10.14 Outcomes in Pediatric Patients with Congenital Colorectal Diseases in Sub-Saharan Africa

Posted on January 18, 2018

L. N. Purcell1, J. Gallaher1, B. Cairns1, A. Charles1  1University Of North Carolina At Chapel Hill,General Surgery,Chapel Hill, NC, USA

Introduction:
In sub-Saharan Africa, there is a high burden of pediatric surgical conditions, particularly traumatic injury. There is a paucity of data regarding outcomes in children with congenital colorectal disease, including imperforate anus and Hirschsprung Disease, especially in sub-Saharan Africa.

Methods:
A retrospective, descriptive analysis of children (≤  18 years) presenting to Kamuzu Central Hospital in Lilongwe, Malawi from February 2012 to October 2015 was performed. Utilizing a pediatric acute care surgery surveillance database, patients diagnosed with congenital colorectal disease that had and did not have surgery were compared with univariate and bivariate analysis.  

Results:

During the study period, 133 pediatric patients with congenital colorectal disease presented to KCH, 82 had Hirschsprung disease (M 70.7%, F 29.3%, 2.4 ± 2.7 years) and 51 had imperforate anus (M 41.2%, F 58.8%, 1.8 ± 2.4 years).

Of those with imperforate anus, 51.0% underwent surgery (M 42.2%, F 57.7%, 1.5 ± 2.5 years, median 0.8 years) and 49.0% had non-operative management (M 40.0%, F 60.0%, 1.9 ± 2.4 years, median 1.0 years). The most common operation performed was exploratory laparotomy with colostomy (57.7%, n = 15), followed by posterior sagittal anorectoplasty (23.1%, n = 6) and dilation (11.5%, n = 3). The average time to the operating room was 12.7 ± 15.7 days.

An equal number (n = 41) with Hirschsprung disease underwent surgery (77.3% M, 33% F, 2.7 ± 3.1 years, median 1.2 years) and had non-surgical management (63.2% M, 36.8% F, 2.2 ± 2.3 years, median 1.4 years). Of those who underwent surgery, the majority had an exploratory laparotomy (41.5%, n = 17), followed by biopsy (34.1%, n = 14), and definitive pull-through operation (19.5%, n = 8). Overall the average time to operating room was 11.7 ± 13.8 days.  

Conclusion:
Surgical access limitations, including limited pediatric surgeons (2 in Malawi) and general surgeons uncomfortable operating on pediatric patients, are highlighted by lack of surgical management and high percentage of colostomies for congenital colorectal diseases. Training general surgeons in pediatric surgery and improving postoperative follow up to increase definitive surgical therapy will improve patient outcomes.

10.12 The Impact of Increasing Surgical Capacity at a Tertiary Hospital in Southern Haiti.

Posted on January 18, 2018

L. E. Ward1, M. M. Padovany1, A. N. Bowder1,2, T. Jean-Baptiste1, R. Patterson1,3, C. M. Dodgion2  1Saint Boniface Hospital,General Surgery,Fond Des Blancs, , Haiti 2Medical College Of Wisconsin,General Surgery,Milwaukee, WI, USA 3Tufts University School Of Medicine,Boston, MA, USA

Introduction: It is estimated over 5 billion people lack access to surgery worldwide. This is often caused by a lack of surgical infrastructure and a paucity of surgical providers. St. Boniface Hospital (SBH), a 124-bed facility on Haiti’s southern peninsula, plays a critical role in providing safe, accessible surgery. SBH has grown its surgery program through three phases; Phase 1 (P1) general surgeries were performed by visiting surgical teams, Phase 2 (P2) general surgery was performed by a full-time surgeon in a single operating suite, Phase 3 (P3) the opening of a surgical center with three operating suites staffed by two general surgeons and surgical residents. We examine the impact of increasing surgical capacity at a rural hospital in Southern Haiti on case volume, patient complexity and mortality.

Methods: We conducted a retrospective review of all surgical cases performed on patients over the age of 18 at SBH between 2015 and 2017. Procedural data and patient demographics were recorded in operative logbooks at the time of the procedure. Postoperative mortality was defined by in-hospital deaths divided by the number of procedures performed.

Results:1507 adult general surgical cases were done at SBH between February 2015 and August 2017. The volume of surgical procedures performed each month increased with stepwise growth in surgical capacity (Figure 1). The average number of surgeries per week were 3.1 with visiting surgical teams (P1), 10.4 with a single general surgeon (P2), and 20.1 with two full time surgeons and residents (P3). This represents a threefold increase in surgical volume between P1 and P2, and a twofold increase between P2 and P3. As the number of surgeries increased so did the complexity of patients. The percentage of patients with ASA scores of 1, 2, 3 and 4 during P2 was 81.3%, 17.3%, 4.2%  and 1.0% respectively. In P3 the percentage of cases with an ASA score of 1,2,3, and 4 was 68.5%, 29.3%, 11.4%, and 1.3%. Surgical mortality during Phase 3 was 1.81% which compares favorably to to other surgical centers in Haiti.

Conclusion: Increasing resources and surgical staff at St. Boniface Hospital allowed for the greater delivery of safe surgical care. The increase in patient complexity represented by ASA scores suggests a greater referral base as a reputation was established. This study highlights the significant impact investments to improve surgical capacity can have in areas of great surgical need.

 

10.10 Development and Validation of a Composite Surgery Availability Score in Malawi

Posted on January 18, 2018

A. E. Giles1,2, A. G. Ramirez1,3, M. G. Shrime4,5  1Harvard School Of Public Health,Boston, MA, USA 2McMaster University,Surgery,Hamilton, ONTARIO, Canada 3University Of Virginia,Surgery,Charlottesville, VA, USA 4Harvard School Of Medicine,Program In Global Surgery And Social Change,Boston, MA, USA 5Massachusetts Eye And Ear Infirmary,Otolaryngology,Boston, MA, USA

Introduction:
Availability of surgery is gaining increasing importance in global health, yet few nationally representative surveys incorporate surgery-relevant indicators. We sought to derive a composite score that predicts surgery availability from existing population-level survey data, and validate it against known surgical data.

Methods:
The Demographic and Health Surveys Program Service Provision Assessment (SPA) survey from Malawi was used to construct a composite score. Sensitivity analysis was conducted to identify an appropriate weighting scheme. Validation was performed through re-creation of the composite score in Kenya’s Access, Bottlenecks, Costs, and Equity (ABCE) Project data and comparison of the score against actual facility surgical volume. Performance of the score was also compared to that of using cesarean section availability as the sole indicator, against an a priori set of surgical volumes as the basis of comparison. 

Results:
Based on the sensitivity analysis, the final composite score was: 0.25[Caesarian Section] + 0.25[Physician Present] + 0.20[Anesthetist Present] + 0.15[Ketamine Available] + 0.15[Transfusion Capability]. A total of 52 facilities (of the 1,060 health care facilities) were identified as providing surgical care in Malawi: 4 central hospitals, 22 district hospitals, 22 community hospitals, and 4 urban clinics. Community hospitals displayed the widest variation in ability to provide surgery. The composite score correlated well with surgical volume when applied to the Kenyan data (beta 1,378, p<0.001). Using a cutoff of 50 or more operations annually to define a facility providing surgery, the score outperformed provision of caesarean section alone with a sensitivity of 97% and specificity of 92%, versus 84% and 95%, respectively (Figure 1).

