Rushin D. Brahmbhatt

Long-term outcomes of laparoscopic totally extraperitoneal inguinal hernia repairs performed by supervised surgical trainees

BACKGROUND Long-term outcomes of laparoscopic totally extraperitoneal (TEP) inguinal hernia repairs performed by supervised surgical trainees are absent. METHODS Retrospective review of TEP inguinal hernioplasties performed by trainees at our institution. RESULTS From 1995 to 2009, a total of 1,479 inguinal hernia repairs on 976 patients were performed by supervised surgical trainees. The mean patient age was 54 years (range 5-86). Men (97%), direct defects (51%), and bilateral repairs (52%) predominated. Recurrent hernias compromised 17%. Four (.4%) patients were converted to open surgery because of scarring. Postoperative complications consisted of urinary retention (8%), seroma (3%), and hematoma (2%). Trainee participation included interns (46%), PGY-2s (10%), PGY-3s (2%), PGY-4s (3%), and PGY-5s (39%). With a mean follow-up of 6.1 years, recurrence and bothersome groin pain rates were 2.6% and 1.5%, respectively. CONCLUSIONS With adequate supervision, surgical trainees can safely perform the TEP repair with good long-term outcomes.

Immune cell quantitation in normal breast tissue lobules with and without lobulitis

While the immune microenvironment has been investigated in breast cancers, little is known about its role in non-malignant breast tissues. Here we quantify and localize cellular immune components in normal breast tissue lobules, with and without visible immune infiltrates (lobulitis). Up to ten representative lobules each in eleven normal breast tissue samples were assessed for B cells (CD20), cytotoxic T cells (CD8), helper T cells (CD4), dendritic cells (CD11c), leukocytes (CD45), and monocytes/macrophages (CD68). Using digital image analysis, immune cell densities were measured and compared between lobules with/without lobulitis. 109 lobules in 11 normal breast tissue samples were evaluated; 31 with lobulitis and 78 without. Immune cells showed consistent patterns in all normal samples, predominantly localized to lobules rather than stroma. Regardless of lobulitis status, most lobules demonstrated CD8+, CD11c+, CD45+, and CD68+ cells, with lower densities of CD4+ and CD20+ cells. Both CD11c+ and CD8+ cells were consistently and intimately associated with the basal aspect of lobule epithelium. Significantly higher densities of CD4+, CD8+, CD20+, and CD45+ cells were observed in lobules with lobulitis. In contrast, densities of monocytes/macrophages and dendritic cells did not vary with lobulitis. In normal breast tissue, myeloid and lymphoid cells are present and localized to lobules, with cytotoxic T and dendritic cells directly integrated with epithelium. Lobules with lobulitis have significantly more adaptive immune (B and T) cells, but no increase in dendritic cells or monocytes/macrophages. These findings indicate an active and dynamic mucosal immune system in normal breast tissue.

A multivariate model to predict cancer upgrade from atypical ductal hyperplasia by core needle biopsy.

3 Background: Atypical ductal hyperplasia (ADH) is a high-risk breast lesion usually diagnosed with core needle biopsy. Although upgraded to cancer at surgical excision in ~15 to 25% of cases, routine excision is questioned due to cost and overtreatment. We evaluated clinical, imaging, and histologic features associated with cancer upgrade and developed a multivariate model to predict risk of upgrade. METHODS With IRB approval a single institution retrospective review was performed of patients who underwent surgical excision of ADH diagnosed by core biopsy from 06/2005 to 06/2013. Review was performed of electronic records, breast imagin,g and biopsy slides. Multiple imputations were used for missing data. Association of cancer upgrade with various features was assessed with logistic regression. RESULTS 409 biopsies with ADH on core biopsy, with later surgical excision, were included. The overall upgrade rate was (16.1%, 95% CI:12.9-20.0%); 10 patients had invasive cancer at excision and 56 DCIS only. Features on core biopsy most strongly associated with upgrade were imaging estimated percent of lesion removed (upgrade 9% for 90% removed, 14% for 50 to 75%, and 27% for < 50% removed), individual cell necrosis (upgrade 34% with necrosis vs. 9.5% without), and # foci of ADH (22% for >1 focus vs 8% for 1 focus). A multivariate predictive model (see Table) showed an average C-statistic of 0.77. Women with no necrosis and either 1 focus with ≥ 50% removal or >1 focus with 90% removal (36% of the sample) have low risk of upgrade (5.0%, 95% CI:1.3-8.7%). CONCLUSIONS ADH on core biopsy with low risk of upgrade to cancer is defined by percent of imaging lesion removed, # of foci of ADH, and lack of individual cell necrosis. If findings are validated, women whose biopsies meet low-risk criteria might be considered for chemoprevention and surveillance rather than surgical excision.[Table: see text].

