Qualitative Analysis of the Host-Perceived Impact of Unidirectional Global Surgery Training in Kijabe, Kenya: Benefits, Challenges, and a Desire for Bidirectional Exchange.

BACKGROUND: As globalization of surgical training increases, growing evidence demonstrates a positive impact of global surgery experiences on trainees from high-income countries (HIC). However, few studies have assessed the impact of these largely unidirectional experiences from the perspectives of host surgical personnel from low- and middle-income countries (LMIC). This study aimed to assess the impact of unidirectional visitor involvement from the perspectives of host surgical personnel in Kijabe, Kenya. METHODS: Voluntary semi-structured interviews were conducted with 43 host surgical personnel at a tertiary referral hospital in Kijabe, Kenya. Qualitative analysis was used to identify salient and recurring themes related to host experiences with visiting surgical personnel. Perceived benefits and challenges of HIC involvement and host interest in bidirectional exchange were assessed. RESULTS: Benefits of visitor involvement included positive learning experiences (95.3%), capacity building (83.7%), exposure to diverse practices and perspectives (74.4%), improved work ethic (51.2%), shared workload (44.2%), access to resources (41.9%), visitor contributions to patient care (41.9%), and mentorship opportunities (37.2%). Challenges included short stays (86.0%), visitor adaptation and integration (83.7%), cultural differences (67.4%), visitors with problematic behaviors (53.5%), learner saturation (34.9%), language barriers (32.6%), and perceived power imbalances between HIC and LMIC personnel (27.9%). Nearly half of host participants expressed concerns about the lack of balanced exchange between HIC and LMIC programs (48.8%). Almost all (96.9%) host trainees expressed interest in a bidirectional exchange program. CONCLUSION: As the field of global surgery continues to evolve, further assessment and representation of host perspectives is necessary to identify and address challenges and promote equitable, mutually beneficial partnerships between surgical programs in HIC and LMIC.

Internal Pathology Review of Invasive Melanoma: An Academic Institution Experience.

BACKGROUND: Prior studies of internal pathology review (IPR) for melanoma have shown that changes in the pathology analysis are common. How these changes impact clinical management of melanoma or how the margin status reports may modify has not been evaluated. Our goal was to determine what changes to staging and surgical management occurred after IPR of newly diagnosed melanomas and to determine how the final surgical pathology report may correlate with the IPR. METHODS: A retrospective study was conducted from 2014 to 2016 of newly diagnosed invasive melanomas referred to a single National Comprehensive Cancer Network tertiary care center. RESULTS: A total of 370 cases met inclusion criteria. The most common feature changed after internal review was mitotic rate, in 155 (41.7%) patients, followed by Breslow depth in 99 (26.9%) patients. Tumor staging was changed in 45 (12.2%) patients. The most common change was a T1a lesion being upgraded to a T1b lesion. These tumor staging changes lead to 38 (10.3%) overall staging differences. A biopsy's deep margin status was changed in 27 (7.3%) patients. Outside hospital reports lacked information about deep margin status in 71 (19.2%) of specimens. Based on the National Comprehensive Cancer Network guidelines, 22 (5.9%) patients had changes in their sentinel lymph node biopsy recommendations and one of these patients had a positive node found on pathology. Of those patients who had changes in the T-stage, 16 (4.3%) of them also had changes in the recommended wide local excision radial margin. CONCLUSIONS: IPR of invasive melanoma leads to both changes in staging and the surgical management of melanoma and should remain an important component of care of melanoma patients at a tertiary referral center.

Global Surgery Electives: A Strategy to Improve Care to Domestic Underserved Populations?

