Roger H. Kim

Estradiol Induces Export of Sphingosine 1-Phosphate from Breast Cancer Cells via ABCC1 and ABCG2

Sphingosine 1-phosphate (S1P), a potent sphingolipid mediator produced by sphingosine kinase isoenzymes (SphK1 and SphK2), regulates diverse cellular processes important for breast cancer progression acting in an autocrine and/or paracrine manner. Here we show that SphK1, but not SphK2, increased S1P export from MCF-7 cells. Whereas for both estradiol (E2) and epidermal growth factor-activated SphK1 and production of S1P, only E2 stimulated rapid release of S1P and dihydro-S1P from MCF-7 cells. E2-induced S1P and dihydro-S1P export required estrogen receptor-α, not GPR30, and was suppressed either by pharmacological inhibitors or gene silencing of ABCC1 (multidrug resistant protein 1) or ABCG2 (breast cancer resistance protein). Inhibiting these transporters also blocked E2-induced activation of ERK1/2, indicating that E2 activates ERK via downstream signaling of S1P. Taken together, our findings suggest that E2-induced export of S1P mediated by ABCC1 and ABCG2 transporters and consequent activation of S1P receptors may contribute to nongenomic signaling of E2 important for breast cancer pathophysiology.

Export and functions of sphingosine-1-phosphate

The sphingolipid metabolite, sphingosine-1-phosphate (S1P), has emerged as a critical player in a number of fundamental biological processes and is important in cancer, angiogenesis, wound healing, cardiovascular function, atherosclerosis, immunity and asthma, among others. Activation of sphingosine kinases, enzymes that catalyze the phosphorylation of sphingosine to S1P, by a variety of agonists, including growth factors, cytokines, hormones, and antigen, increases intracellular S1P. Many of the biological effects of S1P are mediated by its binding to five specific G protein-coupled receptors located on the cell surface in an autocrine and/or paracrine manner. Therefore, understanding the mechanism by which intracellularly generated S1P is released out of cells is both interesting and important. In this review, we will discuss how S1P is formed and released. We will focus particularly on the current knowledge of how the S1P gradient between tissues and blood is maintained, and the role of ABC transporters in S1P release.

Methods of esophagogastric anastomoses following esophagectomy for cancer: A systematic review

Anastomotic complications are responsible for significant morbidity and mortality following esophagectomy for cancer. Conflicting reports exist regarding the superiority of hand‐sewn versus stapled techniques. This systematic review identified eight randomized clinical trials examining this issue. None of the studies reported significant differences in leak rate or early mortality. One study demonstrated a difference in stricture rates, with fewer for hand‐sewn anastomoses. There is insufficient evidence to recommend one anastomotic technique over the other. J. Surg. Oncol. 2010; 101:527–533.

Chemokine receptor CXCR4 level in primary tumors independently predicts outcome for patients with locally advanced breast cancer

BACKGROUND Chemokine receptor CXCR4 is a marker of metastatic disease. We found initially that CXCR4 level is a predictive marker for patients with locally advanced breast cancer (LABC). We now confirm our initial observations. METHODS We evaluated 77 LABC patients who had neoadjuvant therapy. Specimens were taken at the time of definitive operation. CXCR4 levels were detected with Western blots. CXCR4 expression >6.6-fold over known concentration of HeLa cells was defined as high. Primary endpoints were cancer recurrence and death. Statistical analyses were Kaplan-Meier curves, log-rank test, and Cox proportional hazard model. RESULTS Median follow-up time was 42 months; 55 patients (71%) had low CXCR4 level. The 5-year overall survival for the low and high CXCR4 group was 78% and 50%, respectively (P = .015). The 5-year disease-free survival (DFS) for the low and high CXCR4 group was 67% and 41%, respectively (P = .024). On multivariate analysis, CXCR4 overexpression (P = .003) and nodal status (P = .044) were independent predictors of overall survival; CXCR4 overexpression (P = .003) and nodal status (P = .026) were also independent predictors of DFS. CONCLUSION We confirmed that high CXCR4 levels in cancer specimens after neoadjuvant therapy independently predict a poor outcome for patients with LABC.