Conclusion:
The composite surgery availability score is both sensitive and specific for predicting surgical service capability. Implications for adoption of such a score include standardized evaluation of population access to surgical services and monitoring progress over time at the subnational, national, and multinational levels. The proposed methodology may make available time-sensitive findings to inform relevant policy change and investment of resources for surgery as part of achieving universal health coverage.
 

10.11 Global Experience With Implementation Of A Minimum Universal Operative Case Log.

Posted on January 18, 2018

L. M. Baumann1,2, O. Yerokun10, P. Jani5, N. Wetzig6, L. Samad9, K. Park7, K. Nguyen8, M. Meheš4, B. Allen4, F. Abdullah1,2, A. Latif3  4G4 Alliance,New York, NY, USA 5The College Of Surgeons Of East, Central And Southern Africa,Arusha, ARUSHA, Tanzania 6HEAL Africa,Gisenyi, WESTERN PROVINCE, Rwanda 7World Federation Of Neurosurgical Societies,Phnom Penh, PHNOM PENH, Cambodia 8Mending Kids,Burbank, CA, USA 9Indus Hospital,Pediatric Surgery,Karachi, SINDH, Pakistan 10Johns Hopkins Bloomberg School Of Public Health,General Preventative Medicine,Baltimore, MD, USA 1Northwestern University,Department Of Surgery,Chicago, IL, USA 2Ann & Robert H. Lurie Children’s Hospital,Division Of Pediatric Surgery,Chicago, IL, USA 3Johns Hopkins University School Of Medicine,Anesthesiology And Critical Care Medicine,Baltimore, MD, USA

Introduction:
Emergency and essential surgical and anesthesia care are a core component of universal health coverage. The Global Alliance for Surgical, Obstetric, Trauma and Anesthesia Care (G4 Alliance) is a coalition of >80 organizations advocating for access to safe surgical and anesthesia care for all. A critical part of this mission is the development of a minimum operative case log tool that can be used to build a robust global surgical registry. Accurate data is essential for the evaluation and improvement of surgical outcomes, health infrastructure, and operating room processes. This pilot study aimed to assess the utility of the G4 Alliance operative case log in a global setting.

Methods:
A multidisciplinary and multinational team of experts was assembled from amongst G4 member organizations. A review of potential data measures was conducted with development of a 38 variable minimum operative data set over three rounds of a modified Delphi approach from March to December 2016. The tool was piloted by members at 6 sites in low- and middle-income countries (LMICs) across 4 WHO regions from March to June 2017. Data was collected for up to 6 weeks, and the tool was available in paper, electronic PDF, and Microsoft Access formats to facilitate collection according to local resources. 

Results:
A total of 534 cases were logged between 3 local hospitals (89%) and 3 medical missions (11%). The majority of cases were financed through donation/aid (56%) followed by self-pay (31%). Compliance with data collection for individual variables ranged from 25-100% across all sites (Table 1). The largest variability in compliance was seen with date of birth, which was recorded for 97% of cases during mission trips, but for only 16% of cases at local hospitals. Similarly, weight was recorded for 92% of cases during mission trips but only 68% of cases at local hospitals. In feedback from local staff, >90% were satisfied with the information collected and 100% would like to continue using the tool. Less than 50% of sites currently had an operative data collection system in place.

Conclusion:
Most key operative variables were easily collected across a variety of global settings. Predictably, there was poorer compliance with data that need to be collected at a separate time point such as discharge. Surprisingly, basic demographic data was amongst the most difficult to collect. These results may be reflective of systematic differences in the culture regarding data in LMICs as evidenced by the disparity between locally staffed hospitals and foreign medical missions. Successful integration of a global data system must utilize a locally feasible tool with an emphasis on accurate collection and reporting of data in order to improve surgical care.
 

10.07 The Global Availability of Cancer Registry Data

Posted on January 18, 2018

A. H. Siddiqui2, S. Zafar1  1University Of Maryland,Department Of Surgery,Baltimore, MD, USA 2Aga Khan University Medical College,Medical College,Karachi, Sindh, Pakistan

Introduction:

The availability of cancer registries has significantly enhanced cancer research, especially that related to cancer epidemiology, survival and outcomes. However, this data is not consistently available in all parts of the world. In an attempt to understand surgical outcomes related to cancer we first attempted to determine the availability of cancer registry data on a global level. We also aimed to test the association of cancer registry data with metadata such as country income and cancer related policy.

Methods:

The World Health Organization (WHO) International Agency for Research on Cancer (IARC) and Global Cancer Observatory (GCO) was queried to extract data on the availability and scope of cancer registries in each of the 190 WHO countries. Policy related data, country profiles, and GDP were also extracted. Information on country income classification and expenditure on health was collected from the World Bank database. 

We used the chi square and t-tests to determine associations between the availability of cancer registry data and each countries income level, per capita health expenditure, and cancer control policy.  Results were tabulated and depicted as choropleth maps using eSpatial. SPSS version 19 was used for data management and statistical analysis.

Results:

Figure 1 shows the global variation in the availability of cancer registry data. Of the 190 countries 20% did not have any kind of cancer registry. The availability of registry data varied by country income status with only 61% in low income countries (LIC) and 95% in high income countries (HIC). Of the low-income countries that did have a cancer registry, only 50% were population based of which 64% had subnational coverage. An overall 60% of countries had a national cancer policy which ranged from 31% in LICs to 79% in HICs. The availability of having registry data was not associated with country income level (p=0.306). However, countries with a national cancer policy were more likely to have a cancer registry in place (p<0.001). Furthermore, countries with high mean per capita health expenditure were more likely to have a national cancer policy (p=0.023), and a population based (p=0.003) cancer registry with national coverage (p<0.01).

Conclusion:

Country level cancer registry data is inconsistent. Low and lower-middle income countries have the least cancer registry data. The availability of data is related to the mean per capita health expenditure of these countries and presence of a national cancer control policy.

10.08 Prevalence and Predictors of Surgical Site Infections After Cesarean Delivery in Rural Rwanda

Posted on January 18, 2018

T. Nkurunziza1, F. Kateera1, R. Riviello2,3, K. Sonderman2,3, A. Matousek2, E. Nahimana1, G. Ntakiyiruta4, E. Nihiwacu1, B. Ramadhan1, M. Gruendl3, E. Gaju5, C. Habiyakare5, B. L. Hedt-Gauthier3  1Partners In Health,Clinical/ Research,Kigali, CITY OF KIGALI, Rwanda 2Brigham And Women’s Hospital,Boston, MA, USA 3Harvard School Of Medicine,2. Department Of Global Health And Social Medicine,Brookline, MA, USA 4Ejo Heza Surgical Center,Kigali, CITY OF KIGALI, Rwanda 5Ministry Of Health,Kigali, CITY OF KIGALI, Rwanda

Introduction:
Surgical site infections (SSIs) are the most common healthcare-related infections, and can cause considerable morbidity or mortality if untreated. For cesarean deliveries in sub-Saharan Africa, most mothers are discharged 3 days postoperatively, and SSIs in most cases, develop following discharge and are left undetected. Therefore, there are few unbiased estimates of the prevalence of cesarean section related SSIs in sub-Saharan Africa. The aim of this study was to estimate the prevalence and predictors of SSIs following cesarean section at Kirehe District Hospital (KDH) in rural Rwanda.

