Laparoscopic surgery for adrenocortical carcinoma: Estimating the risk of margin-positive resection.

BACKGROUND: Over recent years, there has been increasing adoption of minimally invasive surgery (MIS) in the treatment of adrenocortical carcinoma (ACC). However, MIS has been associated with noncurative resection and locoregional recurrence. We aimed to identify risk factors for margin-positivity among patients who undergo MIS resection for ACC. We hypothesized that a simple nomogram can accurately identify patients most suitable for curative MIS resection. METHODS: Curative-intent resections for ACC were identified through the National Cancer Database spanning 2010-2018. Trends in MIS utilization were reported using Pearson correlation coefficients. Factors associated with margin-positive resection were identified among preoperatively available variables using multivariable logistic regression, then incorporated into a predictive model. Model quality was cross validated using an 80% training data set and 20% test data set. RESULTS: Among 1260 ACC cases, 38.6% (486) underwent MIS resection. MIS utilization increased over time at nonacademic centers (R = 0.818, p = 0.007), but not at academic centers (R = 0.009, p = 0.982). Factors associated with margin-positive MIS resection were increasing age, nonacademic center (odds ratio [OR]: 1.8, p = 0.006), cT3 (OR: 4.7, p < 0.001) or cT4 tumors (OR: 14.6, p < 0.001), and right-sided tumors (OR: 2.0, p = 0.006). A predictive model incorporating these four factors produced favorable c-statistics of 0.75 in the training data set and 0.72 in the test data set. A pragmatic nomogram was created to enable bedside risk stratification. CONCLUSIONS: An increasing proportion of ACC are resected via minimally invasive operations, particularly at nonacademic centers. Patient selection based on a few key factors can minimize the risk of noncurative surgery.

Regional control after precision lymph node dissection for clinically evident melanoma metastasis.

INTRODUCTION: Completion lymph node dissection (CLND) for microscopic lymph node metastases has been replaced by observation; however, CLND is standard for clinically detectable nodal metastases (cLN). CLND has high morbidity, which may be reduced by excision of only the cLN (precision lymph node dissection [PLND]). We hypothesized that same-basin recurrence risk would be low after PLND. METHODS: Retrospective review at four tertiary care hospitals identified patients who underwent PLND. The primary outcome was 3-year cumulative incidence of isolated same-basin recurrence. RESULTS: Twenty-one patients underwent PLND for cLN without synchronous distant metastases. Reasons for forgoing CLND included patient preference (n = 11), comorbidities (n = 5), imaging indeterminate for distant metastases (n = 2), partial response to checkpoint blockade (n = 1), or not reported (n = 2). A median of 2 nodes (range: 1-6) were resected at PLND, and 68% contained melanoma. Recurrence was observed in 33% overall. Only 1 patient (5%) developed an isolated same-basin recurrence. Cumulative incidences at 3 years were 5.0%, 17.3%, and 49.7% for isolated same-basin recurrence, any same-basin recurrence, and any recurrence, respectively. Complications from PLND were reported in 1 patient (5%). CONCLUSIONS: These pilot data suggest that PLND may provide adequate regional disease control with less morbidity than CLND. These data justify prospective evaluation of PLND in select patients.

Eliciting Low-Risk Thyroid Cancer Treatment Preferences Using Clinical Vignettes: A Pilot Study.

OBJECTIVE: While surgical resection has been the traditional standard treatment for small (≤1 cm), differentiated thyroid cancers, active surveillance (AS) and radiofrequency ablation (RFA) are increasingly considered. The aim of this study was to explore patient preferences in thyroid cancer treatment using a series of clinical vignettes. METHODS: Thyroid cancer survivors and general population volunteers were recruited to rank experience-driven clinical vignettes in order of preference. Rankings were compared using Wilcoxon signed rank. Formative qualitative methods were used to develop and refine clinical vignettes that captured 4 treatments-thyroid lobectomy (TL), total thyroidectomy (TT), AS, and RFA-along with 6 treatment complications. Content was validated via interviews with 5 academic subspecialists. RESULTS: Nineteen volunteers participated (10 survivors, 9 general population). Treatment complications were ranked lower than uncomplicated counterparts in 99.0% of cases, indicating excellent comprehension. Counter to our hypothesis, among uncomplicated vignettes, median rankings were 1 for AS, 2 for RFA, 3.5 for TL, and 5 for TT. Trends were consistent between thyroid cancer survivors and the general population. AS was significantly preferred over RFA (P = .02) and TT (P < .01). Among surgical options, TL was significantly preferred over TT (P < .01). CONCLUSION: When treatments for low-risk thyroid cancer are described clearly and accurately through clinical vignettes, patients may be more likely to choose less invasive treatment options over traditional surgical resection.

