Cultural competency and ethical behavior for collaboration in limited-resource settings: Guidelines from the Society of University Surgeons Academic Global Surgery Committee and the Association for Academic Global Surgery.

BACKGROUND: There are an increasing number of global surgery activities worldwide. With such tremendous growth, there is a potential risk for untoward interactions between high-income country members and low-middle income country members, leading to programmatic failure, poor results, and/or low impact. METHODS: Key concepts for cultural competency and ethical behavior were generated by the Academic Global Surgery Committee of the Society for University Surgeons in collaboration with the Association for Academic Global Surgery. Both societies ensured active participation from high-income countries and low-middle income countries. RESULTS: The guidelines provide a framework for cultural competency and ethical behavior for high-income country members when collaborating with low-middle income country partners by offering recommendations for: (1) preparation for work with low-middle income countries; (2) process standardization; (3) working with the local community; (4) limits of practice; (5) patient autonomy and consent; (6) trainees; (7) potential pitfalls; and (8) gray areas. CONCLUSION: The article provides an actionable framework to address potential cultural competency and ethical behavior issues in high-income country - low-middle income country global surgery collaborations.

Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial.

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .

Tamoxifen retinopathy: A comprehensive review.

Tamoxifen is a selective estrogen receptor modulator used mainly for the treatment of breast cancer. Based on the case reports and studies performed to date on the retinal toxicity of tamoxifen, retinopathy appears to occur in as many as 12% of patients taking 20 mg tamoxifen a day for over 2 years. Of this 12%, as many as half develop symptomatic changes in visual acuity. Retinal changes consist primarily of crystalline deposits, cystoid macular edema, hyperreflective deposits in the inner retinal layers, and telangiectasia. Tamoxifen retinopathy is currently managed by discontinuing tamoxifen therapy as the cancer prognosis permits; however, discontinuing therapy demonstrates little to no improvement in visual acuity once visual changes have taken place. Intravitreal injections of steroids or antivascular endothelial growth factor therapy have been performed, but require further studying before conclusions can be made. Until then, optical coherence tomography screening for retinal changes should be performed every 6 months for patients who have been on tamoxifen therapy for 2 years or more. This way, patients can become aware of retinal changes, and their physicians can consider adjusting tamoxifen therapy before they risk developing changes in visual acuity.

In Vitro and in Vivo Study of the Effect of Osteogenic Pulsed Electromagnetic Fields on Breast and Lung Cancer Cells.

Introduction: Although there have been significant advances in research and treatments over the past decades, cancer remains a leading cause of morbidity and mortality, mostly due to resistance to standard therapies. Pulsed electromagnetic field (PEMF), a newly emerged therapeutic strategy, has been highly regarded as less invasive and almost safe to patients, is now a clinically accepted form to treat diseases including cancer. Breast and lung cancer are the most prevalent forms of human cancers, yet reported investigations on exploring regimes including PEMF are limited. Methods: Intended to examine the anti-tumor effects of a clinically accepted osteogenic PEMF and the possibility of including PEMF in breast and lung cancer treatments, we studied the effects of 2 PEMF signals (PMF1 and PMF2) on breast and lung cancer cell growth and proliferation, as well as the possible underline mechanisms in vitro and in vivo. Results: We found that both signals caused modest but significant growth inhibition (∼5%) in MCF-7 and A549 cancer cells. Interestingly, mice xenograft tumors with A549 cells treated by PEMF were smaller in sizes than controls. However, for mice with MCF-7 tumor implants, treatment with PMF1 resulted in a slight increase (2.8%) in mean tumor size, while PMF2 treated tumors showed a 9% reduction in average size. Furthermore, PEMF increased caspase 3/7 expression levels and percentage of annexin stained cells, indicating the induction of apoptosis. It also increased G0 by 8.5%, caused changes in the expression of genes associated with cell growth suppression, DNA damage, cell cycle arrest, and apoptosis. When cancer cells or xenograft tumors treated with combined PEMF and chemotherapy drugs, PEMF showed growth inhibition effect independent of cisplatin in A549 cells, but with added effect by pemetrexed for the inhibition of MCF-7 growth. Conclusion: Together, our data suggested that clinically used osteogenic PEMF signals moderately suppressed cancer cell growth and proliferation both in vitro and in vivo.

Who manages burn injuries in children? A program director survey evaluating burn training during pediatric surgery fellowship.