Methods:
This prospective cohort study included women who underwent cesarean section over a 4 month study period (March – July 2017) at KDH. At discharge, consenting mothers provided their demographic information and were given a voucher to return to the hospital within a time frame of 7-13 days post operatively. At the return visit patients were examined by a physician, who evaluated for an SSI and other postoperative complications.  Patients who were still admitted or readmitted to the hospital at 10 postoperative days were included and screened in the hospital on that day. A bivariate analyses assessing possible risk factors, such as patient demographics (age, occupation, education, income level, insurance, distance to health center and marital status) or clinical care variables (pre-morbidity, weight, smoking, skin preparation, ASA class, cadre of provider, surgery indication, type of anesthesia, duration of surgery and antibiotic therapy), were performed using Fisher’s exact test.

Results:
During the study period, there were 384 cesarean deliveries at KDH, of which 347 were eligible for the follow up and 307 (88.5%) were screened by the physician. Of these, 7 (2.3%) were still admitted at the hospital when they underwent screening. The majority (56.7%, n=174) were between 21 and 30 years old. 83.6% (n=168) received preoperative antibiotics within an hour of incision and 96.1 % (n=295) received at least one dose of postoperative antibiotics. The 10 postoperative day SSI prevalence was 10.3% (n=31). In the bivariate analysis, the only significant risk factor for surgical site infection was time for the patient to travel from home to the nearest health center to have dressing change.  Patients who traveled more than one hour had greater risks of SSI (p=0.028). Interestingly, neither having had preoperative antibiotic nor postoperative antibiotic were significant for a SSI (both with p>0.999).

Conclusion:
The SSI prevalence was 10% which is consistent with the current literature throughout sub-Saharan Africa. Patients who travel farther distances have a greater risk of SSI development. The etiology of this increased risk is unclear and warrants further study.
 

10.09 A Novel Survey-Based Metric for Assessing Injury Severity in Population Studies

Posted on January 18, 2018

S. A. Christie1, D. C. Dickson1, T. Nana1, P. M. Stern1, R. A. Dicker2, A. Chichom-Mefire3, C. Juillard1  1University Of California – San Francisco,Center for Global Surgical Studies,San Francisco, CA, USA 2University Of California – Los Angeles,Los Angeles, CA, USA 3University Of Buea,Department Of Surgery And Obstetrics- Gynecology, Faculty Of Health Sciences,Buea, SOUTHWEST REGION, Cameroon

Introduction:
Population-based injury data are critical for developing trauma systems, particularly in low- and middle-income countries (LMIC) where many patients do not present to formal medical care. Determining injury severity in population studies would greatly aid risk stratification and policy planning. However, severity surrogates like disability outcomes are confounded by treatment access, while anatomic and physiologic scores cannot be ascertained in the community setting. As part of an 8065 subject community-based study on injury in Cameroon, we designed a novel series of 4 survey questions intended to estimate injury severity. Outcomes of subjects with and without severity indicators were compared.

Methods:
Three-stage cluster sampling was used to select 36 enumeration areas in Southwest Cameroon. Household representatives at each site reported all family injuries in the past 12 months that resulted in death, loss of routine activity, or required medical attention. Loss of consciousness, post-injury disorientation, event amnesia, or cessation of breathing on the day of injury were considered severity indicators. Presence of severity indicators was correlated to data on injury outcomes. 

Results:
Among 503 injuries reported in a sample of 8065 subjects, 16.5% resulted at least one severity indicator. Specifically, 8% lost consciousness, 9.4% were disoriented, 1.8% had event amnesia, and 0.4% had respiratory arrest at the scene. All study subjects who died from their injuries had one or more severity indicator. Among subjects who presented to formal care, those with severity indicators had higher rates of hospitalization (50% vs. 26.5%, p=0.004) and longer admissions (11.6 vs. 2.9 hospital nights, p=0.03). Excluding injury deaths and recent injuries, subjects with severity indicators were more likely to report ongoing disability at the time of the survey (OR 1.9, p=0.004). In multiple linear regression adjusted for age and formal care use, presence of severity indicators independently predicted increased disability days (OR 23, p=0.02).

Conclusion:
Survey-based severity indicators were present in all injury deaths and predicted longer hospital stays and increased disability after injury. This novel metric shows promise as a means of estimating severity in population studies, which will improve risk stratification for policy and prevention planning. Prospective hospital-based studies should evaluate correlation of survey-based indicators with conventional severity scoring algorithms.

10.05 Establishing a context-appropriate trauma registry for Uganda using the local providers' perspective

Posted on January 18, 2018

J. A. Igu1, C. Haasbroek1, O. C. Nwanna-Nzewunwa1, I. Feldhaus1, M. Carvalho1, M. M. Ajiko2, F. Kirya2, J. Epodoi2, R. Dicker1, C. Juillard1  2Soroti Regional Referral Hospital,Department Of Surgery,Soroti, , Uganda 1University Of California – San Francisco,Center For Global Surgical Studies,San Francisco, CA, USA

Introduction:  

Trauma registries (TR) are key components of primary trauma data collection in developing countries. TR implementation can fail if stakeholder involvement is not prioritized. Stakeholder input, is required to create a context-appropriate TR that aptly captures trauma in developing countries. We sought to identify the key components of a context-appropriate prospective TR in a Ugandan Regional Referral Hospital and elicit the determinants of success and sustainability in implementing such a TR.

Methods:

Focus group discussions were held with all cadres of clinicians involved in trauma care delivery at the hospital to identify context-appropriate TR variables. These results informed the design of a TR, which was then implemented. After a one-week pilot of the TR form, we obtained providers’ views on the utility of the TR form by generating a satisfaction score (the average score derived from a five-point Likert scale) for each question.

Results:

Five focus groups consisting of 14 providers (4 intern doctors, 3 Ear-Nose-Throat care providers, 3 general surgeons, 2 orthopedic officers and 2 eye care providers) identified 47 context-appropriate TR variables. Variable categories included: demographics, history and physical exam, injury characteristics, prehospital care, prehospital transportation, investigations, interventions, diagnosis, outcome/discharge status, and consent. These providers listed five barriers to TR implementation: the perception that TRs are time-consuming and increase workload, difficulties following-up admitted patients, lack of personnel, lack of equipment and other resources to gather data, and participation and cooperation issues. They also cited the availability of TR forms distinct from patient forms, TR forms at the point of care, a TR point person, a local TR committee, a good file storage system, and provider TR awareness as facilitators of TR implementation. Providers identified lack of finances, motivation, and salary incentive, and loss of momentum of the TR project as barriers to sustainability. They named the creation and proper training of a local TR team, periodic project evaluation, efficient project resource allocation, creating a research culture, and foreign partnership(s) as facilitators of sustainability. The post-pilot survey captured the perceptions (Figure) of 29 providers (intern doctors, surgeons, clinical officers, nurses) who implemented the TR. Providers were mostly satisfied with the TR form and its implementation.