Low-Risk Papillary Thyroid Cancer: Treatment De-Escalation and Cost Implications.

INTRODUCTION: The American Thyroid Association (ATA) updated consensus guidelines in 2015 for radioactive iodine (RAI) and resection for low-risk papillary thyroid cancer. The objective of this study was to describe the evolution of institutional practice patterns and estimate the cost implications of these trends. MATERIALS AND METHODS: Patients with cT1-T2N0 papillary thyroid cancer were identified via an institutional tumor registry. Incidences of total thyroidectomy or RAI were tracked longitudinally using cumulative sum. Real-world costs for RAI and each surgical encounter were adjusted for inflation and standardized to national average costs from National Inpatient Sample cost data. RESULTS: Sixty-one patients met inclusion criteria between 2007 and 2018. Among these, 28 patients underwent total thyroidectomies and received RAI treatments based on criteria pre-dating the 2015 ATA guidelines. Cumulative sum revealed significant decreases in the rate of total thyroidectomy following May 2015 (15.8% versus 59.5%, P = 0.002) and RAI following March 2013 (3.0% versus 32.1%, P = 0.002). There were no locoregional recurrences in either period. The average cost savings attributable to these institutional practice changes was $1580 per patient. CONCLUSIONS: De-escalation in surgical and RAI utilization for low-risk papillary thyroid cancer according to 2015 ATA guidelines is associated with a substantial decrease in real-world costs.

Enhanced Recovery After Major Gastrectomy for Cancer.

Enhanced recovery after surgery (ERAS) protocols have gained increasing popularity over the past 10 years, and its overarching objectives are to improve perioperative morbidity and reduce postoperative length of stay. Consensus guidelines from the ERAS Society specific to major gastrectomy were published in 2014, however since that time, prospective and retrospective studies have expanded the collective evidence for both the content and efficacy of ERAS pathways for gastrectomy. This objective of this review was to summarize recent data pertinent to the preoperative, perioperative, and postoperative management of gastrectomy patients along an ERAS pathway.

Longitudinal Analysis of Quality-of-Life Recovery After Gastrectomy for Cancer.

OBJECTIVE: The purpose of this study was to identify factors associated with quality-of-life recovery after gastrectomy. METHODS: Patients anticipated to undergo gastric cancer resection were invited to complete the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and STO22 surveys in the preoperative setting and at 0-1.5 months (early), > 1.5-6 months (intermediate), and > 6-18 months (late) following resection. Quality-of-life recovery was measured as paired differences between pre- and postoperative results. Multivariable linear regression identified factors associated with preoperative quality of life and degree of change following resection. RESULTS: Across 393 participants, response rates at the intermediate and late postoperative time points were 58% (n = 228) and 71% (n = 277), respectively. Relative to baseline, median global health scale decreased in the early (- 15.1 pts, p < 0.001) and intermediate (- 3.6 pts, p = 0.02) time points, but recovered by the late time point (+ 1.2 pts, p = 0.411). Relative to distal/subtotal gastrectomy, proximal/total gastrectomy was associated with worse recovery in both the early and late time points. Surgical complications were associated with worse early recovery. Patients who presented with locally advanced tumors (T3-T4) had lower preoperative quality-of-life scores, and more readily recovered to baseline after surgery. A minimally invasive approach was not associated with postoperative recovery. CONCLUSIONS: Most patients recover to baseline within 1 year following major gastrectomy, and recovery is easier with more limited resections. Patients with locally advanced tumors tend to have poorer baseline quality of life, which may improve following resection.

Sentinel Lymph Node Biopsy for T1b Melanoma: Balancing Prognostic Value and Cost.