PURPOSE: Burn is one of the leading causes of injury and death in children. Currently, the Residency Review Committee does not require general surgery residents to rotate on a burn service. With many trainees no longer receiving burn training during residency, we sought to evaluate the exposure to burn management in pediatric surgery training programs. MATERIAL AND METHODS: An electronic survey was sent to program directors at accredited pediatric surgery training programs (56) during the 2020 academic year. Case log reviews were performed for 2005-2019. Descriptive statistical analysis was performed. RESULTS: Thirty-six program directors participated in the survey (64%), and 56% reported having an inpatient and outpatient component for burn management. Nearly 20% of program directors reported having no burn management at their institution. Fifty-four percent of responding programs had fellow participation in burn management. Over a fifteen-year period, case logs identified a median of 0-2 burn cases logged each year for graduating fellows. Logistically, 65% of burn centers relied on general pediatric surgeons for management. CONCLUSION: Pediatric surgery trainee involvement in burn management varies with many programs offering no designated burn training. Increasing exposure to pediatric burn management during training is needed to provide improved care for this patient population. LEVEL OF EVIDENCE: III, Retrospective Review.

Bilateral simultaneous postoperative endophthalmitis: review of cases reported over the past 50 years.

A detailed retrospective analysis and literature review were conducted for all previously published reports of bilateral simultaneous postoperative endophthalmitis (BSPOE) since 1970. There have been 7 (9, with 2 currently being reported elsewhere) cases of BSPOE after immediately sequential bilateral cataract surgery (ISBCS) reported over 50 years. Generally, in these cases, the surgical protocol recommended by the International Society of Bilateral Cataract Surgeons ( i SBCS) was breached or uncertain. Bacterial causes were Pseudomonas aeruginosa (3), Staphylococcus epidermidis (3), and Burkholderia cepacia complex (1). One case showed negative results for bacterial infection and 1 was not determined. Visual recovery was light perception, or worse, for Pseudomonas cases, generally good for Staphylococcus and Burkholderia cases, and mixed in cases of unknown etiology. Therefore, BSPOE is rare and causes vary. Strict adherence to the i SBCS General Principles of Excellence in ISBCS 2009 surgical protocol and care with operating room construction seem to considerably lessen the risk.

Human induced pluripotent stem cell-derived platelets loaded with lapatinib effectively target HER2+ breast cancer metastasis to the brain.

Prognosis of patients with HER2+ breast-to-brain-metastasis (BBM) is dismal even after current standard-of-care treatments, including surgical resection, whole-brain radiation, and systemic chemotherapy. Radiation and systemic chemotherapies can also induce cytotoxicity, leading to significant side effects. Studies indicate that donor-derived platelets can serve as immune-compatible drug carriers that interact with and deliver drugs to cancer cells with fewer side effects, making them a promising therapeutic option with enhanced antitumor activity. Moreover, human induced pluripotent stem cells (hiPSCs) provide a potentially renewable source of clinical-grade transfusable platelets that can be drug-loaded to complement the supply of donor-derived platelets. Here, we describe methods for ex vivo generation of megakaryocytes (MKs) and functional platelets from hiPSCs (hiPSC-platelets) in a scalable fashion. We then loaded hiPSC-platelets with lapatinib and infused them into BBM tumor-bearing NOD/SCID mouse models. Such treatment significantly increased intracellular lapatinib accumulation in BBMs in vivo, potentially via tumor cell-induced activation/aggregation. Lapatinib-loaded hiPSC-platelets exhibited normal morphology and function and released lapatinib pH-dependently. Importantly, lapatinib delivery to BBM cells via hiPSC-platelets inhibited tumor growth and prolonged survival of tumor-bearing mice. Overall, use of lapatinib-loaded hiPSC-platelets effectively reduced adverse effects of free lapatinib and enhanced its therapeutic efficacy, suggesting that they represent a novel means to deliver chemotherapeutic drugs as treatment for BBM.

Inhibition of Jumonji Histone Demethylases Selectively Suppresses HER2+ Breast Leptomeningeal Carcinomatosis Growth via Inhibition of GMCSF Expression.