BACKGROUND: In the United States, a shortage of general surgeons exists, primarily in rural, poor, and minority communities. Identification of strategies that increase resident interest in underserved regions provides valuable information in understanding and addressing this shortage. In particular, surgical experience abroad exposes residents to practice in low-resource and rural settings. As residency programs increasingly offer global surgery electives, we explore whether the presence of an international surgical rotation affects graduates' future practice patterns in underserved communities domestically. METHODS: We surveyed general surgery residency graduates at a single academic institution. Those who finished general surgery residency from 2001 to 2018 were included. Participant demographics, current practice demographics, and perceptions related to global surgery and underserved populations were collected. Respondents were stratified based on whether they did ("after") or did not ("before") have the opportunity to participate in the Kijabe rotation (started in 2011), defined by graduation year. RESULTS: Out of 119 eligible program graduates, 64 (53.7%) completed the survey, and 33 (51.6%) of the respondents graduated following the implementation of the Kijabe rotation. Two participants defined their primary current practice location as international. Fifteen (45.5%) in the "After" group indicated an interest in working with underserved populations following residency, compared to 5 (17.8%) of the "Before" group (P = 0.074). Furthermore, 20 (60.6%) respondents in the "After" group expressed interest in working with underserved populations even if it meant making less money. In the "Before" group, only 13 (46.4%) responded similarly (P = 0.268). Eleven (9.2%) residents rotated at Kijabe. Those who participated in the Kijabe rotation reported an uninsured rate of 36.7% for their current patient population, compared to rate of 13.9% in those who did not rotate there (P = 0.22). CONCLUSIONS: At a single institution, our results suggest that participation in an international surgical rotation in a resource-constrained setting may be associated with increased care for underserved populations in future clinical practice. These results could be due to self-selection of residents who prioritize global surgery as part of their residency experience, or due to increased exposure to underserved patients through global surgery.

Specialist Physicians' Attitudes and Practice Patterns Regarding Disclosure of Pre-referral Medical Errors.

OBJECTIVE: Our objective was to determine specialist physicians' attitudes and practices regarding disclosure of pre-referral errors. SUMMARY BACKGROUND DATA: Physicians are encouraged to disclose their own errors to patients. However, no clear professional norms exist regarding disclosure when physicians discover errors in diagnosis or treatment that occurred at other institutions before referral. METHODS: We conducted semistructured interviews of cancer specialists from 2 National Cancer Institute-designated Cancer Centers. We purposively sampled specialists by discipline, sex, and experience-level who self-described a >50% reliance on external referrals (n = 30). Thematic analysis of verbatim interview transcripts was performed to determine physician attitudes regarding disclosure of pre-referral medical errors; whether and how physicians disclose these errors; and barriers to providing full disclosure. RESULTS: Participants described their experiences identifying different types of pre-referral errors including errors of diagnosis, staging and treatment resulting in adverse events ranging from decreased quality of life to premature death. The majority of specialists expressed the belief that disclosure provided no benefit to patients, and might unnecessarily add to their anxiety about their diagnoses or prognoses. Specialists had varying practices of disclosure including none, non-verbal, partial, event-dependent, and full disclosure. They identified a number of barriers to disclosure, including medicolegal implications and damage to referral relationships, the profession's reputation, and to patient-physician relationships. CONCLUSIONS: Specialist physicians identify pre-referral errors but struggle with whether and how to provide disclosure, even when clinical circumstances force disclosure. Education- or communication-based interventions that overcome barriers to disclosing pre-referral errors warrant development.

Age greater than 60 years portends a worse prognosis in patients with papillary thyroid cancer: should there be three age categories for staging?

