BRCA1 and pancreatic cancer: pedigree findings and their causal relationships

Anecdotal reports and series studies indicate that 5-10% of pancreatic cancer (PC) cases are familial. In addition, PC is associated with a variety of hereditary cancer syndromes. PC appears to be an integral cancer in the hereditary breast-ovarian cancer (HBOC) syndrome, with most notice given to the role of BRCA2. Our purpose is to call attention to BRCA1, which also predisposes to PC. Using data from our familial breast cancer registry, we identified 19 BRCA1/2 families that contain PC affecteds in the pedigrees, 15 with BRCA1 mutations and 4 with BRCA2 mutations. The association between BRCA2 and pancreatic cancer is well established; however, a definite link with pancreatic cancer in families carrying a BRCA1 mutation has been far less studied. Thus, the focus of this report is on 9 of the 15 BRCA1 families, in which PC affecteds were either confirmed carriers of the BRCA1 mutation or were inferred as probable obligate BRCA1 mutation carriers. The numbers are small, but nevertheless illustrate the finding of others of an apparent association between PC and BRCA1-mutation-bearing families. Given the dismal prognosis of PC, with the only current hope for survival being through surgical extirpation of the pancreas prior to metastasis, it is prudent that we realize the potential predisposition toward PC via BRCA1, in the hope of early diagnosis and prevention.     

Histiocytic sarcoma with interdigitating dendritic cell differentiation: A case report with fine needle aspiration cytology and review of literature

A hybrid histiocytic sarcoma‐interdigitating dendritic cell sarcoma was found in a small perinephric lymph node of an asymptomatic 80‐year‐old man, who presented a year ago with two small foci of lung metastasis found during routine chest X‐ray. Fine needle aspiration cytology demonstrated interconnecting long and thin cell processes radiating from dendrite‐like neoplastic cells with oval, enlongated, reniform, and irregular nuclei with vesicular chromatin and distinct nucleoli. Histology showed spindled epitheliod and histiocytic cells with abundant, slightly eosinophilic cytoplasm with indistinct cell borders and forming fascicles in a vague storiform pattern with interspersed T‐lymphocytes. Immunohistochemically, the neoplastic cells were strongly positive for histiocytic markers: CD163, CD68, lysozyme, and PU.1, as well as strongly positive for dendritic cell markers: S100 and fascin, but were negative for CD1a (Langerhans cell marker), CD21/CD35 (follicular dendritic cell markers), B‐cell, and T cell markers. This case is compared to the four hybrid histiocytic‐dendritic sarcomas reported since 1983. Diagn. Cytopathol. 2010. © 2009 Wiley‐Liss, Inc.     

A longitudinal examination predicting emergency room use in children with sickle cell disease and their caregivers

OBJECTIVE: To examine in a longitudinal investigation perceptions of disease severity among children and adolescents with sickle cell disease (SCD) and their caregivers and to determine whether perceptions of disease severity and self-reported adjustment would account for a greater percentage of the variance in emergency room (ER) use than objective measures of disease severity. METHODS: Participants were 58 African-American children (ages 8-18 years) diagnosed with SCD who were recruited from an outpatient clinic. Children and their caregivers were administered a series of measures designed to assess caregivers' adjustment and perceptions of children's disease severity. Frequency of ER visits was tabulated over an average 4-year period. RESULTS: Caregivers' and children's social adjustment accounted for a unique portion of the variance beyond that accounted by subjective perceptions of disease severity, demographic, and objective biological markers of disease severity. Poorer psychological adjustment of caregivers as well as communication patterns among children were associated with ER use frequency after controlling for objective disease severity variables and demographic factors. Child social adjustment, specifically friendship quality, accounted for variance in children's use of the ER beyond that accounted for by social class and objective markers of disease severity. CONCLUSIONS: Support is provided for the notion that ER use for children with SCD may be independent of disease severity and predicted by caregivers' psychological adjustment and children's peer adjustment.     

Structural basis by which alternative splicing modulates the organizer activity of FGF8 in the brain

Two of the four human FGF8 splice isoforms, FGF8a and FGF8b, are expressed in the mid-hindbrain region during development. Although the only difference between these isoforms is the presence of an additional 11 amino acids at the N terminus of FGF8b, these isoforms possess remarkably different abilities to pattern the midbrain and anterior hindbrain. To reveal the structural basis by which alternative splicing modulates the organizing activity of FGF8, we solved the crystal structure of FGF8b in complex with the "c" splice isoform of FGF receptor 2 (FGFR2c). Using surface plasmon resonance (SPR), we also characterized the receptor-binding specificity of FGF8a and FGF8b, the "b" isoform of FGF17 (FGF17b), and FGF18. The FGF8b-FGFR2c structure shows that alternative splicing permits a single additional contact between phenylalanine 32 (F32) of FGF8b and a hydrophobic groove within Ig domain 3 of the receptor that is also present in FGFR1c, FGFR3c, and FGFR4. Consistent with the structure, mutation of F32 to alanine reduces the affinity of FGF8b toward all these receptors to levels characteristic of FGF8a. More importantly, analysis of the mid-hindbrain patterning ability of the FGF8b(F32A) mutant in chick embryos and murine midbrain explants shows that this mutation functionally converts FGF8b to FGF8a. Moreover, our data suggest that the intermediate receptor-binding affinities of FGF17b and FGF18, relative to FGF8a and FGF8b, also account for the distinct patterning abilities of these two ligands. We also show that the mode of FGF8 receptor-binding specificity is distinct from that of other FGFs and provide the first biochemical evidence for a physiological FGF8b-FGFR1c interaction during mid-hindbrain development. Consistent with the indispensable role of FGF8 in embryonic development, we show that the FGF8 mode of receptor binding appeared as early as in nematodes and has been preserved throughout evolution.     