Macrophagic “Crown-like Structures” Are Associated with an Increased Risk of Breast Cancer in Benign Breast Disease

In breast adipose tissue, macrophages that encircle damaged adipocytes form “crown-like structures of breast” (CLS-B). Although CLS-B have been associated with breast cancer, their role in benign breast disease (BBD) and early carcinogenesis is not understood. We evaluated breast biopsies from three age-matched groups (n = 86 each, mean age 55 years), including normal tissue donors of the Susan G. Komen for the Cure Tissue Bank (KTB), and subjects in the Mayo Clinic Benign Breast Disease Cohort who developed cancer (BBD cases) or did not develop cancer (BBD controls, median follow-up 14 years). Biopsies were classified into histologic categories, and CD68-immunostained tissue sections were evaluated for the frequency and density of CLS-B. Our data demonstrate that CLS-B are associated with BBD: CLS-B–positive samples were significantly less frequent among KTB biopsies (3/86, 3.5%) than BBD controls (16/86 = 18.6%, P = 0.01) and BBD cases (21/86 = 24%, P = 0.002). CLS-B were strongly associated with body mass index (BMI); BMI < 25: 7% CLS-B positive, BMI 25–29: 13%, and BMI ≥ 30: 29% (P = 0.0005). Among BBD biopsies, a high CLS-B count [>5 CLS-B/sample: 10.5% (BBD cases) vs 4.7% (BBD controls), P = 0.007] conferred a breast cancer OR of 6.8 (95% CI, 1.4–32.4), P = 0.02, after adjusting for adipose tissue area (cm2), histologic impression, and BMI. As high CLS-B densities are independently associated with an increased breast cancer risk, they may be a promising histologic marker of breast cancer risk in BBD. Cancer Prev Res; 11(2); 113–9. ©2017 AACR.

Transcolonic peritoneoscopy by using submucosal endoscopy with mucosal flap for the detection of peritoneal bead targeting in the porcine survival model: a feasibility and effectiveness study

BACKGROUND Staging peritoneoscopy is typically done by laparoscopy in the operating room. Natural orifice transluminal endoscopic surgery peritoneoscopy is an appealing alternative to the current approach. Transcolonic submucosal endoscopy with mucosal flap (SEMF) may provide natural orifice transluminal endoscopic surgery peritoneoscopy. OBJECTIVE The aim was to verify the feasibility and safety of transcolonic peritoneoscopy with SEMF (TCPS) in a porcine survival model. DESIGN Survival study. SETTING Animal research unit. INTERVENTION Seven target beads were placed in the peritoneal cavity by laparoscopy in each of 6 animals, and TCPS was performed to identify and touch beads to simulate biopsy. Animals were euthanized after 1 week, at which time, laparotomy was performed and the SEMF site was resected for histological analysis. MAIN OUTCOME MEASUREMENTS The number of beads identified and touched during peritoneoscopy, rate of successful completion of TCPS, procedure time, mortality equivalent 1 week after TCPS, adverse event rate, histological assessment of SEMF site. RESULTS All 7 beads in all 6 pigs were identified and touched during TCPS. The success rate of TCP was 100%. No major adverse events occurred during the procedure. The median procedure times for the creation of a submucosal tunnel, peritoneoscopy, closure of mucosal incision, and entire procedure were 19.5, 17, 9.5, and 45 minutes, respectively. All pigs survived until euthanasia, and there was no evidence of peritonitis or severe infection. LIMITATIONS Animal study, single endoscopist, small sample size. CONCLUSION Results of this study indicate that TCPS is feasible and safe in a porcine survival model.

Assimilating endocrine anatomy through simulation: a pre-emptive strike!