BACKGROUND: Age is an important prognostic factor in papillary thyroid cancer (PTC), with better survival observed in patients < 45 years of age, regardless of stage. Although the impact of increasing age on PTC-related survival is well-known, previous studies have focused on survival relative to age 45 years only. As the number of patients entering their 7th decade of life increases, PTC-related survival in this demographic becomes increasingly important. Survival in patients ≥ 60 years specifically compared to other groups has not previously been examined. We sought to determine whether age ≥ 60 years is an adverse prognostic factor for disease-specific survival and recurrence in patients with PTC. METHODS: The California Cancer Registry database was linked to inpatient and ambulatory patient records from the Office of Statewide Health Planning and Development for the years 2000-2011. This linked database was queried for patients diagnosed with papillary thyroid cancer and treated with surgery. We then identified prognostic factors related to both 5-year and 10-year disease-specific survival and disease-free survival in patients ≤ 45, 45-59, and ≥ 60 years. Multivariable Cox proportional hazard models were created to test the effect of age ≥ 60 on disease-specific and disease-free survival, controlling for clinical, treatment, and demographic factors. RESULTS: The final cohort included 15,675 patients. Of the group, 46.3% were between 18 and 44 years of age, 33.6% were 45-59 years, and 20.1% were ≥ 60. Univariate analysis showed that compared to other groups, patients ≥ 60 were more likely to be male (p < 0.001), present with tumors > 5 cm (p < 0.001), more likely to have metastatic disease (p < 0.001), less likely to receive radioactive iodine (p < 0.001), and more likely to receive external beam radiation therapy (p < 0.001). In multivariable Cox proportional hazards models for 5 and 10-year disease-free survival, age ≥ 60 was associated with higher risk of disease at 5 and 10-years (HR 2.3 and 1.9 respectively, p < 0.001). Similar results were observed for 5 and 10-year disease-specific survival (HR 38.0 and 30.0 respectively, p < 0.001) after controlling for gender, race, co-morbidity, stage, surgical procedure, radioactive iodine, insurance, and hospital volume. CONCLUSIONS: Patients ≥ 60 years of age have worse DSS and DFS after a diagnosis of PTC, across all stages of disease. Given that patients over the age of 45 years have progressively worse survival as they age, these data support having three age groups, 18-44 years of age, 45-59 years, and ≥ 60 as an independent predictor of survival and recurrence to current staging guidelines.

The Challenges of Providing Feedback to Referring Physicians After Discovering Their Medical Errors.

BACKGROUND: Physicians are encouraged through formalized systems to discuss their own errors with peers for the purposes of quality improvement. However, no clear professional norms exist regarding peer review when physicians discover errors that occurred at other institutions before referral. Our objective was to determine specialist physicians' attitudes and practices regarding providing feedback to referring physicians when prereferral errors are discovered. METHODS: We conducted semistructured interviews of specialists from two National Cancer Institute-designated Cancer Centers. Thematic analysis of transcripts was performed to determine physicians' attitudes toward the delivery of negative feedback regarding prereferral errors, whether and how they communicate these errors to referring physicians, and perceived barriers to doing so. RESULTS: We purposively sampled specialists by discipline, gender, and experience level, who described greater than 50% reliance on external referrals (n = 30). Specialists believed regular, explicit feedback was ideal, but the majority of participants reported practices that did not meet this standard. While there were some structural barriers to providing feedback (lack of time or contact information), the majority of barriers were internal psychological concerns (general discomfort with providing negative feedback, fear of conflict, or defensive reactions) or fears about implications for future referrals or medicolegal risk. CONCLUSIONS: Policies and interventions that structure the approach to this sometimes difficult, yet critically important, opportunity for reducing medical errors warrant investigation as potential mechanisms by which to improve consistency and quality of care while maintaining positive professional relationships.

Mitotic rate is associated with positive lymph nodes in patients with thin melanomas.

BACKGROUND: The American Joint Commission on Cancer will remove mitotic rate from its staging guidelines in 2018. OBJECTIVE: Using a large nationally representative cohort, we examined the association between mitotic rate and lymph node positivity among thin melanomas. METHODS: A total of 149,273 thin melanomas in the National Cancer Database were examined for their association of high-risk features of mitotic rate, ulceration, and Breslow depth with lymph node status. RESULTS: Among 17,204 patients with thin melanomas with data on Breslow depth, ulceration, and mitotic rate who underwent a lymph node biopsy, there was a strong linear relationship between odds of having a positive lymph node and mitotic rate (R2 = 0.96, P < .0001, ß = 3.31). The odds of having a positive node increased by 19% with each 1-point increase in mitotic rate (odds ratio, 1.19; 95% confidence interval, 1.17-1.21). Cases with negative nodes had a mean mitotic rate of 1.54 plus or minus 2.07 mitoses/mm2 compared with 3.30 plus or minus 3.54 mitoses/mm2 for those with positive nodes (P < .0001). LIMITATIONS: The data collected do not allow for survival analyses. CONCLUSIONS: Mitotic rate was strongly associated with the odds of having a positive lymph node and should continue to be reported on pathology reports.

Incorporation of a Global Surgery Rotation into an Academic General Surgery Residency Program: Impact and Perceptions.

