LTßR-RelB signaling in intestinal epithelial cells protects from chemotherapy-induced mucosal damage.

The intricate immune mechanisms governing mucosal healing following intestinal damage induced by cytotoxic drugs remain poorly understood. The goal of this study was to investigate the role of lymphotoxin beta receptor (LTßR) signaling in chemotherapy-induced intestinal damage. LTßR deficient mice exhibited heightened body weight loss, exacerbated intestinal pathology, increased proinflammatory cytokine expression, reduced IL-22 expression, and proliferation of intestinal epithelial cells following methotrexate (MTX) treatment. Furthermore, LTßR-/-IL-22-/- mice succumbed to MTX treatment, suggesting that LTßR- and IL-22- dependent pathways jointly promote mucosal repair. Although both LTßR ligands LIGHT and LTß were upregulated in the intestine early after MTX treatment, LIGHT-/- mice, but not LTß-/- mice, displayed exacerbated disease. Further, we revealed the critical role of T cells in mucosal repair as T cell-deficient mice failed to upregulate intestinal LIGHT expression and exhibited increased body weight loss and intestinal pathology. Analysis of mice with conditional inactivation of LTßR revealed that LTßR signaling in intestinal epithelial cells, but not in Lgr5+ intestinal stem cells, macrophages or dendritic cells was critical for mucosal repair. Furthermore, inactivation of the non-canonical NF-kB pathway member RelB in intestinal epithelial cells promoted MTX-induced disease. Based on these results, we propose a model wherein LIGHT produced by T cells activates LTßR-RelB signaling in intestinal epithelial cells to facilitate mucosal repair following chemotherapy treatment.

Prevalence and outcomes of high versus low ratio plasma to red blood cell resuscitation in a multi-institutional cohort of severely injured children.

BACKGROUND: The benefit of targeting high ratio fresh frozen plasma (FFP)/red blood cell (RBC) transfusion in pediatric trauma resuscitation is unclear as existing studies are limited to patients who retrospectively met criteria for massive transfusion. The purpose of this study is to evaluate the use of high ratio FFP/RBC transfusion and the association with outcomes in children presenting in shock. METHODS: A post hoc analysis of a 24-institution prospective observational study (April 2018 to September 2019) of injured children younger than 18 years with elevated age-adjusted shock index was performed. Patients transfused within 24 hours were stratified into cohorts of low (<1:2) or high (≥1:2) ratio FFP/RBC. Nonparametric Kruskal-Wallis and χ 2 were used to compare characteristics and mortality. Competing risks analysis was used to compare extended (≥75th percentile) ventilator, intensive care, and hospital days while accounting for early deaths. RESULTS: Of 135 children with median (interquartile range) age 10 (5-14) years and weight 40 (20-64) kg, 85 (63%) received low ratio transfusion and 50 (37%) high ratio despite similar activation of institutional massive transfusion protocols (low-38%, high-46%, p = 0.34). Most patients sustained blunt injuries (70%). Median injury severity score was greater in high ratio patients (low-25, high-33, p = 0.01); however, hospital mortality was similar (low-24%, high-20%, p = 0.65) as was the risk of extended ventilator, intensive care unit, and hospital days (all p > 0.05). CONCLUSION: Despite increased injury severity, patients who received a high ratio of FFP/RBC had comparable rates of mortality. These data suggest high ratio FFP/RBC resuscitation is not associated with worst outcomes in children who present in shock. Massive transfusion protocol activation was not associated with receipt of high ratio transfusion, suggesting variability in MTP between centers. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Crystalloid volume is associated with short-term morbidity in children with severe traumatic brain injury: An Eastern Association for the Surgery of Trauma multicenter trial post hoc analysis.

