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Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a potentially devastating disease, seen in 1/800-1000 neonates. FNAIT is the most common cause of early-onset isolated severe neonatal thrombocytopenia in maternity wards. The most feared complication of this disorder is intracranial hemorrhage, leading to death or neurological sequelae. There is no systematic screening of at-risk pregnancies and FNAIT is often discovered when fetal or neonatal bleeding is observed. A working group on fetomaternal platelet alloimmunization was created in 2017, under the auspices on the French Group of Thrombosis and Hemostasis (GFHT). The first objective of this group was to survey clinical practices for treatment of thrombocytopenic neonates in a context of suspected or confirmed FNAIT.

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BACKGROUND: Blood transfusion is common in neonatology, especially in preterm or low birth weight infants. Recommendations were proposed by the French National Authority of Health (HAS) in 2014 and 2015 for red blood cells and platelet transfusion respectively, but an heterogeneity of practical attitudes persist. The objective of this survey is to evaluate transfusion practices in neonatal intensive care units. METHODS: Investigation of practice of neonatal transfusion was organized among 68 neonatal intensive care unit (level 3) between September 2016 and May 2017, by mailing survey focused on systematic training of nurses, patient identification, immunohematology, information and technical aspects of blood components administration. RESULTS: Twenty-three neonatal intensive care units among the 68s answered the questionnaire. One thousand five hundred sixty seven neonates were transfused and 3382 blood products were administered. The results highlight a consensual attitude concerning the procedures of patient identification, immunohematology tests and blood products administration. However, heterogeneity remains concerning information of the parents or the person with parental authority, immediate and delayed follow-up and devices used for the transfusion. However HAS guidelines (2014 and 2015) appear to be well applied by clinicians for blood products, specifications and calcul of transfused volume based on gestational age and weight.

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BACKGROUND: Peritoneal metastasis from biliary carcinoma (PMC) is associated with poor prognosis when treated with chemotherapy. OBJECTIVE: To evaluate the impact on survival of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), and compare with conventional palliative chemotherapy for patients with PMC. MATERIAL AND METHODS: A prospective multicenter international database was retrospectively searched to identify all patients with PMC treated with a potentially curative CRS/HIPEC (CRS/HIPEC group). The overall survival (OS) was compared to patients with PMC treated with palliative chemotherapy (systemic chemotherapy group). Survival was analyzed using Kaplan-Meier method and compared with Log-Rank test. RESULTS: Between 1995 and 2015, 34 patients were included in the surgical group, and compared to 21 in the systemic chemotherapy group. In the surgical group, median peritoneal cancer index was 9 (range 3-26), macroscopically complete resection was obtained for 25 patients (73%). There was more gallbladder localization in the surgical group compared to the chemotherapy group (35% vs. 18%, p = 0.001). Median OS was 21.4 and 9.3 months for surgical and chemotherapy group, respectively (p=0.007). Three-year overall survival was 30% and 10% for surgical and chemotherapy group, respectively. CONCLUSION: Treatment with CRS and HIPEC for biliary carcinoma with peritoneal metastasis is feasible and may provide survival benefit when compared to palliative chemotherapy.

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Pioneer transcription factors initiate cell-fate changes by binding to silent target genes. They are among the first factors to bind key regulatory sites and facilitate chromatin opening. Here, we identify an additional role for pioneer factors. In early Caenorhabditis elegans foregut development, the pioneer factor PHA-4/FoxA binds promoters and recruits RNA polymerase II (Pol II), often in a poised configuration in which Pol II accumulates near transcription start sites. At a later developmental stage, PHA-4 promotes chromatin opening. We found many more genes with poised RNA polymerase than had been observed previously in unstaged embryos, revealing that early embryos accumulate poised Pol II and that poising is dynamic. Our results suggest that Pol II recruitment, in addition to chromatin opening, is an important feature of PHA-4 pioneer factor activity.