INTRODUCTION: Global surgery is increasingly recognized as a vital component of international public health. Access to basic surgical care is limited in much of the world, resulting in a global burden of treatable disease. To address the lack of surgical workforce in underserved environments and to foster ongoing interest in global health among US-trained surgeons, our institution established a residency rotation through partnership with an academic hospital in Kijabe, Kenya. This study evaluates the perceptions of residents involved in the rotation, as well as its impact on their future involvement in global health. MATERIALS AND METHODS: A retrospective review of admission applications from residents matriculating at our institution was conducted to determine stated interest in global surgery. These were compared to post-rotation evaluations and follow-up surveys to assess interest in global surgery and the effects of the rotation on the practices of the participants. RESULTS: A total of 78 residents matriculated from 2006 to 2016. Seventeen participated in the rotation with 76% of these reporting high satisfaction with the rotation. Sixty-five percent had no prior experience providing health care in an international setting. Post-rotation surveys revealed an increase in global surgery interest among participants. Long-term interest was demonstrated in 33% (n = 6) who reported ongoing activity in global health in their current practices. Participation in global rotations was also associated with increased interest in domestically underserved populations and affected economic and cost decisions within graduates' practices.

Predictors of Antiestrogen Recommendation in Women With Estrogen Receptor-Positive Ductal Carcinoma In Situ.

BACKGROUND: Antiestrogen (anti-e) use in estrogen receptor-positive (ER+) ductal carcinoma in situ (DCIS) has been shown to reduce the incidence of noninvasive and invasive breast cancer. Few studies have evaluated factors associated with anti-e recommendation in ER+ DCIS. METHODS: The California Cancer Registry was queried for female patients diagnosed with ER+ DCIS and treated with lumpectomy or unilateral mastectomy from 2004 to 2011. Patient demographics, comorbidities, and clinical characteristics were analyzed for association with anti-e recommendation. RESULTS: Of 5,527 patients identified, 76.4% patients underwent lumpectomy and 23.6% underwent unilateral mastectomy. Of the total cohort, 31.6% patients were recommended anti-e therapy, 60.4% were not, and the remaining 8.0% were recommended anti-e, but administration was not documented. Performance of lumpectomy predicted anti-e use compared with mastectomy (odds ratio [OR], 2.08; 95% CI, 1.77-2.43). Asian/Pacific Islanders were more often recommended anti-e therapy when compared with whites (OR, 1.28; 95% CI, 1.10-1.49). Patients younger than 70 years were more often recommended anti-e (age, 18-49 years: OR, 1.38; CI, 1.12-1.71; and age, 50-69 years: OR, 1.43; CI, 1.20-1.71). CONCLUSIONS: Despite current guidelines to consider the use of anti-e therapy, recommendation of anti-e after surgical treatment of DCIS is low, having been recommended to 40% of patients, and used by fewer than one-third. Significant predictors include lumpectomy compared with unilateral mastectomy, Asian/Pacific Islander race, younger age, and number of comorbidities. Further work is merited to understand patterns of anti-e therapy recommendation by providers in patients with DCIS.

Survival analysis of contralateral prophylactic mastectomy: a question of selection bias.

BACKGROUND: Rates of contralateral prophylactic mastectomy (CPM) in women with breast cancer have increased, but most studies fail to show a survival benefit. We evaluated survival among CPM patients compared to patients undergoing single mastectomy (SM). METHODS: The Surveillance, Epidemiology, and End Results database was used to identify unilateral breast cancer patients who underwent mastectomy with/without CPM from 1998 to 2010. Case-control analysis was performed with CPM cases matched to SM controls on the basis of age group, race/ethnicity, extent of surgery, grade, T classification, N classification, estrogen receptor status, and propensity score. Survival analyses included Kaplan-Meier curves and univariate and multivariate proportional hazard models to determine factors associated with disease-specific (DSS) and overall survival (OS). RESULTS: A total of 26,526 CPM patients were identified. On multivariate regression analysis, increasing age, greater extent of surgery, increasing T and N stage, African American race, Hispanic ethnicity, poorly differentiated grade, and estrogen receptor negativity were associated with increased risk of death. CPM was associated with improved DSS (HR 0.86, 95 % CI 0.79-0.93) and even greater OS (HR 0.76, 95 % CI 0.71-0.81) compared with SM. Contralateral breast cancer (CBC) occurred in 1.6 % of women in the cohort. Removing CBC cases from analysis had little impact on CPM DSS (HR 0.86, 95 % CI 0.79-0.93) and OS (0.77, 95 % CI 0.72-0.82) suggesting that prevention of CBC by CPM does not explain the observed survival benefit. CONCLUSIONS: CPM rates continue to rise. The improved DSS and OS observed with CPM support selection bias. Prospective trials are needed to determine cohorts of patients most likely to benefit from CPM.