OBJECTIVE: This study examined differences in clinical and resuscitation characteristics between injured children with and without severe traumatic brain injury (sTBI) and aimed to identify resuscitation characteristics associated with improved outcomes following sTBI. METHODS: This is a post hoc analysis of a prospective observational study of injured children younger than 18 years (2018-2019) transported from the scene, with elevated shock index pediatric-adjusted on arrival and head Abbreviated Injury Scale score of ≥3. Timing and volume of resuscitation products were assessed using χ 2t test, Fisher's exact t test, Kruskal-Wallis, and multivariable logistic regression analyses. RESULTS: There were 142 patients with sTBI and 547 with non-sTBI injuries. Severe traumatic brain injury patients had lower initial hemoglobin (11.3 vs. 12.4, p < 0.001), greater initial international normalized ratio (1.4 vs. 1.1, p < 0.001), greater Injury Severity Score (25 vs. 5, p < 0.001), greater rates of ventilator (59% vs. 11%, p < 0.001) and intensive care unit (ICU) requirement (79% vs. 27%, p < 0.001), and more inpatient complications (18% vs. 3.3%, p < 0.001). Severe traumatic brain injury patients received more prehospital crystalloid (25% vs. 15%, p = 0.008), ≥1 crystalloid boluses (52% vs. 24%, p < 0.001), and blood transfusion (44% vs. 12%, p < 0.001) than non-sTBI patients. Among sTBI patients, receipt of ≥1 crystalloid bolus (n = 75) was associated with greater ICU need (92% vs. 64%, p < 0.001), longer median ICU (6 vs. 4 days, p = 0.027) and hospital stay (9 vs. 4 days, p < 0.001), and more in-hospital complications (31% vs. 7.5%, p = 0.003) than those who received <1 bolus (n = 67). These findings persisted after adjustment for Injury Severity Score (odds ratio, 3.4-4.4; all p < 0.010). CONCLUSION: Pediatric trauma patients with sTBI received more crystalloid than those without sTBI despite having a greater international normalized ratio at presentation and more frequently requiring blood products. Excessive crystalloid may be associated with worsened outcomes, including in-hospital mortality, seen among pediatric sTBI patients who received ≥1 crystalloid bolus. Further attention to a crystalloid sparing, early transfusion approach to resuscitation of children with sTBI is needed. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Implementation of a Standardized Perioperative Pain Management Protocol to Reduce Opioid Prescriptions in Otolaryngologic Surgery.

OBJECTIVE: To evaluate the efficacy of implementing a standardized multimodal perioperative pain management protocol in reducing opioid prescriptions following otolaryngologic surgery. STUDY DESIGN: Retrospective cohort study. SETTING: County hospital otolaryngology practice. METHODS: A perioperative pain management protocol was implemented in adults undergoing otolaryngologic surgery. This protocol included preoperative patient education and a postoperative multimodal pain regimen stratified by pain level: mild, intermediate, and high. Opioid prescriptions were compared between patient cohorts before and after protocol implementation. Patients in the pain protocol were surveyed regarding pain levels and opioid use. RESULTS: We analyzed 210 patients (105 preprotocol and 105 postprotocol). Mean ± SD morphine milligram equivalents (MMEs) prescribed decreased from 132.5 ± 117.8 to 53.6 ± 63.9 (P < .05) following protocol implementation. Mean MMEs prescribed significantly decreased (P < .05) for each procedure pain tier: mild (107.4 to 40.5), intermediate (112.8 to 48.1), and high (240.4 to 105.0). Mean MMEs prescribed significantly decreased (P < .05) for each procedure type: endocrine (105.6 to 44.4), facial plastics (225.0 to 50.0), general (160.9 to 105.7), head and neck oncology (138.6 to 77.1), laryngology (53.8 to 12.5), otology (77.5 to 42.9), rhinology (142.2 to 44.4), and trauma (288.0 to 24.5). Protocol patients reported a mean 1-week postoperative pain score of 3.4, used opioids for a mean 3.1 days, and used only 39% of their prescribed opioids. CONCLUSION: Preoperative counseling and standardization of a multimodal perioperative pain regimen for otolaryngology procedures can effectively lower amount of opioid prescriptions while maintaining low levels of postoperative pain.

Redefining the Role of Lymphotoxin Beta Receptor in the Maintenance of Lymphoid Organs and Immune Cell Homeostasis in Adulthood.