BACKGROUND: The purpose of this study is to report the additional prognostic information and cost associated with sentinel lymph node biopsy (SLNB) for patients with T1b melanoma. PATIENTS AND METHODS: An institutional database was queried for patients with T1b melanoma (0.8-1.0 mm or < 0.8 mm with ulceration) with at least 5 years of follow-up. Results of SLNB, completion lymphadenectomy (CLND), recurrence, and melanoma-specific survival (MSS) were assessed. Institutional costs of melanoma care were converted to Medicare proportional dollars. A Markov model was created to estimate long-term costs. RESULTS: Among the total 392 patients, 238 underwent SLNB. Median follow-up was 10.5 years. SLNB was positive in 19 patients (8.0%). Patients who underwent SLNB had higher 10-year nodal recurrence-free survival (98.6% vs. 91.2%, p < 0.001) but not MSS (94.4% vs. 93.2%, p = 0.55). Ulceration (HR 4.7, p = 0.022) and positive sentinel node (HR 11.5, p < 0.001) were associated with worse MSS. Estimates for 5-year costs reflect a fourfold increase in total costs of care associated with SLNB. However, a treatment plan that forgoes adjuvant therapy for resected stage IIIA melanoma but offers systemic therapy for a node-basin recurrence would nullify the additional cost of SLNB. CONCLUSIONS: SLNB is prognostic for T1b melanoma. Its impact on the overall cost of melanoma care is intimately tied to systemic therapy in the adjuvant and recurrent settings.

Quality of Life After Curative Resection for Gastric Cancer: Survey Metrics and Implications of Surgical Technique.

Gastric cancer is one of the most common cancers worldwide, and radical gastrectomy is an integral component of curative therapy. With improvements in perioperative morbidity and mortality, attention has turned to short- and long-term post-gastrectomy quality of life (QoL). This article reviews the common psychometric surveys and preference-based measures used among patients following gastrectomy. It also provides an overview of studies that address associations between surgical decision-making and postoperative health-related QoL. Further attention is focused on reported associations between technical aspects of the operation, such as extent of gastric resection, minimally-invasive approach, pouch-based conduits, enteric reconstruction, and postoperative QoL. While there are several randomized studies that include QoL outcomes, much remains to be explored. The relationship between symptom profiles and preference-based measures of health state utility is an area in need of further research.

Close to the Bedside: A Systematic Review of Endogenous Retroviruses and Their Impact in Oncology.

BACKGROUND: Human endogenous retroviruses (HERVs) are genetic elements in the human genome, which resulted from ancient retroviral germline infections. HERVs have strong transcriptional promoters and enhancers that affect a cell's transcriptome. They also encode proteins that can exert effects in human cells. This review examines how our increased understanding of HERVs have led to their potential use as biomarkers and immunologic targets. MATERIAL AND METHODS: PubMed/Medline, Embase, Web of Science, and Cochrane databases were used in a systematic search to identify all articles studying the potential impact of HERVs on surgical diseases. The search included studies that involved clinical patient samples in diseases including cancer, inflammatory conditions, and autoimmune disease. Articles focused on conditions not routinely managed by surgeons were excluded. RESULTS: Eighty six articles met inclusion and quality criteria for this review and were included. Breast cancer and melanoma have robust evidence regarding the use of HERVs as potential tumor markers and immunologic targets. Reported evidence of the activity of HERVs in colorectal cancer, pancreatic cancer, hepatocellular cancer, prostate and ovarian cancer, germ cell tumors as well as idiopathic pulmonary hypertension, and the inflammatory response in burns was also reviewed. CONCLUSIONS: Increasingly convincing evidence indicates that HERVs may play a role in solid organ malignancy and present important biomarkers or immunologic targets in multiple cancers. Innovative investigation of HERVs is a valuable focus of translational research and can deepen our understanding of cellular physiology and the effects of endogenous retroviruses on human biology. As strategies for treatment continue to focus on genome-based interventions, understanding the impact of endogenous retroviruses on human disease will be critical.

Heterogeneity of CD8+ tumor-infiltrating lymphocytes in non-small-cell lung cancer: impact on patient prognostic assessments and comparison of quantification by different sampling strategies.