Incidence of additional primary malignancies in patients with pancreatic and gastrointestinal neuroendocrine tumors.

BACKGROUND: The incidence of secondary malignancies is increased in patients with malignant and premalignant conditions. Although neuroendocrine tumors (NET) are uncommon, their incidence is increasing. We evaluated the rate of additional malignancies in patients with NET. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified a cohort of patients with pancreatic NET (PNET) or gastrointestinal NET (GINET). We determined the incidence of additional cancers diagnosed either before or after the diagnosis of PNET or GINET, by comparing these rates with the general population. Using multivariable regression, we evaluated factors that increased the risk of an additional malignancy. RESULTS: A cohort of 9,727 NET patients was identified. A total of 3,086 additional cancers occurred in 2,508 patients (25.8 %). The most common sites of additional malignancies included colorectal (21.1 %), prostate (14.5 %), breast (13.3 %), and lung (11.6 %). Among patients with PNET, the incidence of breast, lung, uterine, lymph, and pancreatic cancers was less than expected in the general population, whereas in patients with GINET, the observed incidence of nearly all malignancies exceeded that expected. Increasing age, marital status, and localized NET were associated with increased risk. CONCLUSION: Our study shows that the incidence of additional malignancies in patients with PNET and GINET is 25.8 %. Patients with GINET are at increased risk of additional malignancies, whereas patients with PNET have a decreased risk compared with the general population. More vigilant surveillance for secondary malignancies should be performed in patients with GINET. Studies investigating potential etiologic oncogenic pathways are warranted.

Duration of time on intensive insulin therapy predicts severe hypoglycemia in the surgically critically ill population.

BACKGROUND: Hypoglycemia has emerged as a barrier to the practice of intensive insulin therapy. Current literature suggests that hypoglycemia occurs at variable rates and has different effects on outcomes in surgical and medical populations. We sought to determine the incidence, independent predictors, and effect on outcome of severe hypoglycemia (≤ 40 mg/dl) in a surgical population. METHODS: A retrospective analysis was performed on all critically ill surgical patients treated with IIT from October 2004 to February 2007. Euglycemia (goal 80-110 mg/dl) was maintained using automated computerized titration of an insulin infusion. The primary outcome of interest was any episode of severe hypoglycemia (≤ 40 mg/dl). Multivariate logistic regression was used to determine the independent predictors of developing severe hypoglycemia. RESULTS: A total of 60,298 data entries (1,118 patients) for glucose were analyzed. There were 64 severe hypoglycemic episodes in 52 patients (4.6% of the patients). There was a significant increase in deaths among patients who experienced at least one episode of hypoglycemia when compared with those who did not (26.9% vs. 15.3%, P = 0.03). Logistic regression revealed that the time spent on the protocol was the best predictor of developing a hypoglycemic event when controlling for other known risk factors of hypoglycemia. CONCLUSIONS: Intensive insulin therapy can be implemented with a low percentage of patients (4.6%) experiencing severe hypoglycemia. Mortality rate was higher for patients experiencing hypoglycemia. The duration of the time spent on the protocol was the best predictor of hypoglycemia, suggesting that hypoglycemia is a mathematic probability of prolonged illness, not a reflection of illness severity or demographic features.

Design of a Novel Online, Modular, Flipped-classroom Surgical Curriculum for East, Central, and Southern Africa.