Lymphotoxin beta receptor (LTßR) is a promising therapeutic target in autoimmune and infectious diseases as well as cancer. Mice with genetic inactivation of LTßR display multiple defects in development and organization of lymphoid organs, mucosal immune responses, IgA production and an autoimmune phenotype. As these defects are imprinted in embryogenesis and neonate stages, the impact of LTßR signaling in adulthood remains unclear. Here, to overcome developmental defects, we generated mice with inducible ubiquitous genetic inactivation of LTßR in adult mice (iLTßRΔ/Δ mice) and redefined the role of LTßR signaling in organization of lymphoid organs, immune response to mucosal bacterial pathogen, IgA production and autoimmunity. In spleen, postnatal LTßR signaling is required for development of B cell follicles, follicular dendritic cells (FDCs), recruitment of neutrophils and maintenance of the marginal zone. Lymph nodes of iLTßRΔ/Δ mice were reduced in size, lacked FDCs, and had disorganized subcapsular sinus macrophages. Peyer`s patches were smaller in size and numbers, and displayed reduced FDCs. The number of isolated lymphoid follicles in small intestine and colon were also reduced. In contrast to LTßR-/- mice, iLTßRΔ/Δ mice displayed normal thymus structure and did not develop signs of systemic inflammation and autoimmunity. Further, our results suggest that LTßR signaling in adulthood is required for homeostasis of neutrophils, NK, and iNKT cells, but is dispensable for the maintenance of polyclonal IgA production. However, iLTßRΔ/Δ mice exhibited an increased sensitivity to C. rodentium infection and failed to develop pathogen-specific IgA responses. Collectively, our study uncovers new insights of LTßR signaling in adulthood for the maintenance of lymphoid organs, neutrophils, NK and iNKT cells, and IgA production in response to mucosal bacterial pathogen.

Craniocervical Dissociation in Pediatric Patients: Pearls and Pitfalls of Diagnosis and Management.

AIMS: The aims of this study were to document the injury pattern in pediatric traumatic craniocervical dissociation (CCD) and identify features of survivors. METHODS: Pediatric traumatic CCDs, diagnosed between January 2004 and July 2016, were reviewed. Survivors and nonsurvivors were compared. Categorical and continuous variables were analyzed with Fisher exact and t tests, respectively. RESULTS: Twenty-seven children were identified; 10 died (37%). The median age was 60 months (ranges, 6-109 months [survivors], 2-98 months [nonsurvivors]). For survivors, the median follow-up was 13.4 months (range, 1-109 months). The median time to mortality was 1.5 days (range, 1-7 days). The injury modality was motor vehicle collision in 18 (67%), pedestrian struck in 8 (30%), and 1 shaken infant (3%). For nonsurvivors, CCD was equally diagnosed by plain radiograph and head/cervical spine computed tomography scan. For survivors, CCD was diagnosed by computed tomography in 7 (41%), magnetic resonance imaging in 10 (59%), and none by radiograph. Seven diagnosed by magnetic resonance imaging (41%) had nondiagnostic initial imaging but persistent neck pain. Magnetic resonance imaging was obtained and was diagnostic of CCD in all 7 (P < 0.01). Survivors required significantly less cardiopulmonary resuscitation (P < 0.01), had lower Injury Severity Scores (P < 0.01), higher Glasgow Coma Scale scores (P < 0.01), and shorter transport times (P < 0.01). Significantly more involved in motor vehicle collisions survived (P = 0.04). Nine (53%) had no disability at follow-up evaluation. CONCLUSIONS: In pediatric CCD, high-velocity mechanism, cardiac arrest, high Injury Severity Score, and low Glasgow Coma Scale score are associated with mortality. If CCD is correctly managed in the absence of cardiac arrest or traumatic brain or spinal cord injury, children may survive intact.

Cerebral and Renal Oxygenation in Infants Undergoing Laparoscopic Gastrostomy Tube Placement.