Conclusion:

Local providers’ perspectives are key to creating context-appropriate and sustainable TRs developing countries, and TR user satisfaction. Having dedicated resources, well-trained local TR staff, and local ownership of the TR is central to TR success.

10.06 Policy Implications of Road Traffic Injury in Cameroon; Results from a Population-Based Study

Posted on January 18, 2018

S. A. Christie1, D. C. Dickson1, T. Nana1, P. M. Stern1, A. Mbiarikai1, R. A. Dicker2, A. Chichom-Mefire3, C. Juillard1  1University Of California – San Francisco,Center For Global Surgical Studies,San Francisco, CA, USA 2University Of California – Los Angeles,Los Angeles, CA, USA 3University Of Buea,Department Of Surgery And Obstetrics- Gynecology, Faculty Of Health Sciences,Buea, SOUTHWEST REGION, Cameroon

Introduction:
Road traffic injury (RTI) is believed to be a major contributor to death and disability in sub-Saharan Africa. Existing data are predominantly derived from hospital or police records, leading to underreporting in areas where many people do not access formal care. To fill this epidemiologic gap and inform prevention policy, we conducted a community-based survey to identify the yearly incidence, patterns, and impact of road traffic injury in Southwest Cameroon. 

Methods:
Three-stage cluster sampling with selection probability proportionate to population was used to select 36 enumeration areas in Southwest Cameroon. Household representatives at each site were asked to report all injuries in the preceding 12 months that resulted in death, loss of routine activity, or required medical attention. Data on injury mechanism, care-seeking behavior, cost of treatment, disability and economic impact were collected.

Results:
Road traffic injury was the largest single-mechanism contributor to trauma-related death and disability. [Figure] Among 8065 individuals in 15 rural and 18 urban areas, 133 RTI were identified for a total incidence of 16.5 RTI /1000 person-years (95CI 14-20). Incidence of fatal RTI was 37/100,000 person-years (95CI 13-105). Although RTI rates were higher in urban areas (18 vs 11/1000 person-years), incidence of RTI death was higher in rural or semirural regions (60 vs 20/100,000 person-years).  Commercial transport vehicles were involved in 78% of RTI but few commercial drivers participated in first-aid or victim transport (7.5%). Seatbelts and helmets were very rarely utilized (7.6% and 8.7% respectively). Signs of severe injury including loss of consciousness, confusion, amnesia, or respiratory arrest at the scene occured in 34% of RTI. Formal medical services were sought for 79% of road traffic injuries; among those, 45% were admitted to inpatient care and 8.9% underwent at least one operation. Overall, RTI led to 480 disability days/1000 person-years with 24% of injuries resulting in ongoing disability at the time of the survey. Cost of RTI care was more than double the cost for non-RTI injury mechanisms (64,000 vs. 28,000 CFA, p<0.001) and 46% of RTI resulted in the affected household being unable to afford basic necessities.

Conclusion:
RTI occurs commonly in Southwest Cameroon and results in considerable physical and economic disability. As road safety prevention measures are rarely employed, policy modifications including increased monitoring of seatbelt and helmet compliance and offering first-aid training for commercial vehicle operators represent areas of potential opportunity to reduce disability and injury mortality in Cameroon.
 

10.03 Local Impact of General Surgery Task-Sharing in Rural Sierra Leone: A District Hospital Experience.

Posted on January 18, 2018

P. F. Johnston1, S. Jalloh2, A. Samura3, J. A. Bailey1, M. Brittany4, Z. C. Sifri1  1Rutgers New Jersey Medical School,Surgery,Newark, NJ, USA 2College Of Medicine And Allied Health Sciences,Freetown, WESTERN, Sierra Leone 3Kabala Government Hospital,Kabala, KOINADUGU, Sierra Leone 4University Of Maryland – Mercy Medical Center,Baltimore, MD, USA

Introduction:
There exists a disproportionally large burden of surgical disease in low income countries (LICs) but few immediate answers. In Sierra Leone, a handful of trained surgeons serve a country of over 6 million, leaving an excess of surgical burden, particularly in rural regions. This excess burden is borne by non-surgeon physicians and surgically-trained clinical officers (COs). In Sub-Saharan Africa, task-sharing models of CO training have shown some success in the context of caesarian sector. However, limited data exists regarding the contribution of surgical training programs towards tackling the general surgery burden of disease. The aim of this study is to examine the impact of one surgically trained CO on surgical capacity in a district hospital in rural Sierra Leone.

Methods:

Kabala Government Hospital (KGH) is a 100-bed district hospital in the rural Koinadugu district of Sierra Leone serving a population of approximately 325,000. The surgical team consists of one non-surgeon physician, one nurse anesthetist, and a handful of COs with various levels of training in surgery and anesthesia. One CO has been trained to perform basic, yet essential, surgery by a non-profit organization operating within Sierra Leone.

Case logs from the KGH operating theater over a 14 month period were reviewed to examine this CO’s contribution to hospital’s surgical output. Two-sided Pearson Chi-square test was performed to determine statistical differences between cases with a physician versus a CO as the primary surgeon. 

Results:

In total 394 procedures were performed on 375 patients at KGH over the 14 month period examined. The patient population was primarily male (75%) with a mean age 33.9 ± 18.8. The most common procedures performed were inguinal hernia repair (71%), appendectomy (12%), and hydrocelectomy (9%).  Anesthesia was most commonly spinal (50%). The CO was involved in 264 procedures (67%) and primary surgeon for 207 (53%). All cases in the series had a satisfactory immediate surgical outcome as reported in the case logs. No long-term data was available for study.

Physician primaries performed significantly more laparotomies (12% vs. 2%; p = 0.02) than CO primary, but otherwise case types were similar in terms of age, gender, surgery and anesthesia types. 

Conclusion:

A surgically-trained CO can significantly enhance the surgical capacity of a district hospital in rural Sierra Leone, performing over half of all operations with satisfactory results. Top down approaches to scaling surgical workforce and infrastructure are costly and will take time, while a large, immediate need exists. Surgical task-sharing programs may be an easily scalable and effective interim solution in areas of excessive burden and limited-resources. Limitations in the complexity of cases performed are expected and likely appropriate.

Long-term and more complete data is needed to ensure quality and safety of surgery performed by graduates of CO training programs.

10.04 Pre-Op Bowel Prep With Oral Antibiotic Reduces Morbidity After Emergent Colectomy for Diverticulitis

Posted on January 18, 2018

M. Hamidi1, M. Zeeshan1, N. Kulvatunyou1, T. O’Keeffe1, A. Jain1, A. Tang1, E. Zakaria1, L. Gries1, B. Joseph1  1University Of Arizona,Tucson, AZ, USA

Introduction:
The role of preoperative mechanical bowel (MBP) and oral antibiotic preparation (OAP) in elective colectomy has been studied extensively. However, its role is still unknown in patients undergoing emergent colectomy (EC) for acute diverticulitis. The aim of our study was to determine the association between preoperative MBP and OAP and 30-d outcomes after EC for acute diverticulitis.