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BACKGROUND: The learning curves for cytoreductive surgery with intraperitoneal chemotherapy for treatment of pseudomyxoma peritonei (PMP) were explored between international centres/surgeons to identify institutional or other factors that might affect performance. METHODS: Data from patients with PMP treated with the combined procedure across 33 international centres between 1993 and 2012 were analysed retrospectively. A risk-adjusted sequential probability ratio test was conducted after defining the target outcome as early oncological failure (disease progression within 2 years of treatment), an acceptable risk for the target outcome (odds ratio) of 2, and type I/II error rates of 5 per cent. The risk prediction model was elaborated and patients were evaluated sequentially for each centre/surgeon. The learning curve was considered to be overcome and proficiency achieved when the odds ratio for early oncological failure became smaller than 2. RESULTS: Rates of optimal cytoreduction, severe postoperative morbidity and early oncological failure were 84·4, 25·7 and 29·0 per cent respectively. The median annual centre volume was 17 (range 6-66) peritoneal malignancies. Only eight of the 33 centres and six of 47 surgeons achieved proficiency after a median of 100 (range 78-284) and 96 (86-284) procedures respectively. The most important institutional factor affecting surgical performance was centre volume. CONCLUSION: The learning curve is extremely long, so centralization and/or networking of centres is necessary to assure quality of services. One centre for every 10-15 million inhabitants would be ideal.

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Aromatase inhibitors (AIs) block estrogen synthesis and are commonly used as adjuvant treatments for breast cancer patients. A common side effect is joint pain. This was a pilot study to examine implementation of an exercise program in reducing joint pain and improving quality of life (QoL) and functional performance in breast cancer patients treated with AIs. Twenty-six participants completed an 8-week, home-based program that combined upper and lower body resistance exercises with self-selected aerobic exercises. We measured: (1) anthropometry (2) functional performance (grip strength, biceps curl to exhaustion, and sit-to-stand and cardiovascular endurance (3-min step test). Joint pain and QoL were assessed using self-administered surveys. Participants reported a significantly lower number of painful joints, an improvement in QoL and a reduction in depressive symptoms. Significant improvements in grip strength, biceps curl, and sit-to-stand (by 14%, 51% and 15% respectively) were also observed. However, we found no significant changes in cardiovascular endurance or in anthropometric measures. An 8-week, home-based exercise program may provide potential benefit to the breast cancer patients undergoing AI treatment by reducing joint pain, improving functional performance and QoL, and reducing depressive symptoms. Further studies are needed to confirm these results.

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BACKGROUND: The American Society of Peritoneal Surface Malignancies (ASPSM) is a consortium of cancer centers performing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). This is a position paper from the ASPSM on the standardization of the delivery of HIPEC. METHODS: A survey was conducted of all cancer centers performing HIPEC in the United States. We attempted to obtain consensus by the modified method of Delphi on seven key HIPEC parameters: (1) method, (2) inflow temperature, (3) perfusate volume, (4) drug, (5) dosage, (6) timing of drug delivery, and (7) total perfusion time. Statistical analysis was performed using nonparametric tests. RESULTS: Response rates for ASPSM members (n = 45) and non-ASPSM members (n = 24) were 89 and 33 %, respectively. Of the responders from ASPSM members, 95 % agreed with implementing the proposal. Majority of the surgical oncologists favored the closed method of delivery with a standardized dual dose of mitomycin for a 90-min chemoperfusion for patients undergoing cytoreductive surgery for peritoneal carcinomatosis of colorectal origin. CONCLUSIONS: This recommendation on a standardized delivery of HIPEC in patients with colorectal cancer represents an important first step in enhancing research in this field. Studies directed at maximizing the efficacy of each of the seven key elements will need to follow.

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Painful small-fiber peripheral neuropathy is a debilitating complication of chronic alcohol abuse. Evidence from previous studies suggests that neuroendocrine mechanisms, in combination with other, as yet unidentified actions of alcohol, are required to produce this neuropathic pain syndrome. In addition to neurotoxic effects of alcohol, in the setting of alcohol abuse neuroendocrine stress axes release glucocorticoids and catecholamines. Since receptors for these stress hormones are located on nociceptors, at which they can act to cause neuronal dysfunction, we tested the hypothesis that alcohol and stress hormones act on the nociceptor, independently, to produce neuropathic pain. We used a rat model, which allows the distinction of the effects of alcohol from those produced by neuroendocrine stress axis mediators. We now demonstrate that topical application of alcohol and exposure to unpredictable sound stress, each alone, has no effect on the nociceptive threshold. However, when animals that had previous exposure to alcohol were subsequently exposed to stress, they rapidly developed mechanical hyperalgesia. Conversely, sound stress followed by topical alcohol exposure also produced mechanical hyperalgesia. The contribution of stress hormones was prevented by spinal intrathecal administration of oligodeoxynucleotides antisense to ß(2)-adrenergic or glucocorticoid receptor mRNA, which attenuates receptor level in nociceptors, as well as by adrenal medullectomy. These experiments establish an independent role of alcohol and stress hormones on the primary afferent nociceptor in the induction of painful peripheral neuropathy.

