Jonathan C. Samuel

A six-gene signature predicts survival of patients with localized pancreatic ductal adenocarcinoma.

Jen Jen Yeh and colleagues developed and validated a six-gene signature in patients with pancreatic ductal adenocarcinoma that may be used to better stage the disease in these patients and assist in treatment decisions.

Activation and Involvement of Ral GTPases in Colorectal Cancer

Current approaches to block KRAS oncogene function focus on inhibition of K-Ras downstream effector signaling. We evaluated the antitumor activity of selumetinib (AZD6244, ARRY-142886), a potent and selective MEK1/2 inhibitor, on a panel of colorectal carcinoma (CRC) cells and found no inhibition of KRAS mutant CRC cell anchorage-independent growth. Although AKT activity was elevated in KRAS mutant cells, and PI3K inhibition did impair the growth of MEK inhibitor-insensitive CRC cell lines, concurrent treatment with selumetinib did not provide additional antitumor activity. Therefore, we speculated that inhibition of the Ral guanine exchange factor (RalGEF) effector pathway may be a more effective approach for blocking CRC growth. RalGEFs are activators of the related RalA and RalB small GTPases and we found activation of both in CRC cell lines and patient tumors. Interfering RNA stable suppression of RalA expression reduced CRC tumor cell anchorage-independent growth, but surprisingly, stable suppression of RalB greatly enhanced soft agar colony size and formation frequency. Despite their opposing activities, both RalA and RalB regulation of anchorage-independent growth required interaction with RalBP1/RLIP76 and components of the exocyst complex. Interestingly, RalA interaction with the Exo84 but not Sec5 exocyst component was necessary for supporting anchorage-independent growth, whereas RalB interaction with Sec5 but not Exo84 was necessary for inhibition of anchorage-independent growth. We suggest that anti-RalA-selective therapies may provide an effective approach for KRAS mutant CRC.

Under-Reporting of Road Traffic Mortality in Developing Countries: Application of a Capture-Recapture Statistical Model to Refine Mortality Estimates

Road traffic injuries are a major cause of preventable death in sub-Saharan Africa. Accurate epidemiologic data are scarce and under-reporting from primary data sources is common. Our objectives were to estimate the incidence of road traffic deaths in Malawi using capture-recapture statistical analysis and determine what future efforts will best improve upon this estimate. Our capture-recapture model combined primary data from both police and hospital-based registries over a one year period (July 2008 to June 2009). The mortality incidences from the primary data sources were 0.075 and 0.051 deaths/1000 person-years, respectively. Using capture-recapture analysis, the combined incidence of road traffic deaths ranged 0.192–0.209 deaths/1000 person-years. Additionally, police data were more likely to include victims who were male, drivers or pedestrians, and victims from incidents with greater than one vehicle involved. We concluded that capture-recapture analysis is a good tool to estimate the incidence of road traffic deaths, and that capture-recapture analysis overcomes limitations of incomplete data sources. The World Health Organization estimated incidence of road traffic deaths for Malawi utilizing a binomial regression model and survey data and found a similar estimate despite strikingly different methods, suggesting both approaches are valid. Further research should seek to improve capture-recapture data through utilization of more than two data sources and improving accuracy of matches by minimizing missing data, application of geographic information systems, and use of names and civil registration numbers if available.

Surgery and Global Public Health: The UNC-Malawi Surgical Initiative as a Model for Sustainable Collaboration

Addressing global health disparities in the developing world gained prominence during the first decade of the twenty-first century. The HIV/AIDS epidemic triggered much interest in and funding for health improvement and mortality reduction in low- and middle-income nations, particularly in sub-Saharan Africa. Alliances between U.S. academic medical centers and African nations were created through the departments of internal medicine and infectious disease. However, the importance of addressing surgical disease as part of global public health is becoming recognized as part of international health development efforts. We propose a novel model to reduce the global burden of surgical diseases in resource poor settings by incorporating a sustained institutional surgical presence with our residency training experience by placing a senior surgical resident to provide continuity of care and facilitate training of local personnel. We present the experiences of the University of North Carolina (UNC) Department of Surgery as part of the UNC Project in Malawi as an example of this innovative approach.

The Epidemiology, Management, Outcomes and Areas for Improvement of Burn Care in Central Malawi: an Observational Study

This report describes the epidemiology of burn injuries and quantifies the appropriateness of use of available interventions at Kamuzu Central Hospital, Malawi, between July 2008 and June 2009 (370 burn patients). Burns accounted for 4.4% of all injuries and 25.9% of all burns presenting to the hospital were admitted. Most patients (67.6%) were < 15 years old and 56.2% were male. The most frequent cause was scalding (51.4%). Burns occurred most frequently in the cool, dry season and in the evening. The mean burn surface area (second/third degree) was 14.1% and most burns (74%) presented within 8 h. The commonest procedure was debridement and/or amputation. The mean hospital stay was 21.1 days, in-hospital mortality was 27% and wound infection rate was 31%. Available interventions (intravenous fluids, nutrition therapy, physiotherapy) were misapplied in 59% of cases. It is concluded that primary prevention should address paediatric and scald burns, and secondary prevention should train providers to use available interventions appropriately.