AIM: The aim of this study was to evaluate the effects of a carbon dioxide pneumoperitoneum on cerebral and renal oxygenation and oxygen extraction, in a cohort of infants from the neonatal intensive care unit, undergoing laparoscopic gastrostomy. METHODS: After institutional review board approval, between February 2018 and June 2019, infants 0-3 mo corrected age, undergoing laparoscopic gastrostomy tube placement, were included. Strict exclusion criteria created a homogeneous cohort. Cerebral and renal tissue oxygen saturation (rSO2) by near-infrared spectroscopy, skin surface oxygen saturation (SpO2), by pulse oximetry, and amplitude-integrated electroencephalography were measured. Monitoring was divided into preoperative, intraoperative and postoperative time periods. Cerebral and renal fractional tissue oxygen extraction was calculated using arterial (SpO2) and tissue oxygen saturation (rSO2): (SpO2-rSO2SpO2)X100. Data were averaged into one-minute epochs and significant changes from baseline during the intraoperative and postoperative periods were detected using one-way analysis of variance with repeated measures. RESULTS: This pilot study examined sixteen infants, born at a median gestational age of 34.2 wk (range: 23.0-40.6) with a median corrected age of 42.9 wk (range: 40.0-46.3) at operation. None had seizure activity or altered sleep-wake cycles. No statistically significant variations in cerebral and renal tissue oxygenation and extraction were observed. Pulse oximetry did demonstrate significant variation from baseline on analysis of variance, but post hoc analysis did not identify any one specific time point at which this difference was significant. CONCLUSIONS: During a short infant laparoscopic procedure, no significant alteration in cerebral or renal oxygenation or oxygen extraction was observed. No seizure activity or changes in infant sleep-wake cycles occurred.

Timing and volume of crystalloid and blood products in pediatric trauma: An Eastern Association for the Surgery of Trauma multicenter prospective observational study.

BACKGROUND: The purpose of this study was to determine the relationship between timing and volume of crystalloid before blood products and mortality, hypothesizing that earlier transfusion and decreased crystalloid before transfusion would be associated with improved outcomes. METHODS: A multi-institutional prospective observational study of pediatric trauma patients younger than 18 years, transported from the scene of injury with elevated age-adjusted shock index on arrival, was performed from April 2018 to September 2019. Volume and timing of prehospital, emergency department, and initial admission resuscitation were assessed including calculation of 20 ± 10 mL/kg crystalloid boluses overall and before transfusion. Multivariable Cox proportional hazards and logistic regression models identified factors associated with mortality and extended intensive care, ventilator, and hospital days. RESULTS: In 712 children at 24 trauma centers, mean age was 7.6 years, median (interquartile range) Injury Severity Score was 9 (2-20), and in-hospital mortality was 5.3% (n = 38). There were 311 patients(43.7%) who received at least one crystalloid bolus and 149 (20.9%) who received blood including 65 (9.6%) with massive transfusion activation. Half (53.3%) of patients who received greater than one crystalloid bolus required transfusion. Patients who received blood first (n = 41) had shorter median time to transfusion (19.8 vs. 78.0 minutes, p = 0.005) and less total fluid volume (50.4 vs. 86.6 mL/kg, p = 0.033) than those who received crystalloid first despite similar Injury Severity Score (median, 22 vs. 27, p = 0.40). On multivariable analysis, there was no association with mortality (p = 0.51); however, each crystalloid bolus after the first was incrementally associated with increased odds of extended ventilator, intensive care unit, and hospital days (all p < 0.05). Longer time to transfusion was associated with extended ventilator duration (odds ratio, 1.11; p = 0.04). CONCLUSION: Resuscitation with greater than one crystalloid bolus was associated with increased need for transfusion and worse outcomes including extended duration of mechanical ventilation and hospitalization in this prospective study. These data support a crystalloid-sparing, early transfusion approach for resuscitation of injured children. LEVEL OF EVIDENCE: Therapeutic, level IV.

Attenuation of NAD[P]H:quinone oxidoreductase 1 aggravates prostate cancer and tumor cell plasticity through enhanced TGFß signaling.