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This article describes a risk analysis used to inform resource allocation at the Tucson Sector of the U.S. Border Patrol, the busiest sector for alien and drug trafficking along the Southwest land border with Mexico. The model and methodology that underlie this analysis are generally applicable to many resource allocation decisions regarding the management of frequently occurring hazards, decisions regularly made by officials at all levels of the homeland security enterprise. The analysis was executed by agents without previous risk expertise working under a short time frame, and the findings from the analysis were used to inform several resource allocation decisions.

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Peritoneal carcinomatosis (PC) arising from colorectal cancer (CRC) is generally considered a terminal condition with few treatment options. However, over the past few decades, new chemotherapeutic and biologic agents have improved the median overall survival of patients with unresectable metastatic disease up to 20 months. There has also been emergence of combining cytoreductive surgery (CS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with PC. The literature supporting such an approach is significant, though not extensive, mainly consisting of small single-institution series, one international multicenter retrospective review, and one single-institution prospective randomized trial. Yet, there is remarkable homogeneity among the reported clinical outcomes, demonstrating 5-year OS rates of approximately 25-40% for patients undergoing a complete cytoreduction. These studies have fueled increasing interest in the use of CS and HIPEC for metastatic colorectal cancer over the past decade. However, despite the publication of a consensus statement on the role of CS and HIPEC for PC from CRC, there is still controversy regarding its appropriateness, effectiveness, safety, and application in this subset of patients. In this review we analyze the currently available scientific evidence supporting the clinical application of CS and HIPEC in the treatment of PC of colorectal origin.

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In heterozygous mice, attenuation of G-protein-coupled receptor kinase 2 (GRK2) level in nociceptors is associated with enhanced and prolonged inflammatory hyperalgesia. To further elucidate the role of GRK2 in nociceptor function we reversibly decreased GRK2 expression using intrathecal antisense oligodeoxynucleotide (AS-ODN). GRK2 AS-ODN administration led to an enhanced and prolonged hyperalgesia induced by prostaglandin E(2), epinephrine and carrageenan. Moreover, this effect persisted unattenuated 2weeks after the last dose of antisense, well after GRK2 protein recovered, suggesting that transient attenuation of GRK2 produced neuroplastic changes in nociceptor function. Unlike hyperalgesic priming induced by transient activation of protein kinase C epsilon (PKCε), (Aley et al., 2000; Parada et al., 2003b), the enhanced and prolonged hyperalgesia following attenuation of GRK2 is PKCε- and cytoplasmic polyadenylation element binding protein (CPEB)-independent and is protein kinase A (PKA)- and Src tyrosine kinase (Src)-dependent. Finally, rats treated with GRK2 AS-ODN exhibited enhanced and prolonged hyperalgesia induced by direct activation of second messengers, adenyl cyclase, Epac or PKA, suggesting changes downstream of G-protein-coupled receptors. Because inflammation can produce a decrease in GRK2, such a mechanism could help explain a predilection to develop chronic pain, after resolution of acute inflammation.

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Many analyses conducted to inform security decisions depend on estimates of the conditional probabilities of different attack alternatives. These probabilities are difficult to estimate since analysts have limited access to the adversary and limited knowledge of the adversary's utility function, so subject matter experts often provide the estimates through direct elicitation. In this article, we describe a method of using uncertainty in utility function value tradeoffs to model the adversary's decision process and solve for the conditional probabilities of different attacks in closed form. The conditional probabilities are suitable to be used as inputs to probabilistic risk assessments and other decision support techniques. The process we describe is an extension of value-focused thinking and is broadly applicable, including in general business decision making. We demonstrate the use of this technique with simple examples.