INTRODUCTION: Infiltration of non-small-cell lung cancer (NSCLC) by CD8+ T lymphocytes predicts improved patient survival; however, heterogeneity of intratumoral localization complicates this assessment. Strategies for tumor sampling may not accurately represent the whole tumor. We hypothesized that sampling strategies may alter the identification of tumors with high CD8 density and affect the prognostic significance. PATIENTS AND METHODS: Twenty-three primary NSCLC tumors were immunohistochemically stained for CD8 and were assessed using automated software with eight different sampling strategies or the whole tumor. Results of all sampling strategies were compared to the whole tumor counts (paired t tests, Pearson's r). Associations between CD8 densities and overall survival were assessed (log-rank test). RESULTS: Counts from all eight sampling strategies significantly correlated with whole tumor counts (p ≤ 0.001). However, the magnitude of CD8+ cell counts and categorization into high vs low infiltrate groups were affected by the sampling strategy. The most concordant values were derived from random sampling of 20 % of the tumor, a simulated core biopsy, or from sampling the tumor center. TIL infiltration was associated with survival when sampling the center (p = 0.038), but not the invasive margin (p > 0.2) or other strategies. CONCLUSION: Different tumor sampling strategies may yield discordant TIL density results and different stratification for risk assessment. Small biopsies may be particularly unrepresentative. Random sampling of larger tumor areas is recommended. Enumerating CD8+ T cells in the tumor center may have prognostic value.

Sentinel Lymph Node Biopsy for Recurrent Melanoma: A Multicenter Study.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is routinely performed for primary cutaneous melanomas; however, limited data exist for SLNB after locally recurrent (LR) or in-transit (IT) melanoma. METHODS: Data from three centers performing SLNB for LR/IT melanoma (1997 to the present) were reviewed, with the aim of assessing (1) success rate; (2) SLNB positivity; and (3) prognostic value of SLNB in this population. RESULTS: The study cohort included 107 patients. Management of the primary melanoma included prior SLNB for 56 patients (52%), of whom 10 (18%) were positive and 12 had complete lymph node dissections (CLNDs). In the present study, SLNB was performed for IT disease (48/107, 45%) or LR melanoma (59/107, 55%). A sentinel lymph node (SLN) was removed in 96% (103/107) of cases. Nodes were not removed for four patients due to lymphoscintigraphy failures (2) or nodes not found during surgery (2). SLNB was positive in 41 patients (40%, 95% confidence interval (CI) 31.5-50.5), of whom 35 (88%) had CLND, with 13 (37%) having positive nonsentinel nodes. Median time to disease progression after LR/IT metastasis was 1.4 years (95% CI 0.75-2.0) for patients with a positive SLNB, and 5.9 years (95% CI 1.7-10.2) in SLNB-negative patients (p = 0.18). There was a trend towards improved overall survival for patients with a negative SLNB (p = 0.06). CONCLUSION: SLNB can be successful in patients with LR/IT melanoma, even if prior SLNB was performed. In this population, the rates of SLNB positivity and nonsentinel node metastases were 40% and 37%, respectively. SLNB may guide management and prognosis after LR/IT disease.

Localization of the Sentinel Lymph Node in Melanoma Without Blue Dye.

OBJECTIVE: The purpose of this study was to assess regional recurrence rates of patients who underwent sentinel lymph node biopsy (SLNB) using radiocolloid guidance alone. BACKGROUND: Isosulfan blue dye is commonly used along with Tc99-labeled radiocolloid localization in SLNB for melanoma. Blue dye has, however, been associated with allergic reactions, long-term staining of skin, and increased cost. We hypothesized that the rate of regional recurrence when SLNB is performed with radiocolloid alone would be comparable to established reports using both radiocolloid and blue dye. METHODS: A prospectively collected database was retrospectively queried for patients who underwent SLNB for melanoma during the years 2005 through 2008. Data collected included patient demographics, primary lesion characteristics, operative details, and recurrence. The primary outcome was the rate of recurrence within the biopsied basin after negative SLNB's performed without isosulfan blue dye. RESULTS: In 215 patients, 279 nodal basins were identified. All patients underwent successful radiocolloid localization, and positive sentinel nodes were found in 40 patients (18.6%). Six of 175 patients with a negative SLNB developed a regional node recurrence as the first site of metastasis (3.4%). Among all 215 patients, 44 experienced recurrence of any kind (20.5%). Higher mitotic rate and Breslow depth were significantly associated with likelihood of recurrence. CONCLUSIONS: Success rates, node positivity rates, and rates of regional recurrence after SLNB for melanoma using radiocolloid alone are acceptable and similar to those of prior reports using blue dye plus radiocolloid.