Survival after burn in a sub-Saharan burn unit: Challenges and opportunities

BACKGROUND Burns are among the most devastating of all injuries and a major global public health crisis, particularly in sub-Saharan Africa. In developed countries, aggressive management of burns continues to lower overall mortality and increase lethal total body surface area (TBSA) at which 50% of patients die (LA50). However, lack of resources and inadequate infrastructure significantly impede such improvements in developing countries. METHODS This study is a retrospective analysis of patients admitted to the burn center at Kamuzu Central Hospital in Lilongwe, Malawi between June 2011 and December 2012. We collected information including patient age, gender, date of admission, mechanism of injury, time to presentation to hospital, total body surface area (TBSA) burn, comorbidities, date and type of operative procedures, date of discharge, length of hospital stay, and survival. We then performed bivariate analysis and logistic regression to identify characteristics associated with increased mortality. RESULTS A total of 454 patients were admitted during the study period with a median age of 4 years (range 0.5 months to 79 years). Of these patients, 53% were male. The overall mean TBSA was 18.5%, and average TBSA increased with age--17% for 0-18 year olds, 24% for 19-60 year olds, and 41% for patients over 60 years old. Scald and flame burns were the commonest mechanisms, 52% and 41% respectively, and flame burns were associated with higher mortality. Overall survival in this population was 82%; however survival reduced with increasing age categories (84% in patients 0-18 years old, 79% in patients 19-60 years old, and 36% in patients older than 60 years). TBSA remained the strongest predictor of mortality after adjusting for age and mechanism of burn. The LA50 for this population was 39% TBSA. DISCUSSION Our data reiterate that burn in Malawi is largely a pediatric disease and that the high burn mortality and relatively low LA50 have modestly improved over the past two decades. The lack of financial resources, health care personnel, and necessary infrastructure will continue to pose a significant challenge in this developing nation. Efforts to increase burn education and prevention in addition to improvement of burn care delivery are imperative.

Hospital-based injury data in Malawi: strategies for data collection and feasibility of trauma scoring tools

Injury is a major cause of morbidity and mortality in developing countries. Utilizing a partnership between Kamuzu Central Hospital (KCH) and the University of North Carolina Departments of Surgery, we describe an approach to injury surveillance, examine the utility of trauma scoring systems, and outline steps necessary before such scoring systems can be reliably instituted in a resource-constrained setting.

Prophylaxis and screening options: recommendations for young women with BRCA mutations.

Young women who carry a BRCA mutation face difficult decisions regarding radiologic screening modalities and prophylactic surgery. Decisions regarding these choices may have short and/or long-term consequences and significant impacts on breast cancer risk. A comprehensive review of currently available data supports the following recommendations for young women with BRCA mutations: perform monthly self breast exam, obtain clinical breast exam 2-4 times per year, discuss annual imaging options with a breast specialist, complete child-bearing by 35 with subsequent prophylactic oopherectomy, avoid hormone replacement therapy, and consider prophylactic mastectomy.

Epidemiology of pediatric injury in Malawi: Burden of disease and implications for prevention

PURPOSE Pediatric injuries pose a significant health burden in sub-Saharan Africa, though historic data are too scarce to appreciate the extent of the problem. The purpose of this study is to utilize a comprehensive database to describe the epidemiology of pediatric injuries at a tertiary hospital in Malawi. METHODS Data were prospectively collected on patients presenting to the emergency department for treatment of injuries from 2008 to 2010 (n = 23,625). The subset of pediatric patients (n = 7233) underwent cross-sectional analysis to examine demographics, injury environment, timing and mechanisms. RESULTS Pediatric patients, (0-16 years) comprised 30.6% of all trauma patients. Mean age was 7.2 years. Falls were the most common injury (43%), followed by burns (11.1%), pedestrian road traffic injuries (9.7%), foreign bodies (7.5%), and assaults (7.2%). Statistically significant differences in injury pattern were observed between gender, age groups and season. After logistic regression, predictors of fall included male gender, home setting, and rainy season, whereas predictors of burn included female gender, age 0-5 yrs, home setting, and cold season. Predictors of pedestrian injury included age 6-10 yrs, female, and roadside setting. Predictors of foreign body ingestion included age 0-5 yrs, female gender, home setting, and daytime, and predictors of assault include male gender, age 11-16 yrs, nighttime hours. All predictors were statistically significant (p < 0.05). CONCLUSIONS This study revealed patterns of injury based upon age, gender, location, and season. Our results may prove useful to stakeholders in injury prevention for designing, evaluating, and implementing programs to improve public safety in children in Malawi and similar resource poor nations.

The role of the anatomy of the sigmoid colon in developing sigmoid volvulus: A case–control study

Sigmoid volvulus is a common condition throughout much of the world. To this date, there are no adequately controlled clinical trials examining the role of anatomy in sigmoid volvulus. Therefore, the objective of this study was to determine if the anatomic dimensions of the sigmoid colon differ in sigmoid volvulus compared to controls. This prospective case–control study was conducted at Kamuzu Central Hospital, Lilongwe, Malawi. Cases included individuals 18 years or older with surgically confirmed sigmoid volvulus, while controls included individuals undergoing surgery for reasons unrelated to the descending or sigmoid colon, or rectum. Intraoperative measurements of the sigmoid colon were taken, including mesosigmoid root width and mesosigmoid length. A total of 26 cases and 12 controls were enrolled. When compared to controls, the mesosigmoid of cases had a greater length and maximal width; however, mesosigmoid root width was similar between groups. These findings support the assertion that sigmoid volvulus is due to a long and wide mesosigmoid that rotates on a constant mesosigmoid root width. This is the first adequately controlled trial examining anatomy in sigmoid volvulus and provides strong evidence that refines prior hypotheses regarding the anatomic basis of sigmoid volvulus. Clin. Anat. 24:634–637, 2011.