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BACKGROUND: Combined therapy involving cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy has been shown to improve survival outcomes for patients with diffuse malignant peritoneal mesothelioma (DMPM). The present study aims to investigate gender as a potential prognostic factor on overall survival. PATIENTS AND METHODS: Over a period of two decades, 294 patients who underwent CRS and perioperative intraperitoneal chemotherapy were selected from a large multi-institutional registry to assess the prognostic significance of gender on overall survival. RESULTS: Female patients were shown to have a significantly improved survival outcome than male patients (P < 0.001). Staging according to a recently proposed tumor-node-metastasis categorization system was significant in both genders. Older female patients had significantly worse survival than younger female patients (P = 0.019), a finding that was absent in male patients. Female patients with low-stage disease were found to have a very favorable long-term outcome after combined treatment. CONCLUSIONS: Gender has demonstrated a significant impact on overall survival for patients with DMPM after CRS and perioperative intraperitoneal chemotherapy. An improved understanding of the role of estrogen in the pathogenesis of DMPM may improve the prognostication of patients and determine the role of adjuvant hormonal treatment in the future.

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BACKGROUND: Evaluation of peritoneal metastases by computed tomography (CT) scans is challenging and has been reported to be inaccurate. METHODS: A multi-institutional prospective observational registry study of patients with peritoneal carcinomatosis from colorectal cancer was conducted and a subset analysis was performed to examine peritoneal cancer index (PCI) based on CT and intraoperative exploration. RESULTS: Fifty-two patients (mean age 52.6 ± 12.4 years) from 16 institutions were included in this study. Inaccuracies of CT-based assessment of lesion sizes were observed in the RUQ (P = 0.004), LLQ (P < 0.0005), RLQ (P = 0.003), distal jejunum (P = 0.004), and distal ileum (P < 0.0005). When CT-PCI was classified based on the extent of carcinomatosis, 17 cases (33%) were underestimations, of which, 11 cases (21%) were upstaged from low to moderate, 4 cases (8%) were upstaged from low to severe, and 2 cases (4%) were upstaged from moderate to severe. Relevant clinical discordance where an upstage occurred to severe carcinomatosis constituted a true inaccuracy and was observed in six cases (12%). CONCLUSIONS: The actual clinical impact of inaccuracies of CT-PCI was modest. CT-PCI will remain as a mandatory imaging tool and may be supplemented with other tools including positron emission tomography scan or diagnostic laparoscopy, in the patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

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BACKGROUND: The aim of this study was to investigate the safety of neoadjuvant chemoradiation using radiotherapy (RT) combined with concurrent capecitabine and irinotecan for locally advanced rectal cancer before surgery. METHODS: Forty-six patients were recruited and treated on the basis that MRI scanning had shown poor-risk tumours with threatening (< or =1 mm) or involvement of the mesorectal fascia. Conformal RT was given using 3 or 4 fields at daily fractions of 1.8 Gy on 5 days per week to a total dose of 45 Gy. Concurrently oral capecitabine was given twice daily throughout radiotherapy continuously from days 1 to 35 and intravenous irinotecan was given once per week during weeks 1 to 4 of RT. Dose levels were gradually escalated as follows. Dose level 1: capecitabine 650 mg m(-2) b.i.d. and irinotecan 50 mg m(-2); Dose level 2: capecitabine 650 mg m(-2) b.i.d. and irinotecan 60 mg m(-2); Dose level 3: capecitabine 825 mg m(-2) b.i.d. and irinotecan 60 mg m(2); Dose level 4: capecitabine 825 mg m(-2) b.i.d. and irinotecan 70 mg m(-2). RESULTS: Diarrhoea (grade 3, no grade 4) was the main serious acute toxicity with lesser degrees of fatigue, neutropenia, anorexia and palmar-plantar erythrodysesthesia. The recommended dose for future study was dose level 2 at which 3 of 14 patients (21%) developed grade 3 diarrhoea. Postoperative complications included seven pelvic or wound infections and two anastomotic and two perineal wound dehiscences. There were no deaths in the first 30 days postoperatively. Of 41 resected specimens, 11 (27%) showed a pathological complete response (pCR) and five (12%) showed an involved circumferential resection margin (defined as < or =1 mm). The 3-year disease-free survival (intent-to-treat) was 53.2%. CONCLUSION: In patients with poor-risk MRI-defined locally advanced rectal cancer threatening or involving the mesorectal fascia, preoperative chemoradiation based on RT at 45 Gy in 25 daily fractions over 5 weeks with continuous daily oral capecitabine at 650 mg m(-2) b.i.d. days 1-35 and weekly IV irinotecan at 60 mg m(-2) weeks 1-4, provides acceptable acute toxicity and postoperative morbidity with encouraging response and curative resection rates.