Objective: We describe a structured approach to developing a standardized curriculum for surgical trainees in East, Central, and Southern Africa (ECSA). Summary Background Data: Surgical education is essential to closing the surgical access gap in ECSA. Given its importance for surgical education, the development of a standardized curriculum was deemed necessary. Methods: We utilized Kern's 6-step approach to curriculum development to design an online, modular, flipped-classroom surgical curriculum. Steps included global and targeted needs assessments, determination of goals and objectives, the establishment of educational strategies, implementation, and evaluation. Results: Global needs assessment identified the development of a standardized curriculum as an essential next step in the growth of surgical education programs in ECSA. Targeted needs assessment of stakeholders found medical knowledge challenges, regulatory requirements, language variance, content gaps, expense and availability of resources, faculty numbers, and content delivery method to be factors to inform curriculum design. Goals emerged to increase uniformity and consistency in training, create contextually relevant material, incorporate best educational practices, reduce faculty burden, and ease content delivery and updates. Educational strategies centered on developing an online, flipped-classroom, modular curriculum emphasizing textual simplicity, multimedia components, and incorporation of active learning strategies. The implementation process involved establishing thematic topics and subtopics, the content of which was authored by regional surgeon educators and edited by content experts. Evaluation was performed by recording participation, soliciting user feedback, and evaluating scores on a certification examination. Conclusions: We present the systematic design of a large-scale, context-relevant, data-driven surgical curriculum for the ECSA region.

Increasing blood glucose variability heralds hypoglycemia in the critically ill.

BACKGROUND: Control of hyperglycemia improves outcomes, but increases the risk of hypoglycemia. Recent evidence suggests that blood glucose variability (BGV) is more closely associated with mortality than either isolated or mean BG. We hypothesized that differences in BGV over time are associated with hypoglycemia and can be utilized to estimate risk of hypoglycemia (<50 mg/dL). MATERIALS AND METHODS: Patients treated with intravenous insulin in the Surgical Intensive Care Unit of a tertiary care center formed the retrospective cohort. Exclusion criteria included death within 24 h of admission. We describe BGV in patients over time and its temporal relationship to hypoglycemic events. The risk of hypoglycemia for each BG measurement was estimated in a multivariable regression model. Predictors were measures of BGV, infusions of dextrose and vasopressors, patient demographics, illness severity, and BG measurements. RESULTS: A total of 66,592 BG measurements were collected on 1392 patients. Hypoglycemia occurred in 154 patients (11.1%). Patient BGV fluctuated over time, and increased in the 24 h preceding a hypoglycemic event. In crude and adjusted analyses, higher BGV was positively associated with a hypoglycemia (OR 1.41, P < 0.001). Previous hypoglycemic events and time since previous BG measurement were also positively associated with hypoglycemic events. Severity of illness, vasopressor use, and diabetes were not independently associated with hypoglycemia. CONCLUSIONS: BGV increases in the 24 h preceding hypoglycemia, and patients are at increased risk during periods of elevated BG variability. Prospective measurement of variability may identify periods of increased risk for hypoglycemia, and provide an opportunity to mitigate this risk.

Does Intentional Support of Degree Programs in General Surgery Residency Affect Research Productivity or Pursuit of Academic Surgery? A Multi-Institutional Study.

OBJECTIVE: To determine whether pursuit of an advanced degree during dedicated research time (DRT) in a general surgery residency training program impacts a resident's research productivity. DESIGN: A retrospective, multi-institutional cohort study. SETTING: General surgery residency programs that were approved to graduate more than 5 categorical residents per year and that offered at least 1 year of DRT were contacted for participation in the study. A total of 10 general surgery residency programs agreed to participate in the study. PARTICIPANTS: Residents who started their residency between 2000 and 2012 and spent at least one full year in DRT (n = 511) were included. Those who completed an advanced degree were compared on the following parameters to those who did not complete one: total number of papers, first-author papers, the Journal Citation Reports impact factors of publication (2018, or most recent), and first position after residency or fellowship training. RESULTS: During DRT, 87 (17%) residents obtained an advanced degree. The most common degree obtained was a Master of Public Health (MPH, n = 42 (48.8%)). Residents who did not obtain an advanced degree during DRT published fewer papers (median 8, [interquartile range 4-12]) than those who obtained a degree (9, [6-17]) (p = 0.002). They also published fewer first author papers (3, [2-6]) vs (5, [2-9]) (p = 0.002) than those who obtained a degree. Resident impact factor (RIF) was calculated using Journal Citation Reports impact factor and author position. Those who did not earn an advanced degree had a lower RIF (adjusted RIF, 84 ± 4 vs 134 ± 5, p < 0.001) compared to those who did. There was no association between obtaining a degree and pursuit of academic surgery (p = 0.13) CONCLUSIONS: Pursuit of an advanced degree during DRT is associated with increased research productivity but is not associated with pursuit of an academic career.