NAD[P]H:quinone oxidoreductase 1 (NQO1) regulates cell fate decisions in response to stress. Oxidative stress supports cancer maintenance and progression. Previously we showed that knockdown of NQO1 (NQO1low) prostate cancer cells upregulate pro-inflammatory cytokines and survival under hormone-deprived conditions. Here, we tested the ability of NQO1low cells to form tumors. We found NQO1low cells form aggressive tumors compared with NQO1high cells. Biopsy specimens and circulating tumor cells showed biochemical recurrent prostate cancer was associated with low NQO1. NQO1 silencing was sufficient to induce SMAD-mediated TGFß signaling and mesenchymal markers. TGFß treatment decreased NQO1 levels and induced molecular changes similar to NQO1 knockdown cells. Functionally, NQO1 depletion increased migration and sensitivity to oxidative stress. Collectively, this work reveals a possible new gatekeeper role for NQO1 in counteracting cellular plasticity in prostate cancer cells. Further, combining NQO1 with TGFß signaling molecules may serve as a better signature to predict biochemical recurrence.

Long term complications and outcomes in omphalocele.

After a diagnosis of omphalocele during pregnancy, questions regarding long-term prognosis are of primary importance for parents. It is imperative that their questions are answered with substantiated data to promote confident decisions for their children. They frequently express concerns regarding long-term survival, quality of life, need for more operations, feeding issues, motor and cognitive development, cosmesis, and the unique difficulties of giant omphaloceles. The available outcome studies that address these questions are discussed.

Safe phlebotomy reduction in stable pediatric liver and spleen injuries.

PURPOSE: Pediatric blunt solid organ injury management based on hemodynamic monitoring rather than grade may safely reduce resource expenditure and improve outcomes. Previously we have reported a retrospectively validated management algorithm for pediatric liver and spleen injuries which monitors hemodynamics without use of routine phlebotomy. We hypothesize that stable blunt pediatric isolated splenic/liver injuries can be managed safely using a protocol reliant on vital signs and not repeat hemoglobin levels. METHODS: A prospective multi-institutional study was performed at three pediatric trauma centers. All pediatric patients from 07/2016-12/2017 diagnosed with liver or splenic injuries were identified. If appropriate for the protocol, only a baseline hemoglobin was obtained unless hemodynamic instability as defined in an age-appropriate fashion was determined by treating physician discretion. Descriptive statistics were conducted. RESULTS: One hundred four patients were identified of which 38 were excluded from the protocol. There was a significant difference in abnormal shock index, pediatric age-adjusted (SIPA) values, hematocrit, and percentage of patients with hemoglobin less than 10 between the excluded and included patients. Of the 66 patients managed on the protocol, four patients had to be removed, two each on day one and day two. Of those four patients, only one required intervention. There were no mortalities. CONCLUSION: A phlebotomy limiting protocol may be a safe option for stable pediatric splenic and liver injuries cared for in a pediatric trauma center with the resources for rapid intervention should the need arise. The differences in groups highlight the importance of utilizing this protocol in the correct patient population. Reduced phlebotomy offers the potential for reduced resource expenditure without any evidence of increased morbidity or mortality. LEVEL OF EVIDENCE: Level IV.

Intestinal Function after Early versus Late Appendectomy in Children with Perforated Appendicitis.

The aim was to prospectively document the impact of early versus late appendectomy on intestinal function in pediatric perforated appendicitis. After Institutional Review Board approval, between September 2016 and August 2017, complete data were prospectively collected for children undergoing planned appendectomy for perforated appendicitis. One hundred children with pathologist-confirmed transmural perforations were included. The median time to operation after pain onset was three days. Operation on day 1 or 2 (early) was compared with that on day 3 or after (late) (range, 3-9 days). Emesis, nasogastric tubes, and time to tolerate diet evaluated intestinal function. Categorical and continuous variables were analyzed by chi-square and t tests. Of the 100, there were 45 in the early and 55 in the late group, with 22/55(40%) operated on day 3. Children with early appendectomy were significantly younger, 7.8 (3.5) versus 9.5 (3.8) years (P = 0.02). Pre-appendectomy, more than 80 per cent of each group had emesis (P = 0.84), but the late group had a 10-fold increase in nasogastric tube use (P = 0.02). The early group tolerated regular diet significantly faster, 2.5 (2.1) versus 4.4 (4.1) days (P = 0.01), and had a significantly shorter hospital stay, 3.5 (2.2) versus 5.6 (4.3) days (P = 0.01). When pain onset to appendectomy is less than three days, the time to return of intestinal function is significantly reduced.