Methods:
We analyzed patients from the 2012-15 colectomy-targeted NSQIP database who underwent EC for the indication of acute diverticulitis. Patients were stratified into 1 of the 4 group based on type of preoperative preparation [MBP+OAP, MBP only, OAP only, and no bowel preparation (NBP)]. Multivariate regression analysis was performed to analyze the association between preoperative bowel preparation and 30-d postoperative outcomes. 30-d outcomes were anastomotic leaks requiring intervention, surgical site infections (SSI), hospital length of stay (h-LOS), readmission and mortality.

Results:
3004 patients included. Mean age was 61±14y, and 53% were females. 11% (n=339) patients received preoperative bowel preparation [MBP+OAP (17%), MBP only (38%), and OAP only (45%)]. Most common indication for EC was perforation. Figure 1 demonstrates multivariate regression analysis for 30-d outcomes. Patients who underwent OAP only had lower adjusted rates for anastomotic leaks (OR: 0.7[0.5-0.9]), SSI (0.6 [0.3-0.9]), and readmission (0.6 [0.5-0.7]) compared to NBP. However, patients who received MBP (OR: 1.6 [1.3-2.1]) and MBP+OAP (OR: 1.3 [1.1-1.6]) were more likely to develop postoperative ileus.

Conclusion:
Bowel preparation with oral antibiotics only results in a significantly lower incidence of anastomotic leakage, incisional surgical site infection, and hospital readmission when compared to no bowel preparation. In addition, mechanical bowel preparation might be harmful and reduces the protective effect of oral antibiotic preparation.
 

10.02 Does Insurance Protect Individuals from Catastrophic Payments for Surgical Care in Ghana?

Posted on January 18, 2018

J. S. Okoroh1,4, S. Essoun3, R. Riviello2, H. Harris1, J. S. Weissman2  1University Of California – San Francisco,Department Of Surgery,San Francisco, CA, USA 2Brigham And Women’s Hospital,Center For Surgery And Public Health,Boston, MA, USA 3University Of Ghana,Korle-Bu Teaching Hospital/ Department Of Surgery,Accra, GREATER ACCRA, Ghana 4Fogarty International Center,UcGloCal Consortium,Bethesda, MD, USA

Introduction:
According to the WHO, essential surgery should be recognized as integral to achieving Universal Health Coverage. We previously reported that surgical conditions were commonly included in national health plans, yet catastrophic health expenditures persist. Insurance is associated with a reduction in maternal mortality and improved access to essential medications in Ghana, but whether it eliminates financial barriers to care for surgical patients is unknown. We sought to describe amounts and payments for general surgical conditions included under Ghana’s national health insurance scheme, and test the hypothesis that insurance protects surgical patients against financial catastrophe. 

Methods:
We interviewed patients admitted to the general surgery wards of Korle-Bu Teaching Hospital between February 1 – June 30, 2017 to obtain demographic data, annual income, occupation, household expenditures and insurance status. Surgical diagnoses and procedures, procedural fees, anesthesia fees, medicines and all other costs incurred were collected through chart review. The data was collected on a Qualtrics platform and analyzed in STATA. T-tests and chi-square tests were used to compare insured and uninsured groups. Threshold for financial catastrophe was defined as >10% of annual household expenditures, >40% of non-food expenditures, or >20% of individual income. 

Results:
Among 107 enrolled patients, demographic characteristics did not significantly differ between the insured and uninsured except the insured were slightly older [mean 49 years vs 40 years P<0.05.] and more likely to be female [65% vs 40% p<0.05]. The most common surgical procedures for both groups were laparotomy, inguinal hernia repair and appendectomy. Insurance paid on average 40% of the total cost of surgical care, thus protecting some patients from financial catastrophe. However, 50% of the insured patients experienced financially catastrophic payments and almost all reported out-of-pocket payments in addition to hospital payments for medicines and laboratory tests. 

Conclusion:
This study—the first to evaluate the impact of insurance on financial risk protection for surgical patients in a resource-limited setting—shows that despite its benefits, about half of insured surgical patients are not protected from financial catastrophe under the Ghanaian national health insurance scheme due to out-of- pocket payments. Government-specific strategies to enroll uninsured individuals at the point of care and to increase the proportion of cost covered are crucial to protecting individuals from financial catastrophe due to surgical care in Ghana thus achieving Universal Health Coverage. 
 

10.01 Estimating the Global Need for Cancer Surgery

Posted on January 18, 2018

A. H. Siddiqui1, A. A. Javed3, S. Zafar2  1Aga Khan University Medical College,Medical College,Karachi, Sindh, Pakistan 2University Of Maryland,Department Of Surgery,Baltimore, MD, USA 3Johns Hopkins University School Of Medicine,Department Of Surgery,Baltimore, MD, USA

Introduction:
Cancer surgery is an essential component of healthcare. However, its availability is disparate around the world. Resource mobilization and advocacy requires better measurement of the burden of cancer surgery. We aimed to estimate the global need for cancer surgery and identify disparities by country income status.

Methods:
The WHO International Agency for Research on Cancer (IARC) and Global Cancer Observatory (GCO) were queried for data on the incidence of various malignancies in each country. As the incidence of cancer is dependent upon the ability to detect it we only estimate the ‘known’ need for cancer surgery. From the United States Surveillance, Epidemiology and End Result (SEER) database we extracted all patients with a new cancer diagnosis. The proportion of patients requiring surgery for each of these cancers was calculated. This was used to estimate the need for cancer surgery by multiplying with the incidence of each corresponding cancer in each country. The sum for each country was then divided by the population and multiplied by 1,000 to obtain a cancer surgery index (CSI). The Chi square test, t-tests, and Pearson coefficients were used to test associations between CSI and country income, national cancer policy, and presence of cancer registry. Results were tabulated and depicted as choropleth maps using eSpatial (Figure 1).

Results:
The number of people known to be in need of cancer surgery around the world in 2015 was 7,225,695 (± 9,524). The highest need was for breast cancer at 1.17 million patients requiring surgery followed by colorectal cancer (1.06 million). While low and lower-middle income countries make up 48% of the world’s population the reported cancer surgery need was only 21% of the global need highlighting disparities in detecting cancer in resource poor settings. The overall CSI was 0.99 per 1,000 population. The CSI varied almost linearly by income status, with the CSI being 1.95 per 1000 population for high income, 0.85 for upper middle income, 0.53 for lower middle income and 0.29 for low-income countries. Countries with national cancer policies and population based registries had higher CSIs (p<0.01). There was a significant positive relationship between a country’s human development index and the CSI (r=0.7, p<0.01).

Conclusion:
At least 7.2 million people around the world are known to require cancer surgery annually. Variations in the need for cancer surgery are related to a country’s income status, health care expenditure, availability of cancer data, and the presence of cancer control policies. There is an urgent need for systems strengthening in low and middle-income countries to ensure adequate access to cancer surgery.