Comparative Effectiveness of Esophagectomy Versus Endoscopic Treatment for Esophageal High-grade Dysplasia.

OBJECTIVE: The purpose of this study is to determine the comparative effectiveness of esophagectomy versus endoscopic mucosal resection followed by radiofrequency ablation (EMR-RFA) for the treatment of Barrett esophagus with high-grade dysplasia (HGD). BACKGROUND: HGD of the esophagus may be managed by surgical resection or EMR-RFA. National guidelines suggest that EMR-RFA is effective at eradicating HGD. The comparative effectiveness and cost-effectiveness of EMR-RFA versus esophagectomy for HGD remains unclear. METHODS: A decision-analysis model was constructed to represent 3 management strategies for HGD: (1) esophagectomy, (2) EMR-RFA, and (3) endoscopic surveillance. Estimates for model variables were obtained from literature review, and costs were estimated from Medicare fee schedules. Costs and utilities were discounted at an annual rate of 3%. The baseline model was adjusted for alternative age groups and high-risk dysplastic variants. One-way and multivariable probabilistic sensitivity analyses were conducted. RESULTS: For a 65-year-old patient, compared to esophagectomy, EMR-RFA yields equivalent utility (11.5 vs 11.4 discounted quality-adjusted life years) with lower total cost ($52.5K vs $74.3K) over the first 20 years. Dominance of EMR-RFA over esophagectomy persists for all age groups. Patients with diffuse or ulcerated HGD are more effectively treated with esophagectomy. Model outcomes are sensitive to estimated rates of disease progression and postintervention utility parameters. CONCLUSIONS: Existing evidence supports EMR-RFA over esophagectomy for the treatment of esophageal HGD. Long-term outcomes and more definitive quality-of-life studies for both interventions are crucial to better inform decision-making.

Relationships between preclinical course grades and standardized exam performance.

Success in residency matching is largely contingent upon standardized exam scores. Identifying predictors of standardized exam performance could promote primary intervention and lead to design insights for preclinical courses. We hypothesized that clinically relevant courses with an emphasis on higher-order cognitive understanding are most strongly associated with performance on United States Medical Licensing Examination Step exams and National Board of Medical Examiners clinical subject exams. Academic data from students between 2007 and 2012 were collected. Preclinical course scores and standardized exam scores were used for statistical modeling with multiple linear regression. Preclinical courses were categorized as having either a basic science or a clinical knowledge focus. Medical College Admissions Test scores were included as an additional predictive variable. The study sample comprised 795 graduating medical students. Median score on Step 1 was 234 (interquartile range 219-245.5), and 10.2 % (81/795) scored lower than one standard deviation below the national average (205). Pathology course score was the strongest predictor of performance on all clinical subject exams and Step exams, outperforming the Medical College Admissions Test in strength of association. Using Pathology score <75 as a screening metric for Step 1 score <205 results in sensitivity and specificity of 37 and 97 %, respectively, and a likelihood ratio of 11.9. Performance in Pathology, a clinically relevant course with case-based learning, is significantly related to subsequent performance on standardized exams. Multiple linear regression is useful for identifying courses that have potential as risk stratifiers.

Long-term outcomes of helper peptide vaccination for metastatic melanoma.