Young children with perforated appendicitis benefit from prompt appendectomy.

BACKGROUND/PURPOSE: To identify factors associated with nonoperative treatment failure in pediatric perforated appendicitis compared to immediate appendectomy. METHODS: After IRB approval, between September 2016 and August 2017, prospective data were recorded for children (age: 1-18 years) with completed appendectomies and pathologist-confirmed perforations. Children were treated according to clinician-designated preference. Nonoperative treatment was considered failed if a nonresolving obstruction developed or any return of symptoms before the planned interval. The median time from pain onset to treatment initiation was 3 days (range: 1-14). Presentation on days 1 or 2 (early) was compared to day 3 or after(late). The nonoperatives were compared to appendectomies stratified by presentation time. Variables were compared by chi-square, Fisher exact or t-tests. Logistic regression evaluated for independence. RESULTS: Of 201 suspected perforations, 176 were included, 101 (57%) immediate appendectomies and 75 (43%) nonoperatives. Of 75, 24 (32%) failed; 6 (25%) in hospital, 18 (75%) after discharge. In 51 (68%), nonoperative treatment succeeded. Significantly younger children failed nonoperative treatment (p = 0.03). Failure was independently associated with treatment initiation within 2.75 days from pain onset (OR: 0.07, 95% CI: 0.57-0.98) (p = 0.010) and lower WBC at presentation (OR: 0.03, 95% CI: 0.81-0.98) (p = 0.014). When compared to immediate appendectomy, nonoperatives had more morbidity. CONCLUSION: Younger children fail nonoperative treatment, perforate rapidly and have a significantly lower WBC, but benefit from immediate appendectomy. LEVEL OF EVIDENCE: Treatment Study Level II.

Hospital-Based Study of Compliance with NCCN Guidelines and Predictive Factors of Sentinel Lymph Node Biopsy in the Setting of Thin Melanoma Using the National Cancer Database.

Thin melanoma is the most common form of melanoma in the United States. The National Comprehensive Cancer Network (NCCN) has guidelines for sentinel lymph node biopsy (SLNB) which recommend "discuss and consider" SLNB for invasion >0.75 mm and "discuss and offer" SLNB for invasion >0.75 mm with suspicious features. This study looked at compliance with NCCN guidelines and factors that are predictive of a positive SLNB. This is a retrospective study of patients diagnosed with thin melanoma 2012-2013 using the National Cancer Database. A total of 26,456 patients met study qualifications. Univariate analysis showed that 76 per cent of patients meeting criteria underwent SLNB. Patients recommended to "discuss and consider" received SLNB 53 per cent of the time and those not recommended for SLNB received SLNB 20 per cent of the time. On multivariate analysis, depth was not predictive for positive SLNB whereas mitoses and ulceration were. Other factors predictive of positive SLNB were nodular cell type, lymphovascular invasion, and Clark's level greater than or equal to IV. Patients with thin melanoma that meet NCCN guidelines for SLNB undergo this procedure in good compliance but those who do not meet criteria continue to receive SLNB. Positive predictive factors for positive SLNB include mitoses, ulceration, Clark's level, and primary site.

Palmatine suppresses glutamine-mediated interaction between pancreatic cancer and stellate cells through simultaneous inhibition of survivin and COL1A1.

Reciprocal interaction between pancreatic stellate cells (PSCs) and cancer cells (PCCs) in the tumor microenvironment (TME) promotes tumor cell survival and progression to lethal, therapeutically resistant pancreatic cancer. The goal of this study was to test the ability of Palmatine (PMT) to disrupt this reciprocal interaction in vitro and examine the underlying mechanism of interaction. We show that PSCs secrete glutamine into the extracellular environment under nutrient deprivation. PMT suppresses glutamine-mediated changes in GLI signaling in PCCs resulting in the inhibition of growth and migration while inducing apoptosis by inhibition of survivin. PMT-mediated inhibition of (glioma-associated oncogene 1) GLI activity in stellate cells leads to suppression (collagen type 1 alpha 1) COL1A1 activation. Remarkably, PMT potentiated gemcitabine's growth inhibitory activity in PSCs, PCCs and inherently gemcitabine-resistant pancreatic cancer cells. This is the first study that shows the ability of PMT to inhibit growth of PSCs and PCCs either alone or in combination with gemcitabine. These studies warrant additional investigations using preclinical models to develop PMT as an agent for clinical management of pancreatic cancer.

