of at least ±10% from the weight-appropriate recommended dose. RESULTS AND DISCUSSION: The analyses were based on the assessment of 676 manually prescribed drugs from NICU A (58 different drugs from 93 newborns and 240 daily prescriptions) and 354 manually prescribed drugs from NICU B (73 different drugs from 131 newborns and 241 daily prescriptions). The dosage error rate per 100 manually prescribed drugs was similar in both NICU: 3·8% (95% CI: 2·5-5·6%) in NICU A and 3·1% (95% CI: 1·6-5·5%) in NICU B (P = 0·54). Among all the 37 identified dosage errors, the over-dosing was almost as frequent as the under-dosing (17 and 20 errors, respectively). Potentially severe dosage errors occurred in a total of seven drug prescriptions. None of the dosage PME was recorded in the corresponding medical files and information on clinical outcome was not sufficient to identify clinical conditions related to dosage PME. Overall, 46·8% of manually prescribed drugs were off label or unlicensed, with no significant differences between prescriptions with or without dosage error. The risk of a dosage PME increased significantly if the drug was included in the CPOE system but was manually prescribed (OR = 3·3; 95% CI: 1·6-7·0, P < 0·001). WHAT IS NEW AND CONCLUSION: The presence of dosage PME in the manual prescriptions written within mixed prescription systems suggests that manual prescriptions should be totally avoided in neonatal units.

Reduced intensity-conditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation.

Outcomes and prognostic factors of reduced intensity-conditioned allo-SCT (RIC allo-SCT) for multiple myeloma (MM) relapsing or progressing after prior autologous (auto)-SCT are not well defined. We performed an analysis of 413 MM patients who received a related or unrelated RIC allo-SCT for the treatment of relapse/progression after prior auto-SCT. Median age at RIC allo-SCT was 54.1 years, and 44.6% of patients had undergone two or more prior auto-SCTs. Median OS and PFS from the time of RIC allo-SCT for the entire population were 24.7 and 9.6 months, respectively. Cumulative non-relapse mortality (NRM) at 1 year was 21.5%. In multivariate analysis, CMV seronegativity of both patient and donor was associated with significantly better PFS, OS and NRM. Patient-donor gender mismatch was associated with better PFS, fewer than two prior auto-SCT was associated with better OS, and shorter time from the first auto-SCT to the RIC allo-SCT was associated with lower NRM. The results of this study identify patient and donor CMV seronegativity as the key prognostic factor for outcome after RIC allo-SCT for MM relapsing or progressing after prior auto-SCT.

[Perinatal outcome of monochorionic and dichorionic twin gestations: a study of 775 pregnancies at Reunion Island]. / Morbidité et mortalité périnatale des jumeaux et influence de la chorionicité: expérience de 10ans dans le Sud-Réunion. Étude de 775 grossesses.

OBJECTIVES: To compare the perinatal mortality and morbidity of infants born from monochorionic versus dichorionic twin pregnancies (TP). PATIENTS AND METHODS: Retrospective, comparative study of monochorionic and dichorionic TP over 10 years in the south of Reunion Island. Information regarding demographic, gestational and perinatal variables of mothers and infants was collected from the hospital perinatal database. RESULTS: Six hundred and twenty dichorionic and 155 monochorionic TP were analyzed. In case of monochorionic TP, mothers had higher rates of pregnancy-related hypertension (OR=1.82, 95%CI=[1.02-3.29] ; P=0.03) and hospitalization (OR=1.48, 95%CI=[1.02-2.16]; P=0.03). Newborns from monochorionic TP had higher morbidity for : very preterm birth (birth before 33 weeks gestation) (OR=1.65, 95%CI=[1.02-2.66]; P=0.02), very low birth weight (birth weight<1500g) (OR=1.73, 95%CI=[1.57-3.13]; P<0.001), Apgar<7 at 1 minute (OR=1.76, 95%CI=[1.18-2.61]; P<0.01) and hospitalization (OR=2.08, 95%CI=[1.58-2.73]; P<0.001). Perinatal mortality was also significantly higher (OR=2.47, 95%CI=[1.54-3.94]; P<0.001), as well intrauterine fetal death (OR=3.96, 95%CI=[1.95-8.05]; P<0.001) CONCLUSION: This study confirms that few differences exist among dichorionic and monochorionic TP with regard to maternal morbidity, while neonatal morbidity and mortality are higher in twins born from monochorionic pregnancies.

Clinical diagnostic clues in Crohn's disease: a 41-year experience.

Determining the diagnosis of Crohn's disease has been highly difficult mainly during the first years of this study carried out at the Pontificia Universidad Catolica (PUC) Clinical Hospital. For instance, it has been frequently confused with Irritable bowel syndrome and sometimes misdiagnosed as ulcerative colitis, infectious colitis or enterocolitis, intestinal lymphoma, or coeliac disease. Consequently, it seems advisable to characterize what the most relevant clinical features are, in order to establish a clear concept of Crohn's disease. This difficulty may still be a problem at other medical centers in developing countries. Thus, sharing this information may contribute to a better understanding of this disease. Based on the clinical experience gained between 1963 and 2004 and reported herein, the main clinical characteristics of the disease are long-lasting day and night abdominal pain, which becomes more intense after eating and diarrhoea, sometimes associated to a mass in the abdomen, anal lesions, and other additional digestive and nondigestive clinical features. Nevertheless, the main aim of this work has been the following: is it possible to make, in an early stage, the diagnosis of Crohn's disease with a high degree of certainty exclusively with clinical data?

Sex moderates circadian chemotherapy effects on survival of patients with metastatic colorectal cancer: a meta-analysis.

BACKGROUND: Molecular circadian clocks can modify cancer chemotherapy effects, with a possible moderation according to sex differences. We investigated whether sex determine the optimal delivery schedule of chemotherapy for metastatic colorectal cancer. PATIENTS AND METHODS: A meta-analysis was performed using individual data from three international Phase III trials comparing 5-fluorouracil, leucovorin and oxaliplatin administered in chronomodulated (chronoFLO) or conventional (CONV) infusions. The data from 345 females and 497 males were updated at 9 years. The main end point was survival. RESULTS: Overall survival was improved in males on chronoFLO when compared with CONV (P = 0.009), with respective median values of 20.8 (95% CL, 18.7 to 22.9) and 17.5 months (16.1 to 18.8). Conversely, median survival was 16.6 months (13.9 to 19.3) on chronoFLO and 18.4 months (16.6 to 20.2) on CONV in females (P = 0.012). The sex versus schedule interaction was a strong predictive factor of optimal treatment schedule, with a hazard ratio of 1.59 (1.30 to 1.75) for overall survival (P = 0.002) in multivariate analysis. CONCLUSIONS: Males lived significantly longer on chronomodulated chemotherapy rather than on conventional chemotherapy. The current chronoFLO schedule deserves prospective assessment as a safe and more effective first-line treatment option than conventional delivery for male patients.