1.19 Early Pancreatic Carcinoma Tumorigenesis is Driven by Macrophages and TGF-ß

Posted on January 18, 2018

M. A. Alvarez1, S. M. Husain1, L. F. Reed1, P. V. Dickson1,2, J. L. Deneve1,2, D. Shibata1,2, E. S. Glazer1,2  1University Of Tennessee Health Science Center,Memphis, TN, USA 2UT West Cancer Center,Memphis, TN, USA

Introduction: In pancreatic adenocarcinoma (PDAC), TGF-ß is a tumor suppressor known to drive inflammation in the tumor microenvironment (TME). The role of tumor associated macrophages and interleukins in the PDAC TME is not well described though both likely play critical roles.  We hypothesized that pre-treatment of a primary PDAC cell line, Panc-1, with combinations of TGF-ß, macrophages, or IL23, would result in variations in tumorigenesis and metastases in an orthotopic murine model. 

Methods:  Panc-1 cells, a line derived from primary pancreatic cancer, were pre-treated with TGF-ß alone (10 ng/mL), IL23 alone (10 ng/mL), macrophages (ATCC cell line, 10:1 ratio of Panc-1 cells to macrophages), IL23 + macrophages, TGF-ß + macrophages, or TGF-ß + macrophages + IL23.  Control cells were treated with PBS. Cells were treated twice weekly for 1 week in complete media then implanted into the pancreas of NOD scid gamma mice (NSG, severely immunocompromised) with 5 mice per group. Mouse weights were taken twice weekly for 4 weeks. At that point, mice were sacrificed and tumors harvested.  We investigated mouse weight, pancreas tumor weight, pancreas tumor diameter, and the number of surface hepatic metastases.  Mean values were compared with ANOVA.

Results: Throughout the study, the mean weight of the mice in the TGF-ß alone and IL23 alone treatment groups was stable whereas all other mice increased weight by 10% (P<0.001). Pancreatic tumor weights were highest in macrophage treatment groups. TGF-ß + macrophage treatment decreased the tumor weight compared to macrophage treatment alone (P<0.001). Macrophage treatment of Panc-1 cells was associated with the highest number of surface liver metastasis after implant (>3 per mouse) and TGF-ß treatment alone was associated with the least number of surface liver metastasis (<1 per mouse, P<0.01). Importantly, TGF-ß treatment did not modulate the rate of macrophage induced surface liver metastasis, but IL23 + macrophage + TGF-ß treatment did result in fewer surface liver metastasis compared to macrophage treatment alone (> 3 vs 2 per mouse, overall P=0.02). Macrophage treated Panc-1 cells were associated with the largest primary Panc-1 tumor growth after 4 weeks, TGF-ß treatment diminished the effect the macrophages had on the Panc-1 cell primary tumor growth (P<0.001).

Conclusion: We found that macrophages drive the development of metastases in this model of early PDAC.  While other research groups have shown that TGF-ß is associated with survival in PDAC, we demonstrated that macrophages play a critical role in early PDAC and likely modulate the TME through interleukins such as IL23 and TGF-ß.   

1.20 Cannabinoid in the Management of Melanoma: A Potential New and Novel Treatment

Posted on January 18, 2018

E. L. Simmerman1, X. Qin2, J. C. Yu1, B. Baban2  1Augusta University Medical Center,Department Of Surgery / Division Of Plastic Surgery,Augusta, GA, USA 2Augusta University Medical Center,Department Of Oral Biology / Dental College Of Georgia,Augusta, GA, USA

Introduction:

Malignant Melanoma is a complex malignancy with significant morbidity and mortality.  The incidence continues to rise and despite advances in treatment, the prognosis is poor.  Thus, it is necessary to develop novel strategies to treat this aggressive cancer.  Synthetic cannabinoids have been implicated in inhibiting cancer cell proliferation, reducing tumor growth, and reducing metastasis.  We developed a unique study focusing on the effects of treatment with a cannabinoid derivative on malignant melanoma tumors in a murine model.

Methods:

Murine B16F10 melanoma tumors were established subcutaneously in C57BL/6 mice.  Mice were then treated with intraperitoneal injection of vehicle (PBS) injection (control – group 1, n=6), cisplatin of 5 mg/kg/week (group 2; n=6), and Cannabidiol (CBD) injection of 5 mg/kg twice per week (group 3; n=6) for 14 days.  Tumors were measured and volume calculated as 4π/3) x (width/2)2 x (length/2).  Tumor size and survival curves were measured.  Results were compared using a one-way ANOVA with Multiple Comparison Test.

Results:

A significant decrease was detected in tumor size of mice treated with CBD when compared to the control group (p=0.01). The survival curve of melanoma tumors treated with CBD increased when compared to the control group and was statistically significant (p=0.04). The growth curve and survival curve of melanoma tumors treated with cisplatin were significantly decreased and increased respectively when compared with the control. Mice treated with cisplatin demonstrated the longest survival time but the life quality and movement of CBD-treated mice were significantly better.

Conclusions:

We demonstrate a beneficial therapeutic effect of cannabinoids, significantly influencing the course of melanoma in a murine model.  Increased survival and less tumorgenicity are novel findings that should guide research to better understand the mechanisms by which cannabinoids could be utilized for treating cancers. Further studies are necessary to evaluate this potentially new and novel treatment of malignant melanoma. 

1.17 Novel Chemotherapeutic Agent, FND4b, Inhibits Colorectal Cancer Cell Proliferation

Posted on January 18, 2018

H. A. Frohman1,2, P. G. Rychahou1,2, D. S. Watt3,4, Y. Y. Zaytseva2,5, C. Liu2,3, N. Roller2, K. Wang1, B. M. Evers1,2  1University Of Kentucky,Department Of Surgery,Lexington, KY, USA 2University Of Kentucky,Markey Cancer Center,Lexington, KY, USA 3University Of Kentucky,Department Of Molecular And Cellular Biochemistry,Lexington, KY, USA 4University Of Kentucky,Center For Molecular Medicine, Organic Synthesis Core,Lexington, KY, USA 5University Of Kentucky,Department Of Toxicology And Cancer Biology,Lexington, KY, USA

Introduction:  Colorectal cancer (CRC) is the second leading cause of cancer deaths in the US with the majority of deaths due to metastatic disease. Current chemotherapeutic regimens involve highly toxic agents, which limits their utility; therefore, more effective and less toxic agents are required to see a reduction in CRC morbidity and mortality. Novel fluorinated N,N’-diarylureas (FND) were developed and characterized by our group as potent activators of adenosine monophosphate-activated kinase (AMPK) that inhibit cell cycle progression. The purpose of this study was to determine the effect of a lead FND compound, FND4b, either alone or combined with PI103 (a PI3K inhibitor) or SN38 (active metabolite of irinotecan) on cell cycle arrest and apoptosis of established CRC cell lines and primary CRC lines established from patient-derived xenografts (PDXs).