Surgery Residents and Family Dynamics: Are Our Trainees Equipped to Handle Patient Care Beyond Disease?

Surgical trainees are expected to demonstrate family-centered care. However, it is unclear if residents know how to address psychosocial issues of pediatric patients and their families. Our aim was to evaluate surgical trainees' knowledge of family dynamics. Over a six-month period, trainees (n = 16) were surveyed regarding their comfort and familiarity with the psychosocial aspects of patient care and family dynamics. Residents recorded their comfort level with managing various behaviors using a Likert scale, and indicated which family issues they felt least prepared to handle. Most trainees lacked knowledge of family adjustment phases (50%), relational triangles (78%), developmental stages of families (40%), ambiguous loss (75%), ABCX model of family stress (100%), and the SPIKES model (88%). Excluding anxiety and sadness, almost half of residents felt unprepared for dealing with a variety of challenging behaviors. Finally, trainees were least comfortable with breaking bad news. A Family Dynamics curriculum could potentially increase resident management skills and improve patient care.

Downregulation of STAT3/NF-κB potentiates gemcitabine activity in pancreatic cancer cells.

There is an unmet need to develop new agents or strategies against therapy resistant pancreatic cancer (PanCA). Recent studies from our laboratory showed that STAT3 negatively regulates NF-κB and that inhibition of this crosstalk using Nexrutine® (Nx) reduces transcriptional activity of COX-2. Inhibition of these molecular interactions impedes pancreatic cancer cell growth as well as reduces fibrosis in a preclinical animal model. Nx is an extract derived from the bark of Phellodendron amurense and has been utilized in traditional Chinese medicine as antidiarrheal, astringent, and anti-inflammatory agent for centuries. We hypothesized that "Nx-mediated inhibition of survival molecules like STAT3 and NF-κB in pancreatic cancer cells will improve the efficacy of the conventional chemotherapeutic agent, gemcitabine (GEM)." Therefore, we explored the utility of Nx, one of its active constituents berberine and its derivatives, to enhance the effects of GEM. Using multiple human pancreatic cancer cells we found that combination treatment with Nx and GEM resulted in significant alterations of proteins in the STAT3/NF-κB signaling axis culminating in growth inhibition in a synergistic manner. Furthermore, GEM resistant cells were more sensitive to Nx treatment than their parental GEM-sensitive cells. Interestingly, although berberine, the Nx active component used, and its derivatives were biologically active in GEM sensitive cells they did not potentiate GEM activity when used in combination. Taken together, these results suggest that the natural extract, Nx, but not its active component, berberine, has the potential to improve GEM sensitivity, perhaps by down regulating STAT3/NF-κB signaling. © 2016 Wiley Periodicals, Inc.

Pancreatic cancer: Current status and Challenges.

PURPOSE OF THE REVIEW: The 5-year survival rate of patients with pancreatic cancer (PanCA) has remained stagnant. Unfortunately, the incidence is almost equal to mortality rates. These facts underscore the importance of concerted efforts to understand the pathology of this disease. Deregulation of multiple signaling pathways involved in a wide variety of cellular processes including proliferation, apoptosis, invasion, and metastasis contribute not only to cancer development but also to therapeutic resistance. The purpose of this review is to summarize current understanding of etiological factors including emerging evidence on the role of infectious agents, factors associated with therapeutic resistance and therapeutic options. RECENT FINDINGS: The unique aspect of PanCA is "desmoplasia", a process that involves proliferation of stromal fibroblasts and collagen deposition in and around the filtrating cancer. Recent studies have identified pancreatic stellate cells (PSCs) as a potential source of such desmoplasia. Biphasic interactions between PSCs and cancer cells, endothelial cells, and/or myeloid derived suppressor cells in the tumor microenvironment contribute to pancreatic carcinogenesis. SUMMARY: We summarize limitations of current therapeutic approaches and potential strategies to overcome these limitations using natural products including botanicals as adjuvant/neo-adjuvant for effective management of PanCA.