The Effect of Surgical Resident Learning Style Preferences on American Board of Surgery In-Training Examination Scores

BACKGROUND There is a growing body of literature that suggests that learners assimilate information differently, depending on their preferred learning style. The VARK model categorizes learners as visual (V), aural (A), read/write (R), kinesthetic (K), or multimodal (MM). We hypothesized that resident VARK learning style preferences and American Board of Surgery In-Training Examination (ABSITE) performance are associated. METHODS The Fleming VARK learning styles inventory was administered to all general surgery residents at a university hospital-based program each year to determine their preferred learning style. Resident scores from the 2012 and 2013 ABSITE were examined to identify any correlation with learning style preferences. RESULTS Over a 2-year period, residents completed 53 VARK inventory assessments. Most (51%) had a multimodal preference. Dominant aural and read/write learners had the lowest and highest mean ABSITE scores, respectively (p = 0.03). CONCLUSION Residents with dominant read/write learning preferences perform better on the ABSITE than their peers did, whereas residents with dominant aural learning preferences underperform on the ABSITE. This may reflect an inherent and inadvertent bias of the examination against residents who prefer to learn via aural modalities.

Overexpression of Eukaryotic Initiation Factor 4E Is Correlated with Increased Risk for Systemic Dissemination in Node-Positive Breast Cancer Patients

BACKGROUND Molecular events impact systemic dissemination. Overexpression of eukaryotic initiation factor 4E (eIF4E) has been shown to predict worse clinical outcomes in breast cancer. Node-positive breast cancer patients were specifically studied to determine if eIF4E elevation increases risk for systemic dissemination. STUDY DESIGN Two hundred two node-positive breast cancer patients were prospectively accrued and treated with standardized treatment and surveillance protocol. Tumor eIF4E protein level was quantified by Western blots as x-fold over benign samples from noncancer patients. Primary end point was systemic metastasis. RESULTS Systemic recurrence was detected in 22.2% of the low eIF4E group, 27.3% of the intermediate group, and 49% of the high group, at a median follow-up of 47 months. A greater risk for systemic metastasis was seen in the high eIF4E group compared with the low group (log-rank test, p = 0.0084). Patients in the high eIF4E group had a 1.5-fold (hazard ratio = 1.52; 95% CI, 1.07-2.17; p = 0.0206) higher risk for systemic metastasis than the low group. Sixty percent of the patients with high eIF4E were observed to have metastasis to multiple sites, compared with 50% in the intermediate group, and 14.5% in the low group (p = 0.02, Fishers exact test). When patients were segregated based on nodal classification (N1, N2, and N3), eIF4E overexpression continued to be a predictor for systemic dissemination in patients with N1 disease. CONCLUSIONS High eIF4E is correlated with an increased risk for systemic metastasis in node-positive breast cancer patients. High eIF4E overexpression was associated with a higher incidence of metastasis to multiple sites. Therefore, high eIF4E overexpression appears to be a marker for molecular events that increases risk for systemic dissemination.

Should a Routine Metastatic Workup Be Performed for all Patients with Pathologic N2/N3 Breast Cancer?

BACKGROUND Node-positive breast cancer patients are at risk for metastatic disease. A routine metastatic workup might or might not be necessary for all patients with N2 or N3 diseases. The National Comprehensive Cancer Network guidelines recommend a metastatic workup for patients with T3N1 disease, yet no definitive recommendations are made for N2/N3 diseases. We hypothesized that for patients with operable pathologic N2/N3 diseases, a metastatic workup should only be considered for patients with T3/T4 lesions. STUDY DESIGN Two hundred and fifty-six patients with pathologic N2/N3 diseases were identified from a prospective breast cancer database of 1,329 patients with stage 0 to III breast cancer. A metastatic workup included chest x-rays, bone scans, CT scans, and PET scans. Primary end point was incidence of stage IV disease at the time of diagnosis or within 1 month of definitive surgery. Statistical analysis included chi-square test, independent t-test, Kaplan-Meier Survival method, log-rank test, and Cox proportional hazard model. A p value ≤ 0.05 was considered statistically significant. RESULTS There were 158 patients with N2 disease (62%) and 98 with N3 disease (38%). Overall, 16% had stage IV disease (N2 = 15%, N3 = 16%). There was no significant difference in age (p = 0.37), tumor size (p = 0.89), tumor grade (p = 0.09), estrogen-receptor status (p = 0.23), or progesterone-receptor status (p = 0.35) between the N2 and N3 groups. Incidences of stage IV disease were T0/T1, 0%; T2, 6%; T3, 22%; and T4, 36%. Multivariate analysis demonstrated that only T stage (p = 0.0006) and grade (p = 0.026) were independent predictors of overall survival. CONCLUSIONS A metastatic workup is only indicated for N2/N3 patients with T3 or T4 primary lesions.