Metastatic Melanoma Patient-Derived Xenografts Respond to MDM2 Inhibition as a Single Agent or in Combination with BRAF/MEK Inhibition.

PURPOSE: Over 60% of patients with melanoma respond to immune checkpoint inhibitor (ICI) therapy, but many subsequently progress on these therapies. Second-line targeted therapy is based on BRAF mutation status, but no available agents are available for NRAS, NF1, CDKN2A, PTEN, and TP53 mutations. Over 70% of melanoma tumors have activation of the MAPK pathway due to BRAF or NRAS mutations, while loss or mutation of CDKN2A occurs in approximately 40% of melanomas, resulting in unregulated MDM2-mediated ubiquitination and degradation of p53. Here, we investigated the therapeutic efficacy of over-riding MDM2-mediated degradation of p53 in melanoma with an MDM2 inhibitor that interrupts MDM2 ubiquitination of p53, treating tumor-bearing mice with the MDM2 inhibitor alone or combined with MAPK-targeted therapy. EXPERIMENTAL DESIGN: To characterize the ability of the MDM2 antagonist, KRT-232, to inhibit tumor growth, we established patient-derived xenografts (PDX) from 15 patients with melanoma. Mice were treated with KRT-232 or a combination with BRAF and/or MEK inhibitors. Tumor growth, gene mutation status, as well as protein and protein-phosphoprotein changes, were analyzed. RESULTS: One-hundred percent of the 15 PDX tumors exhibited significant growth inhibition either in response to KRT-232 alone or in combination with BRAF and/or MEK inhibitors. Only BRAFV600WT tumors responded to KRT-232 treatment alone while BRAFV600E/M PDXs exhibited a synergistic response to the combination of KRT-232 and BRAF/MEK inhibitors. CONCLUSIONS: KRT-232 is an effective therapy for the treatment of either BRAFWT or PAN WT (BRAFWT, NRASWT) TP53WT melanomas. In combination with BRAF and/or MEK inhibitors, KRT-232 may be an effective treatment strategy for BRAFV600-mutant tumors.

Early Melanoma Nodal Positivity and Biopsy Rates Before and After Implementation of the 7th Edition of the AJCC Cancer Staging Manual.

Importance: There has been a continued increase in the incidence of newly diagnosed melanomas, most of which are T1 melanomas. The associations between changes in tumor staging, implemented with the 7th edition of the AJCC Cancer Staging Manual (AJCC 7), and sentinel lymph node biopsy rates and nodal positivity rates remain to be seen. Objective: To evaluate the change that the implementation of the AJCC 7 had on staging criteria and the distribution of thin melanomas requiring nodal surgery and nodal positivity rates. Design, Setting, and Participants: Retrospective cross-sectional study from 2004 through 2013 of all adults (≥18 years) diagnosed with a T1 (Breslow depth ≤1.0 mm) melanoma using The National Cancer Database that captures 70% of all newly diagnosed cancers from accredited Commission on Cancer organizations, including both academic and community settings. Data were analyzed in May 2017. Exposures: Patients were grouped together based on year of diagnosis, before and after 2009. Main Outcomes and Measures: To determine the sentinel lymph node biopsy rate before and after the implementation of the AJCC 7. Results: A total of 141 280 patients met inclusion criteria. Of 86 846 patients diagnosed from 2004 through 2009, 53.7% (49 644) were male and had a mean (SD) age of 57.7 (16.4) years. Of 54 434 patients diagnosed from 2010 through 2013, 54.3% (31 086) were male and had a mean (SD) age of 59.5 (15.9) years. After 2010, there was a 3.8% decrease in the number of nodal surgeries performed (32 485 of 86 846 patients [37.6%] vs 18 379 of 54 434 patients [33.8%]; P < .001). The nodal positivity rate decreased 1.0% from (9.8% [3166 of 86 846] to 8.8% [1618 of 54 434]) (P < .001). An increase in the proportion of T1b melanomas being evaluated, from 48.8% to 62.2%, was seen (P < .001). Of T1b melanomas that underwent nodal evaluation from 2004 through 2009, 74.0% had Clark level IV (invasion of the reticular dermis) or Clark level V (invasion of the deep, subcutaneous tissue) and 9.5% were ulcerated. From 2010 through 2013, of the T1b melanomas undergoing nodal evaluation, 82.6% had an elevated mitotic rate only, 3.7% were ulcerated, and 13.7% had both ulceration and an elevated mitotic rate. Conclusions and Relevance: It appears that after the institution of AJCC 7, there was an overall decrease in the number of T1 melanomas undergoing nodal biopsy without a clinically relevant change in sentinel lymph node positivity, with an increase in the number of T1b melanomas undergoing nodal evaluation.

MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21.

Intrinsic resistance of unknown mechanism impedes the clinical utility of inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) in malignancies other than breast cancer. Here, we used melanoma patient-derived xenografts (PDXs) to study the mechanisms for CDK4/6i resistance in preclinical settings. We observed that melanoma PDXs resistant to CDK4/6i frequently displayed activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, and inhibition of this pathway improved CDK4/6i response in a p21-dependent manner. We showed that a target of p21, CDK2, was necessary for proliferation in CDK4/6i-treated cells. Upon treatment with CDK4/6i, melanoma cells up-regulated cyclin D1, which sequestered p21 and another CDK inhibitor, p27, leaving a shortage of p21 and p27 available to bind and inhibit CDK2. Therefore, we tested whether induction of p21 in resistant melanoma cells would render them responsive to CDK4/6i. Because p21 is transcriptionally driven by p53, we coadministered CDK4/6i with a murine double minute (MDM2) antagonist to stabilize p53, allowing p21 accumulation. This resulted in improved antitumor activity in PDXs and in murine melanoma. Furthermore, coadministration of CDK4/6 and MDM2 antagonists with standard of care therapy caused tumor regression. Notably, the molecular features associated with response to CDK4/6 and MDM2 inhibitors in PDXs were recapitulated by an ex vivo organotypic slice culture assay, which could potentially be adopted in the clinic for patient stratification. Our findings provide a rationale for cotargeting CDK4/6 and MDM2 in melanoma.

Resection for anal melanoma: Is there an optimal approach?

BACKGROUND: Anal melanoma is a lethal disease, but its rarity makes understanding the behavior and effects of intervention challenging. Local resection and abdominal perineal resection are the proposed treatments for nonmetastatic disease. We hypothesize that there is no difference in overall survival between surgical therapies. METHODS: The National Cancer Database (2004-2014) was queried for adults with a diagnosis of anal melanoma who underwent curative resection. Patients with metastatic disease were excluded. Patients were divided into 2 groups based on surgical approach (local resection versus abdominal perineal resection). Unadjusted and adjusted analyses were used to examine the association between surgical approach and R0 resection rate, short-term survival, and overall survival. RESULTS: A total of 570 patients with anal melanoma who underwent resection were identified. The median age was 68 and 59% of patients were female. A total of 383 (67%) underwent local resection. Abdominal perineal resection was associated with higher rates of R0 resection rates (abdominal perineal resection 91% versus local resection 73%; P < .001). Overall 5-year survival for the entire cohort was 20%. There was no significant difference in 5-year overall survival (abdominal perineal resection 21% vs local resection 17%; P = .31). This persisted in a Cox proportional hazard multivariable model (odds ratio 0.84; 95% confidence interval 0.66-1.06; P = .15). Additionally, there was no improvement in overall survival for patients who underwent R0 resection (odds ratio 1.18; 95% confidence interval 0.90-1.56; P = .22). CONCLUSION: Anal melanoma has a very poor prognosis, with only 1 of 5 patients alive at 5 years. Although local resection was associated with lower rates of R0 resection, there was no discernable difference in overall survival in both unadjusted and adjusted analysis.