HER2+ breast leptomeningeal carcinomatosis (HER2+ LC) occurs when tumor cells spread to cerebrospinal fluid-containing leptomeninges surrounding the brain and spinal cord, a complication with a dire prognosis. HER2+ LC remains incurable, with few treatment options. Currently, much effort is devoted toward development of therapies that target mutations. However, targeting epigenetic or transcriptional states of HER2+ LC tumors might efficiently target HER2+ LC growth via inhibition of oncogenic signaling; this approach remains promising but is less explored. To test this possibility, we established primary HER2+ LC (Lepto) cell lines from nodular HER2+ LC tissues. These lines are phenotypically CD326+CD49f-, confirming that they are derived from HER2+ LC tumors, and express surface CD44+CD24-, a cancer stem cell (CSC) phenotype. Like CSCs, Lepto lines showed greater drug resistance and more aggressive behavior compared with other HER2+ breast cancer lines in vitro and in vivo. Interestingly, the three Lepto lines overexpressed Jumonji domain-containing histone lysine demethylases KDM4A/4C. Treatment with JIB04, a selective inhibitor of Jumonji demethylases, or genetic loss of function of KDM4A/4C induced apoptosis and cell-cycle arrest and reduced Lepto cell viability, tumorsphere formation, regrowth, and invasion in vitro. JIB04 treatment of patient-derived xenograft mouse models in vivo reduced HER2+ LC tumor growth and prolonged animal survival. Mechanistically, KDM4A/4C inhibition downregulated GMCSF expression and prevented GMCSF-dependent Lepto cell proliferation. Collectively, these results establish KDM4A/4C as a viable therapeutic target in HER2+ LC and spotlight the benefits of targeting the tumorigenic transcriptional network. SIGNIFICANCE: HER2+ LC tumors overexpress KDM4A/4C and are sensitive to the Jumonji demethylase inhibitor JIB04, which reduces the viability of primary HER2+ LC cells and increases survival in mouse models.

The diminishing experience in pediatric surgery for general surgery residents in the United States.

PURPOSE: The Accreditation Council for Graduate Medical Education (ACGME) regulates the general surgery residency curriculum. Case volume remains a priority as recent concerns surrounding a lack of proficiency for certain surgical cases have circulated. We hypothesize that there is a significant decrease in pediatric surgery case numbers during general surgery residency despite residents meeting the minimum case requirements. METHODS: We reviewed publicly available ACGME case reports for general surgery residency from 1999 to 2018. Cases are classified as Surgeon Chief or Surgeon Junior. Analyzed data included case classifications, number of residents, and number of residency programs. Simple linear regression analysis was performed. RESULTS: We identified a significant decrease in total number of logged pediatric surgery cases over the past 20 years (p<0.001). Nearly 60% of cases were logged under a single category - inguinal/umbilical hernia. From the past five years, pyloric stenosis was the only other category with an average of greater than two cases logged (range 2.1-2.8). CONCLUSION: We identified a significant decrease in total pediatric surgery case numbers during general surgery residency from 1999 to 2018. Though meeting set requirements, overall case variety was limited. With minimal number of cases required by the ACGME, graduating general surgery residents may lack proficiency in simple pediatric surgery cases.

Trending diversity: Reviewing four-decades of graduating fellows and the current leadership in pediatric surgery.

PURPOSE: Diversity in the physician workforce remains a priority in healthcare as it has been shown to improve outcomes. Decisions for choosing specific fields in medicine are partly influenced by mentors, which tend to be the same sex or ethnicity. Females are starting to outnumber males in medical school and minorities are targeted for recruitment. We hypothesized that diversity in pediatric surgery has increased over time. METHODS: The recently published A Genealogy of North American Pediatric Surgery was utilized to identify graduating pediatric surgery fellows from 1981 to 2018. Organization websites were used to identify past and current leaders. A web-based analysis, including online facial recognition software, was performed. A year-to-year and decade-to-decade demographic comparison was completed. RESULTS: 1217 pediatric surgery fellows graduated between 1981 and 2018. When comparing graduates from the first and last decades, an increase from 16.9% to 39.5% for female graduates was observed (p = 0.046). A significant increase in nonwhite graduates was seen for all races (p < 0.05). Representation in leadership was White and male dominant. CONCLUSION: There was a significant increase in diversity in pediatric surgery fellowship graduates. There were increasing trends in female graduates and all nonwhite racial groups. Focusing on enhancing the pipeline and mentoring underrepresented minorities will continue to enhance this trend for the field of pediatric surgery. LEVEL OF EVIDENCE: III; Retrospective Review.

Utility of Preoperative Blood-Oxygen-Level-Dependent Functional MR Imaging in Patients with a Central Nervous System Neoplasm.