OBJECTIVE: The objective of this study was to compare the long-term outcome of patients with metastatic melanoma vaccinated with 6MHP to that of a group of unvaccinated historical controls. BACKGROUND: A multipeptide vaccine (6MHP), designed to induce helper T cells against melanocytic and cancer-testis antigens, has been shown to induce specific Th1-dominant CD4+ T cell responses. METHODS: The 6MHP vaccine was administered to patients with metastatic melanoma. Circulating CD4+ T cell responses were measured by proliferation or direct IFN-gamma ELIspot assay. Overall survival of vaccinated patients was compared to a group of clinically comparable historical controls using multivariable Cox regression analysis and Kaplan-Meier survival analysis, taking into account age, metastatic site, and resection status. RESULTS: Across 40 vaccinated patients and 87 controls, resection status (HR 0.54, P = 0.004) and vaccination (HR 0.24, P < 0.001) were associated with improved overall survival. Forty pairs of vaccinated patients and controls were matched by metastatic site, resection status, and age within 10 years. Median survival was significantly longer for vaccinated patients (5.4 vs 1.3 years, P < 0.001). Among the vaccinated patients, the development of a specific immune response after vaccination was associated with improved survival (HR 0.35, P = 0.040). CONCLUSIONS: Helper peptide vaccination is associated with improved overall survival among patients with metastatic melanoma. These data support a randomized prospective trial of the 6MHP vaccine.

Defining the effects of age and gender on immune response and outcomes to melanoma vaccination: a retrospective analysis of a single-institution clinical trials' experience.

BACKGROUND: The impacts of patient age and gender on immune response (IR) and clinical outcome after cancer vaccines are not known. We hypothesized younger and female patients would have higher IR rates and better survival. METHODS: Patients with resected stage IIB-IV melanoma in three clinical trials (Mel43, Mel44, Mel48) were vaccinated with 12 melanoma-associated peptides restricted by class I MHC. The cumulative incidence rate of CD8(+) T cell responses (direct interferon-gamma ELIspot assay) by week 7 was compared by age and gender. Overall survival (OS) and disease-free survival (DFS) landmark analyses were compared by Kaplan-Meier estimates and in multivariate analyses. RESULTS: T cell responses were evaluated in 327 patients and detected in 50 % of males and 48 % of females, with no difference in IR by gender or menopausal status. Males had trends toward longer DFS (p = 0.12) and OS (p = 0.09). Cumulative incidence of IR was higher in patients <64 years of age versus older patients (p = 0.03). OS and DFS were similar by age group (p > 0.50). In multivariate modeling, younger age was associated with better IR (OR 0.40, p value 0.003), without an impact of age or gender on clinical outcomes. CONCLUSION: These data support the hypothesis that older patients are less likely to develop T cell responses to a cancer vaccine. Nonetheless, significant proportions of older patients mount immune responses with comparable survival outcomes. Thus, these data support including older patients in cancer vaccine trials, but suggest value in stratifying patients by age 64 years.

Assistant instructors facilitate simulation for medical students.

BACKGROUND: A procedural training protocol for medical students must be cognizant of faculty opportunity costs, which may preclude individually supervised practice. Meanwhile, sporadic exposure in large group settings yields suboptimal proficiency. The purpose of this study is to assess the effectiveness of undergraduate assistant instructors in providing one-on-one simulation-based instruction for basic invasive techniques. MATERIALS AND METHODS: Investigators designed proficiency-based checklists by faculty consensus for three simulation tasks as follows: orotracheal intubation, central venous catheterization, and suturing. Four undergraduate students were trained as instructors. Interrater agreement between instructors using the task checklists ranged from 0.754-0.866. Instructors conducted up to seven flexibly scheduled, one-on-one practice sessions with clinically inexperienced medical student participants. Sessions comprised repetitive task attempts with an evaluation after every attempt. On completion of the training protocol, participants underwent evaluation by an experienced surgeon blinded to practice session performance. Study participants were surveyed to assess satisfaction. RESULTS: Twenty-nine participants completed the study. Median total practice time was 8.75 h (interquartile range 7.12-8.75). Posttest pass rates were 93% (26/28), 71% (20/28), and 68% (19/28) for suturing, intubation, and central venous catheterization, respectively. Ninety-seven percent (27/28) of participants were satisfied with their experience, and 62% (18/29) advocated for protocol adoption into the standard preclinical curriculum. Estimated cost saved using student instructors, based on departmental collections for surgical faculty, was $43,760. CONCLUSIONS: Clinically inexperienced assistants may be trained as instructors for basic simulation tasks with excellent interrater reliability. Deploying these assistant instructors makes effective, one-on-one technical training for preclinical medical students financially feasible.