Outcomes of a hybrid technique for video-assisted thoracoscopic surgery (VATS) pulmonary resection in a community setting

BACKGROUND Video-assisted thoracoscopic surgery (VATS) for pulmonary resection was first described 18 years ago; however, it has yet to gain widespread acceptance in community hospitals in the United States. The majority of surgeons who routinely perform VATS resections work in academic or government institutions. There is little data reporting outcomes of VATS pulmonary resections by community-based surgeons. This article reports the outcomes of a hybrid technique for VATS pulmonary resection in a single-surgeon, community-based practice. METHODS A retrospective study was performed on all VATS pulmonary resections performed from January 2000 to March 2008 by a community-based, solo-practice surgeon using a hybrid VATS technique, which utilizes dual access through a thoracoscopy port and a utility incision. RESULTS A total of 1170 VATS pulmonary resections were performed over the study period, which is the largest single-surgeon series on VATS pulmonary resection to our knowledge. Among them, 746 cases were for malignant disease. Mean operative time was 52 minutes (median 48 minutes). Mean length of stay was 7 days (median 4 days). Mean length of ICU stay was 1.4 days, with 83% of patients having no days spent in the ICU. Mean length of chest tube duration was 4.5 days. The morbidity rate was 21.1 %, with neuropraxia as the most frequent complication. Perioperative mortality was 4.3% and overall mortality was 16.4%, with a mean follow-up of 425 days. CONCLUSIONS This series shows that our hybrid VATS approach to pulmonary resection is safe and feasible at community hospital-based practices.

National Trends in General Surgery Resident Exposure to Complex Oncology-Relevant Cases

OBJECTIVE To evaluate trends in surgical resident exposure to complex oncologic procedures in order to determine whether additional fellowship training is necessary. DESIGN An observational study of national Accreditation Council for Graduate Medical Education case log statistical reports was conducted to determine the average number of cases for selected oncology-relevant procedures completed during training. Linear regression and Cusick trend tests were used to assess temporal trends with the null hypothesis assuming an estimated slope of zero. Instrumental variable estimation was used to study the effect of duty-hour restrictions on oncologic cases per year. SETTING United States general surgery residency training programs. PARTICIPANTS Graduating surgical residents completing their training between 2000 and 2016. RESULTS Across the study interval, mean case volume was 950.6 ± 29.7 (standard deviation) cases with 38.9 ± 3.1 complex oncologic cases per graduating resident. Decreasing trends were noted for average exposure to lymphadenectomies (-7.8 cases/decade; 95% confidence interval [CI] -8.8 to -6.8) and low rectal procedures (-0.9 cases/decade; 95% CI -1.2 to -0.6). There was no clinically important change in complex soft-tissue resections and foregut cases. A significant increase was seen in number of hepatopancreaticobiliary procedures (+3.9 cases/decade; 95% CI 3.1-4.7). Using instrumental variable estimation, there was a modest decline in cancer-relevant cases by 5.0 cases/decade (95% CI 4.5-5.6), while there was an increase in 38.5 total cases/decade (95% CI 10.4-66.7) associated with duty-hour restrictions. CONCLUSIONS Case numbers for several complex oncologic procedures remain low, justifying a need for further fellowship training depending on individual resident experience.

Getting Involved at a National Level

Developing a successful academic career depends on networking. Out of necessity, much of networking in the context of surgical education takes place at a national level. Unfortunately, the majority of surgeons have had little or no instruction on how to get involved in national organizations and professional societies. This chapter describes a strategy and tips on how junior faculty can successfully increase their national profile in surgical education. In addition, specific opportunities at a selection of national organizations are presented as reference.