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OBJECTIVE: Our aim was to determine the range of neo-adjuvant therapy the multidisciplinary team (MDT) currently offers patients with curable (M(0)) rectal cancer. METHOD: A senior oncologist from each of the four oncology centres in north Wales and the north-west of England (approximate target population 8 million - Glan Clwyd, Clatterbridge, Christie and Preston) reviewed his/her understanding of the current evidence of neo-adjuvant therapy in rectal cancer. Then a representative from each centre was asked to identify which of three neo-adjuvant options (no neo-adjuvant therapy, short-course radiotherapy 25 Gy over five fractions and long-course chemoradiotherapy) he/she would use for a rectal cancer in the upper, middle or lower third of the rectum staged by magnetic resonance imaging as being T(2)-T(4) and/or N(0)-N(2). RESULTS: In all cases of locally advanced rectal cancer (T(3a) N(1)-T(4)), oncologists from the four oncology centres recommended long-course chemoradiotherapy before rectal resection. This consensus was maintained for cases of lower third T(3a) N(0) cancers. Thereafter, the majority of patients with rectal cancer are offered adjuvant short-course radiotherapy. CONCLUSION: Neo-adjuvant therapy is less likely to be offered if the tumour is early (T(2), N(0)) and/or situated in the upper third of the rectum.

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Normal tissue reactions to radiation therapy vary in severity among patients and cannot be accurately predicted, limiting treatment doses. The existence of heritable radiosensitivity syndromes suggests that normal tissue reaction severity is determined, at least in part, by genetic factors and these may be revealed by differences in gene expression. To test this hypothesis, peripheral blood lymphocyte cultures from 22 breast cancer patients with either minimal (11) or very severe acute skin reactions (11) have been used to analyse gene expression. Basal and post-irradiation expression of four radiation-responsive genes (CDKN1A, GADD45A, CCNB1, and BBC3) was determined by quantitative real-time PCR in T-cell cultures established from the two patient groups before radiotherapy. Relative expression levels of BBC3, CCNB1, and GADD45A 2 h following 2 Gy X-rays did not discriminate between groups. However, post-irradiation expression response was significantly reduced for CDKN1A (P<0.002) in severe reactors compared to normal. Prediction of reaction severity of approximately 91% of individuals sampled was achieved using this end point. Analysis of TP53 Arg72Pro and CDKN1A Ser31Arg single nucleotide polymorphisms did not show any significant association with reaction sensitivity. Although these results require confirmation and extension, this study demonstrates the possibility of predicting the severity of acute skin radiation toxicity in simple tests.

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BACKGROUND: Microsatellite instability (MSI) in colorectal cancer is caused by defective DNA mismatch repair (MMR). It is present in 15 per cent of sporadic colorectal cancers owing to epigenetic mutL homologue 1 (MLH1) inactivation. The evidence suggests that patients with tumours caused by defective DNA MMR do not benefit from 5-fluorouracil (5-FU)-based chemotherapy. METHODS: The proportion of cancers with defective DNA MMR identified by MSI analysis or immunohistochemistry was calculated from published data. The cost of analysis was compared with the potential savings if 5-FU-based chemotherapy was not administered to these patients. RESULTS: Some 16.3 per cent of sporadic colorectal cancers had defective DNA MMR. Immunostaining for MLH1 and mutS homologue 2 (MSH2) had a sensitivity of 92.4 per cent and a specificity of 99.6 per cent for identifying MSI-high tumours. The strongest predictive variable was right-sidedness, with positive and negative predictive values of 0.329 and 0.948 respectively. If 5-FU-based chemotherapy were not administered, potential savings of up to pound 1.2 million per 1000 patients tested could be made. Costs would be higher if alternative chemotherapeutic regimens were substituted as a result of testing. CONCLUSION: Knowledge of MMR status may enable participation in trials of non-5-FU-based chemotherapy. The cost of MMR testing may be offset by more efficient use of chemotherapy.

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