STAT3 down regulates LC3 to inhibit autophagy and pancreatic cancer cell growth.

The dismal 5-year survival (<5%) for pancreatic cancer (PanCA) underscores the need for developing effective therapeutic options. Recent studies from our laboratory have shown that Nexrutine® (Nx), a bark extract from Phellodendron amurense exhibits excellent anticancer activity in human pancreatic cancer cells through inhibition of inflammatory signaling via STAT3/NFκB/Cox-2. Given the apparent high oxidative stress and autophagic activity in pancreatic tumors, we investigated the potential of Nx to modulate autophagy, reactive oxygen species (ROS), and their crosstalk. Our results show that Nx inhibits autophagy and decreases ROS generation. Pharmacological inhibition of autophagy led to decreased ROS generation and proliferation with no significant effect on apoptosis. Further, using combination index analysis we also found that combination of late-stage autophagy inhibitor with Nx exhibited a moderate synergistic to additive effect. Additionally, genetic or pharmacological inactivation of STAT3 reduced LC3-II levels and expression indicating a possible role for STAT3 in transcriptional regulation of autophagy. Since both inflammatory and oxidative stress signaling activate STAT3, our data implicates that STAT3 plays a vital role in the regulation of autophagy through its contributions to the positive feedback loop between ROS and autophagy. Overall, our findings reveal an important role for STAT3/LC3/ROS in Nx-mediated anti-pancreatic cancer effects.

Morbilidad y mortalidad materna en una institución de salud en el año 2012 / Morbidity and mortality maternal health in an institution 2012

Objetivo: Analizar la morbilidad y mortalidad materna en una institución de salud en 2012. Materiales y método: Estudio descriptivo transversal retrospectivo. La población estudiada fue tomada de la base datos del Comité materno-infantil del Hospital Universidad del Norte (hun). Casos que clasificaron en los criterios mme establecidos durante 2012. Ya obtenida la información, en el análisis de los datos se utilizó la herramienta Statgraphics, para gestionar y analizar los valores estadísticos. También se utilizó Microsoft Word y Excel para organizar gráficos, tablas y redactar su respectivo análisis. Resultados: Del total de casos presentados, un alto porcentaje (97 %) presentó morbilidad materna extrema, seguido de un 3 % que presentó mortalidad materna en 2012. Del total de casos presentados, un alto porcentaje (72 %) se presentó en el primer semestre y un 28 % en el segundo semestre. Conclusión: Este tipo de análisis es el punto de partida para obtener una mayor comprensión del problema de Morbimortalidad Materna. Después de hacer una primera aproximación mediante la descripción de la situación, es decir, conocer los criterios que más incidencia tienen, el siguiente paso es identificar los factores determinantes que están influyendo para su presentación, pero ante todo, reconocer cuáles fueron las conductas o las condiciones que impidieron que estas madres murieran, con el fin de aplicar este conocimiento en la atención de futuras mujeres.

Methods: Retrospective cross-sectional descriptive study. The study population is taken from the datábase of mother to infant Committee Hospital Universidad del Norte (hun). Cases classified mme criteria established in 2012. Since the information obtained in the data analysis Stat graphics tool was used to manage and analyze statistical values. Also used Microsoft Word and Excel to organize graphics, tables and write their analysis Results Influencingfor presentation, but above all, recognize what were the behaviors or conditions that prevented these mothers die, in order to apply this knowledge in the care of future women. Of the cases presented a high percentage (97 %) presented extreme maternal morbidity, followed by a 3 % maternal mortality presented in 2012. Of the cases presented a high percentage (72 %) occurred in the first half, 28 % occurred in the second half. Conclusión: This type of analysis is the starting point for a better understanding of the problem of Maternal Morbidity. After a first approximation by describing the situation, that is to say, knowing the greatest incidence criteria, the next step is to identify the de-terminants that are.