Methods:  We tested the effects of FND4b, PI103 and SN38 on cell cycle arrest and apoptosis using commercially available CRC cell lines (HT29 and HCT116) and primary cell lines from PDXs established from patients following surgical resection. Briefly, CRC tissues were implanted into NOD scid gamma (NSG) and PDXs (Pt93, Pt130, Pt2377-Primary Tumor [PT], Pt2377-Liver Metastasis [LM]) were established after sequential generations in NSG mice. These PDX models were authenticated as unique human cell lines and genetic profile of 198 oncogenes was determined by Next Generation Sequencing.

Results: Treatment with FND4b for 24h resulted in a marked induction of phosphorylated AMPK expression and a concomitant reduction in Cyclin D1 expression in all six CRC cell lines. Cleaved PARP expression was also notably increased in CRC cells treated with FND4b, which indicated increased apoptosis. Three of the six CRC cell lines had PI3K mutations (HT29, Pt2377-PT, Pt2377-LM), as determined by oncogenic mutation profiling. Other mutations included KRAS, APC, and BRAF. Regardless of the genetic profile of the CRC cells, FND4b treatment resulted in decreased cell proliferation. When CRC cells were treated with combinations of FND4b, PI103, and SN38, there was no change in cell cycle arrest or apoptosis, as compared to treatment with FND4b alone.

Conclusion: Our findings identify FND4b as a novel and effective inhibitor of CRC growth either alone or in combination with PI103 and SN38. Moreover, FND4b activates AMPK at micromolar concentrations, which consistently result in cell cycle arrest and apoptosis in commercially available and PDX-derived CRC cells. Future studies will delineate the effectiveness of FND4b in an in vivo CRC model.

1.18 The Roles of Sphingosine-1-phosphate Produced by Sphingosine Kinases in Tumor and Its Microenvironment

Posted on January 18, 2018

K. Miura1, M. Nagahashi1, M. Nakajima1, K. Yuza1, J. Tsuchida1, Y. Hirose1, M. Abe2, K. Sakimura2, T. Wakai1  1Niigata University Graduate School Of Medical And Dental Sciences,Division Of Digestive And General Surgery,Niigata, NIIGATA, Japan 2Brain Research Institute, Niigata University,Department Of Cellular Neurobiology,Niigata, NIIGATA, Japan

Introduction: Sphingosine-1-phosphate (S1P) is a pleiotropic lipid mediator that regulates cell survival, migration, angiogenesis and lymphangiogenesis, which are all factors involved in cancer progression. S1P is generated inside the cell by two sphingosine kinases (SphK1 and SphK2) and then exported into the tumor microenvironment. We have reported that SphK1 plays an important role in S1P secretion (J Biol Chem 2010) and cancer progression (Cancer Res 2012, J Surg Res 2016), and that SphK2 has a unique role in regulating cellular functions in the liver (Hepatology 2015). Although S1P can be secreted from both cancer cells and non-cancer components such as immune cells and vascular/lymphatic endothelial cells in the tumor microenvironment (Tumor Biology 2017), the roles of S1P produced by tumor and its microenvironment on cancer progression has not been fully investigated. The aim of this study is to investigate the role of SphKs in tumor and its microenvironment using SphK-knockout (KO) cells and SphK KO mice generated by CRISPR/Cas9 technology.

Methods:  We generated E0771 murine breast cancer cell lines with a CRISPR/Cas9 mediated targeted deletion of the SphK1 or SphK2 gene. To investigate the role of SphK1 or SphK2 in cellular proliferation, we assessed cell growth by a spectrophotometric technique using the water-soluble tetrazolium salt, WST-8. Cell migration was measured by an in vitro scratch assay. In the animal experiments, the SphK1 KO or SphK2 KO E0771 cells were injected into the subcutaneous tissue of chest of C57BL6 mice, and prognosis of C57BL/6 mice were determined.

Results: Utilizing in vitro proliferation assay of WST-8, we observed significantly less proliferation in SphK1 KO E0771 cells and more proliferation in SphK2 KO E0771 cells compared with their corresponding wild-type (WT) cells, respectively. On the other hand, there were no difference of migration between SphK1 KO and the WT or between Sph2 KO and the WT. The animal experiments showed that mice injected with SphK1 KO cells showed smaller tumor with longer survival than those injected with SphK1 WT cells. Mice injected with SphK2 KO cells also showed similar trend with smaller tumor and longer survival than those injected with SphK2 WT cells. We next implanted WT cells into SphK1 and SphK2 KO mice, and less tumors were developed in the SphK1 KO and SphK2 KO compared with the WT mice, respectively. Finally, we implanted SphK1 KO cells into SphK1 KO mice and WT mice, and found that there were much less growth of tumor of SphK1 KO cells implanted in the SphK1 KO mouse. This indicates that S1P is necessary to the tumor growth, which can be provided from cancer and tumor microenvironment.

Conclusion: Our findings indicate that S1P produced by SphKs in tumor and its microenvironment. Targeting both SphKs and S1P signaling pathways not only cancer, but also in tumor microenvironment will be a key to success to develop new targeted therapy to block S1P signaling.

 

1.14 Src Inhibition Reverses Epithelial-Mesenchymal Transition in Pancreatic Ductal Adenocarcinoma

Posted on January 18, 2018

A. A. Gaidarski1, N. Nagathihalli1, M. Van Saun1, N. Merchant1  1University Of Miami,Department Of Surgery,Miami, FL, USA

Introduction:  Pancreatic ductal adenocarcinoma (PDAC) is extremely fatal due to its predilection for early metastasis. The hallmark of this tremendous metastatic potential is the epithelial-mesenchymal transition (EMT), signaled by loss of membranous E-cadherin expression. EMT thus represents a crucial target for PDAC therapy but remains elusive due to our poor understanding of its underlying biology. Recently, activation of the Src family of non-receptor tyrosine kinases has been implicated in tumor progression, invasion, and metastasis of PDAC. Moreover, Src has been shown to regulate E-cadherin-induced EMT. The purpose of this study was to examine the effect of Src kinase inhibition on the transcriptional regulation of E-cadherin in PDAC cells.

Methods:  Drug-sensitive and -resistant PDAC cell lines were treated with dasatinib (BMS-354825) a novel, multi-targeted kinase inhibitor that targets Src family kinases. The effects of dasatinib on E-cadherin and β-catenin expression were measured by western blot and immunofluorescence for sub-cellular localization. Dasatinib-treated cells were further analyzed for mRNA expression of E-cadherin and its various transcriptional repressors. Finally, E-cadherin promoter activity was measured in both drug-sensitive and drug-resistant PDAC cell lines. 

Results: Src kinase inhibition with dasatinib resulted in enhanced E-cadherin and β-catenin expression in the drug-sensitive PDAC cells (BxPC-3 and SW-1990), whereas no change was seen in the more resistant Panc-1 cells. The sensitive cell lines demonstrated an increased expression and membranous localization of E-cadherin and β-catenin upon dasatinib treatment, which was not observed in the resistant cell line. Dasatinib treatment also increased E-cadherin expression at the transcriptional level with a concomitant decrease in the expression of the EMT-associated transcription factor Slug but not LEF-1, ZEB or Snail. Repression of Slug further correlated with an increase in the E-cadherin promoter activity in the sensitive cell lines. 