MKK4 and metastasis suppression: a marriage of signal transduction and metastasis research

MAP kinase kinase 4 (MKK4) is a member of the stress-activated protein kinase (SAPK) signaling cascade and is involved in the regulation of many cellular processes. We have recently demonstrated a functional role for MKK4 in the suppression of metastases. In this review, we discuss the established cellular and biochemical functions of MKK4, as well as a new function for MKK4 as a metastasis suppressor gene. Because of the importance of signaling studies to this translational work, a detailed example of the strategy and tools that can be employed to define the biochemical mechanism of MKK4-mediated metastasis suppression is presented. Finally, the potential therapeutic utility of these findings is discussed.     

Enhanced Recovery after Minimally Invasive Gynecologic Procedures with Bowel Surgery: A Systematic Review

Enhanced recovery after surgery (ERAS) is an evidence-based approach to perioperative care of the surgical patient. A mounting body of literature in gynecologic surgery has demonstrated that ERAS improves postoperative outcomes, shortens hospital length of stay, and reduces cost without increasing complications or readmissions. Most of the existing literature has concentrated on open surgery, questioning if patients undergoing minimally invasive surgery also derive benefit. Our aim was to systematically review the literature on ERAS after minimally invasive gynecologic surgery (MIGS) with and without bowel surgery. Given the paucity of studies on ERAS in MIGS with bowel surgery (1 study), we expanded our search to include studies of ERAS in patients undergoing minimally invasive colorectal resections alone. Twelve studies were identified through an electronic database search of PubMed, Medline, and Ovid EMBASE. These studies included patients undergoing MIGS for benign and/or malignant indications and showed that ERAS pathways decreased length of stay and/or increased the proportion of same-day discharge surgeries, improved patient satisfaction, and reduced hospital costs while maintaining low postoperative complication and readmission rates. Although limited, data from a single study suggest that ERAS in MIGS with bowel surgery leads to shortened hospital stay, stable postoperative morbidity, and less readmissions. Although the variation between the published protocols underscores the need for standardization, existing literature supports the adoption of ERAS as safe and effective when planning MIGS.     

Feasibility of elementary school children’s use of hand gel and facemasks during influenza season

Please cite this paper as: Allison et al. (2010) Feasibility of elementary school children’s use of hand gel and facemasks during influenza season. Influenza and Other Respiratory Viruses 4(4), 223–229. Background The feasibility of non-pharmacologic interventions to prevent influenza’s spread in schools is not well known. Objectives To determine the acceptability of, adherence with, and barriers to the use of hand gel and facemasks in elementary schools. Patients and Methods Intervention: We provided hand gel and facemasks to 20 teachers and their students over 4 weeks. Gel use was promoted for the first 2 weeks; mask use was promoted for the second 2 weeks. Outcomes: Acceptability, adherence, and barriers were measured by teachers’ responses on weekly surveys. Mask use was also measured by observation. Results The weekly survey response rate ranged from 70% to 100%. Averaged over 2 weeks, 89% of teachers thought gel use was not disruptive (week 1 – 17/20, week 2 – 16/17), 95% would use gel next winter (week 1 – 19/20, week 2 – 16/17), and 97% would use gel in a pandemic (week 1 – 20/20, week 2 – 16/17). Averaged over 2 weeks, 39% thought mask use was not disruptive (week 1 – 6/17, week 2 – 6/14), 35% would use masks next winter (week 1 – 5/17, week 2 – 6/14), and 97% would use masks in a pandemic (week 1 – 16/17, week 2 – 14/14). About 70% estimated that their students used hand gel ≥4×/day for both weeks (week 1 – 14/20, week 2 – 13/17). Students’ mask use declined over time with 59% of teachers (10/17) estimating regular mask use during week 1 and 29% (4/14) during week 2. By observation, 30% of students wore masks in week 1, while 15% wore masks in week 2. Few barriers to gel use were identified; barriers to mask use were difficulty reading facial expressions and physical discomfort. Conclusions Hand gel use is a feasible strategy in elementary schools. Acceptability and adherence with facemasks was low, but some students and teachers did use facemasks for 2 weeks, and most teachers would use masks in their classroom in a pandemic.