Functional neuroimaging provides means to understand the relationship between brain structure and associated functions. Functional MR (fMR) imaging can offer a unique insight into preoperative planning for central nervous system (CNS) neoplasms by identifying areas of the brain effected or spared by the neoplasm. BOLD (blood-oxygen-level-dependent) fMR imaging can be reliably used to map eloquent cortex presurgically and is sufficiently accurate for neurosurgical planning. In patients with brain tumors undergoing neurosurgical intervention, fMR imaging can decrease postoperative morbidity. This article discusses the applications, significance, and interpretation of BOLD fMR imaging, and its applications in presurgical planning for CNS neoplasms.

Upregulated CBX8 Promotes Cancer Metastasis via the WNK2/MMP2 Pathway.

Metastasis is associated with poor prognosis in cancer and is a multistep process that includes invasion and migration. Several epigenetic factors are involved in this process, including chromobox protein homolog 8 (CBX8). Here, we show that CBX8 is overexpressed in many cancers compared with normal tissues. Functional analyses indicated that CBX8 promoted invasion and migration in glioblastoma, breast cancer, and lung cancer in vitro and in vivo. WNK2 was identified as a target gene of CBX8, which interacted with the WNK2 promoter to suppress WNK2 expression and activity. WNK2 acted as an antioncogene, and decreased WNK2 levels resulted in high activity of matrix metalloprotease (MMP)-2 and RAC1, which play a central role in invasion and migration, respectively. There was a positive relationship between MMP2 and RAC1 activity in CBX8-modulated cell lines. In addition, WNK2 negatively regulated MMP2 and RAC1 activity. Collectively, the results indicated that CBX8 promoted invasion and migration by targeting WNK2, which resulted in increased RAC1 and MMP2 expression and activity. Therefore, CBX8 may be a novel therapeutic target to treat metastatic cancers.

Esophageal Foreign Body Management in Children: Can It Wait?

Introduction: Pediatric foreign body ingestion remains a common reason for emergency department (ED) visits. Button battery ingestion is an established surgical emergency, requiring immediate removal. Timing of removal for other foreign bodies remains controversial. We hypothesize that there is no difference in complication rate or successful removal of esophageal foreign bodies that wait until the following morning for removal. Materials and Methods: A retrospective review for cases involving esophageal foreign body removal by pediatric surgery or pediatric gastroenterology from November 2015 to November 2019 was performed. Patients were divided into two groups based on ED arrival-daytime (05:00-16:59); nighttime (17:00-04:59). Imaging confirmed an esophageal foreign body. Data collected included basic demographics, time of presentation, time of procedure, symptoms, location of the foreign body, and complications within 30 days. Statistical analysis was performed. Results: After excluding button batteries, 273 children underwent esophageal foreign body removal. Two-thirds presented at night. A significant difference was identified in the median time from ED to the operating room when comparing daytime (194.8 minutes; interquartile range [IQR]: 108.5-347) versus nighttime groups (643 minutes; IQR: 471.5-745; P < .001). Nine children had a complication or readmission within 30 days of their procedure and 25 patients had migration of their foreign body into the stomach, both with no significant difference (P = .94; P = .98, respectively). Conclusion: We found that waiting until the following morning had minimal impact on complications or success rate when removing esophageal foreign bodies. By waiting, institutions with limited personnel can keep resources and staff available for more pressing emergencies.

Astrocytic IGFBP2 and CHI3L1 in cerebrospinal fluid drive cortical metastasis of HER2+breast cancer.

The brain is often reported as the first site of recurrence among breast cancer patients overexpressing human epidermal growth factor receptor 2 (HER2). Although most HER2+tumors metastasize to the subcortical region of the brain, a subset develops in the cortical region. We hypothesize that factors in cerebrospinal fluid (CSF) play a critical role in the adaptation, proliferation, and establishment of cortical metastases. We established novel cell lines using patient biopsies to model breast cancer cortical and subcortical metastases. We assessed the localization and growth of these cells in vivo and proliferation and apoptosis in vitro under various conditions. Proteomic analysis of human CSF identified astrocyte-derived factors that support the proliferation of cortical metastases, and we used neutralizing antibodies to test the effects of inhibiting these factors both in vivo and in vitro. The cortical breast cancer brain metastatic cells exhibited greater proliferation than subcortical breast cancer brain metastatic cells in CSF containing several growth factors that nourish both the CNS and tumor cells. Specifically, the astrocytic paracrine factors IGFBP2 and CHI3LI promoted the proliferation of cortical metastatic cells and the formation of metastatic lesions. Disruption of these factors suppressed astrocyte-tumor cell interactions in vitro and the growth of cortical tumors in vivo. Our findings suggest that inhibition of IGFBP2 and CHI3LI signaling, in addition to existing treatment modalities, may be an effective therapeutic strategy targeting breast cancer cortical metastasis.