Conclusion: This study elucidates a novel pathway of epithelial-mesenchymal transition in PDAC. In certain populations, Src activation induces the transcription factor Slug, leading to the repression of E-cadherin, precipitating EMT. Dasatinib, a Src-inhibitor, reverses this process and reverts cells back to an epithelial phenotype. Hence, we identify Src as a potential therapeutic target in PDAC and distinguish resistant tumors as those that can upregulate Slug in the face of Src repression.

 

1.15 An Inactivating Patched 1 Gene Mutation in the Hedgehog Pathway Defines a New Subset of Plexiform Fibromyxoma

Posted on January 18, 2018

S. Banerjee1, C. Tang1, M. Yerba1, R. Ustoy1, A. M. Burgoyne2, T. J. Savides3, A. M. Tipps4, J. K. Sicklick1  1University Of California – San Diego,Department Of Surgery,San Diego, CA, USA 2University Of California – San Diego,Department Of Medical Oncology,San Diego, CA, USA 3University Of California – San Diego,Department Of Gastroenterology,San Diego, CA, USA 4University Of California – San Diego,Department Of Pathology,San Diego, CA, USA

Introduction:

Plexiform fibromyxoma (PF) is a rare submucosal gastric tumor that can be confused with gastrointestinal stromal tumor (GIST). While slow growth and lack of metastases suggest an indolent natural history, these so-called benign tumors often present with upper GI bleeding and have a propensity to locally recur. As there are no known drug treatments for PF, resection remains the only treatment. In 2016, the first insight into the molecular biology of 16 PFs demonstrated 4 tumors (25%) with activation of the GLI1 oncogene, a transcription factor in the Hedgehog (Hh) signaling pathway. Despite this discovery, the underlying biology of most PFs remains unknown.

 

Methods:

Following patient consent to an IRB-approved protocol, clinical data and tumor tissue were collected. After pathologic diagnosis, FoundationOne Heme next generation sequencing (NGS) of >400 genes was performed. Real-time reverse transcription polymerase chain reaction (RT-PCR) for Hh pathway components was performed on mRNA extracted from resected tumor tissue. Additionally, tumor cells were dissociated, placed in primary culture, treated with Hh inhibitor, sonidegib (Novartis/Sun Pharma), and assessed for cell viability using Cell Titer Glo assay.

 

Results:

We report a 65-year-old male that presented with acute upper GI bleeding from a 5.0 cm gastric mass. Upper endoscopy revealed an ulcerated tumor and biopsy demonstrated a PF. He underwent partial gastrectomy with R0 resection. The immunohistochemical profile (positive: SMA; negative: CD34, S-100, DOG-1, CD117) and histomorphology (transmural myxoid stroma, plexiform growth pattern with spindle cells, and prominent thin capillaries) were consistent with the diagnosis of PF. On NGS, an inactivating Patched 1 (PTCH1) deletion of exons 15-24 was detected. PTCH1, a known tumor suppressor gene implicated in basal cell carcinoma and medulloblastoma tumorigenesis, functions upstream of GLI1 in the Hh pathway. Thus, this tumor’s loss of PTCH1 function can induce downstream GLI1 activation and transcription of target genes. To confirm activation of the Hh pathway in PF, quantitative RT-PCR analysis of mRNA transcripts demonstrated expression of SMO and GLI1, as well as downstream GLI1 transcriptional targets, including Cyclin D1 and HHIP. In turn, treatment with Hh pathway inhibitor, sonidegib (50 μM), demonstrated cell killing with 97.4% efficiency (P=0.0002) after 48-hours.

 

Conclusion:

For the first time, we report that an inactivating PTCH1 mutation is associated with the development of plexiform fibromyxoma. We show that tumor suppressor gene alterations, rather than oncogenic mutations, within the Hh pathway can also cause plexiform fibromyxoma. In turn, targeted Hh pathway inhibition may represent a viable approach for treating a subset of recurrent plexiform fibromyxomas. Further studies are warranted to investigate the clinical efficacy of these agents in appropriately selected patients.

1.16 Effect of JQ1 treatment on human MYCN-amplified vs non-amplified Neuroblastoma cells

Posted on January 18, 2018

V. Naga1, C. Gordon1, J. Mazar1, T. Westmoreland1  1Nemours Children’s Hospital,Biomedical Research,Orlando, FL, USA

Introduction: MYCN amplification is a prognostic biomarker associated with poor prognosis of neuroblastoma in children, accounting for 40 to 50 percent of all high-risk cases. The overall survival of children with MYCN amplified neuroblastoma has only marginally improved within the last 20 years. The bromodomain inhibitor JQ1 has been shown to downregulate MYCN in sensitive MYCN amplified neuroblastoma cells (Pussaint et al.).  We hypothesize that JQ1 treatment will result in a greater decreased viability in MYCN amplified versus MYCN non-amplified neuroblastoma cells, which, in turn, may have therapeutic implications.

Methods: We used three MYCN amplified neuroblastoma lines [IMR-32, SMS-KAN, and SK-N-Be(1)] and three MYCN non-amplified neuroblastoma lines (SK-N-AS, LAN-6, and CHLA-42) to perform MTS cell viability assays and caspase 3/7 apoptosis assays. Cells were treated at four different concentrations (1 µM, 2 µM, 4 µM, and 8 µM) of JQ1 and its ortho-isomer. Cell viability assays were performed by adding MTS reagent 72 hours after JQ1 treatment and measuring the resulting change in absorbance. For the apoptosis assays, cells were treated at 8 µM of JQ1 and its ortho-isomer. After 48 hours of treatment, a caspase 3/7 substrate was added to the cells and changes in luminescence were measured.

Results: After treatment with JQ1, cell viability decreased in a dose-dependent manner in all cell lines tested. The difference in cell viability between the MYCN amplified and MYCN non-amplified cell lines was most pronounced at the 8 µM concentration of JQ1; cell survival was significantly lower in all the MYCN amplified cells compared to MYCN non-amplified cells. However, responses to the ortho-isomer of JQ1 were not consistent with respect to cell viability. An analysis of the changes in caspase 3/7-dependant apoptosis indicated significant increases in both MYCN amplified and MYCN non-amplified cell lines, though MYCN amplified cells appeared to be more sensitive.

Conclusion: MYCN amplified cell lines demonstrated a more pronounced decrease in cell viability after treatment with JQ1 than the MYCN non-amplified cell lines. This is supported by the caspase 3/7-dependant apoptosis data, which showed that MYCN amplified cell lines showed higher rates of apoptosis after JQ1 treatment. The ortho-isomer of JQ1 had a limited effect on the induction of apoptosis but had a variable effect on cell viability, which suggests that these changes in cell viability may induce a form of cell cycle arrest, indicating it is not entirely harmless as previously reported.  Regardless, these data support the hypothesis that JQ1 may serve as an effective therapeutic in the treatment of MYCN amplified neuroblastoma by decreasing both cell viability and increasing the rate of cellular apoptosis in these high-risk pediatric cancers.

 

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