Weight Loss and Health Status 5 Years After Adjustable Gastric Banding in Adolescents.

OBJECTIVE: This prospective cohort analysis describes changes in weight, cardiometabolic health, and weight-related quality of life (WRQOL) following adolescent LAGB. METHODS: Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) collected demographic, anthropometric, micronutrient, cardiometabolic risk, and WRQOL data for 242 adolescents. Data through 5 years were analyzed for 14 participants who underwent LAGB with 2 patients lost to follow-up. RESULTS: Participants (mean age 18.2 ± 0.4 years) were mostly female (86%) and white (71%) with a median body mass index (BMI) of 48.7 kg/m2 (45.5-54.1). Preoperatively, 100%(13/13), 62%(8/13), 57%(8/14), and 7%(1/14) had elevated high sensitivity C-reactive protein (hs-CRP), dyslipidemia, elevated blood pressure (EBP), and type 2 diabetes (T2D), respectively. At 5 years, mean BMI decreased by 3.3% (51.0 vs. 49.3 kg/m2, p = 0.6), 43%(6/14) had BMI values exceeding baseline and 21% (3/14) underwent band removal. Postoperative prevalence of hs-CRP, dyslipidemia, EBP, and T2D was 45% (4/11), 36% (5/11), 33% (4/12), and 0% (0/11), respectively. CONCLUSION: Adolescents undergoing LAGB experienced modest initial weight loss and improvements in cardiovascular risk factors with later weight regain and frequent need for band removal. Despite the small sample size, this prospective study highlights long-term outcomes with high rates of participant retention over time. CLINICAL TRIAL REGISTRATION: NCT00465829.

Nutritional Risks in Adolescents After Bariatric Surgery.

BACKGROUND & AIMS: Little is known about prevalence and risk factors for nutritional deficiencies in adolescents after metabolic bariatric surgery. We performed a 5-year prospective cohort study of these. METHODS: Adolescents who had Roux-en-Y gastric bypass (RYGB, n = 161) or vertical sleeve gastrectomy (VSG, n = 67) were enrolled at 5 tertiary-care centers from March 2007 through February 2012. The final analysis cohort included 226 participants (161 who had RYGB and 65 who had VSG). We measured serum levels of ferritin; red blood cell folate; vitamins A, D, B1, B12; and parathyroid hormone at baseline and annually for 5 years. General linear mixed models were used to examine changes over time and identify factors associated with nutritional deficiencies. RESULTS: The participants were 75% female and 72% white, with a mean age of 16.5 ± 1.6 years and mean body mass index of 52.7 ± 9.4 kg/m2 at surgery. Mean body mass index decreased 23% at 5 years, and did not differ significantly between procedures. After RYGB, but not VSG, serum concentrations of vitamin B12 significantly decreased whereas serum levels of transferrin and parathyroid hormone increased. Ferritin levels decreased significantly after both procedures. Hypo-ferritinemia was observed in 2.5% of patients before RYGB and 71% at 5 y after RYGB (P < .0001), and 11% of patients before VSG and 45% 5 y after VSG (P = .002). No significant changes in serum levels of folate or vitamins A, B1, or D were found between baseline and 5 y after either procedure. By 5 y, 59% of RYGB and 27% of VSG recipients had 2 or more nutritional deficiencies. Risk factors associated with specific deficiencies included surgery type, female sex, black race, supplementation intake, weight regain, and for females, pregnancy. CONCLUSIONS: In a prospective study of adolescents who underwent RYGB or VSG, we observed nutritional deficiencies by 5 y after the procedures-particularly in iron and B12 after RYGB. Ongoing nutrient monitoring and supplementation are recommended for all patients, but surgery type, supplementation intake, sex, and race might affect risk. (Clinical trial registration: Adolescent Bariatrics: Assessing Health Benefits and Risk [also known as Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS)], NCT00474318.).