BACKGROUND We sought to determine if endocrine anatomy could be learned with the aid of a hands-on, low-cost, low-fidelity surgical simulation curriculum and pre-emptive 60-second YouTube video clip. METHODS A 3-hour endocrine surgery simulation session was held on back-to-back Fridays. A video clip was made available to the 2nd group of learners. A comprehensive 40-point test was administered before (pre-test) and after (post-test) the sessions. RESULTS General surgery interns (n = 26) participated. The video was viewed 19 times by 80% (12 of 15) of interns with access. Viewers outperformed nonviewers on subsequent post-testing (mean [SD], 29.7 [1.3] vs 24.4 [1.6]; P = .015). Mean scores on the anatomy section of the post-test were higher among viewers than nonviewers (mean [SD] 14.2 [.9] vs 10.3 [1.0]; P = .012). CONCLUSIONS Low-cost simulation models can be used to teach endocrine anatomy. Pre-emptive viewing of a 60-second video may have been a key factor resulting in higher post-test scores compared with controls, suggesting that the video intervention improved the educational effectiveness of the session.

Abstract P4-04-09: CD4 and CD8 T cell densities are increased in benign breast disease compared to normal breast tissue

Introduction: CD4+ and CD8+ T cells are important effector cells in the adaptive immune response against cancers. In premalignant proliferative breast tissues, the role of the immune system remains relatively undefined. In this study, we sought to investigate and quantify the presence of CD4 and CD8 expressing immune cells in benign breast tissues and their association with breast cancer risk. Method: Archived breast tissue samples from women with benign breast disease (BBD) or no clinical breast disease [Komen Tissue Bank (KTB)] were obtained for this age-matched case-control study. BBD samples included BBD cases (subsequently developed breast cancer) and BBD controls). Tissue sections were characterized for non-proliferative or proliferative disease and degree of lobular involution. CD4+ and CD8+ cell densities (cells/mm 2 ) were obtained by digital image quantitation for up to 10 individual lobules per sample and a per-sample estimate of cell density was calculated as the median cell density across lobules within a sample. Statistical analysis was performed using Wilcoxon signed-rank and Kruskal-Wallis tests. Results: Among 267 women (median age 52, range 35-75) comprising 89 age-matched triplets, 2417 lobules were evaluated [783 KTB, 804 BBD case, 830 BBD control]. 1372 (57%) lobules were normal and 1045 (43%) were fibrocystic. CD4+ cells were present in 1903 (79%) lobules while CD8+ cells were present in 2214 (92%) lobules. CD4 and CD8 densities showed a moderate positive correlation (r = 0.39) with each other, but overall, lobules showed a lower density of CD4+ than CD8+ cells (mean difference -54 cells/mm 2 , 95% CI: -68 to -39 cells/mm 2 ). At the per sample level (see Table), BBD controls showed significantly higher levels of both CD4+ (p=0.009) and CD8+ cells (p=0.0001) compared to KTB samples. In contrast, the BBD cases only showed elevated CD8 (p=0.007) and not CD4 (p=0.21) cell infiltrates compared to KTB samples. Comparing BBD cases to BBD controls, BBD cases showed significantly lower CD8 cell density as compared to BBD controls (p=0.002) and cases had lower CD4 cell density but the difference was not significant (p=0.07). Despite these differences in the cell densities, the ratio of CD4:CD8+ cells did not differ significantly across groups (p=0.83). The CD4:CD8+ ratio also did not differ significantly by histologic impression (p=0.74), degree of involution (p=0.27), or age (p=0.32). Conclusion: Our findings suggest that BBD is associated with increased infiltration of T cells into the breast tissue. Furthermore, these immune responses appear more robust in BBD patients at lower risk of developing breast cancer. Citation Format: Pena Jimenez A, Hoskin TL, Arshad MA, Visscher DW, Brahmbhatt RD, Miller EE, Stallings Mann ML, Carter JM, Murphy LM, Winham SJ, Radisky DC, Denison LA, Knutson KA, Degnim AC. CD4 and CD8 T cell densities are increased in benign breast disease compared to normal breast tissue. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-04-09.

Abstract 2364: CD68+ immune cells show different infiltration patterns in tissue samples from women with no clinical breast disease and those who have benign breast disease

Introduction: The role of macrophages in the tumor microenvironment is of increasing interest for tumor progression and invasion. Here we investigated the difference in CD68+ cell density in tissue samples from women with Benign Breast Disease (BBD) and women with no clinical breast disease from the Komen Tissue Bank (KTB) at Indiana University. Method: Archived breast tissue samples from women with BBD and no clinical breast disease were obtained for this age-matched case-control study. BBD samples included cases [later got Breast Cancer (BC)] and controls (did not get BC). Samples were characterized via HE 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2364. doi:10.1158/1538-7445.AM2015-2364

Abstract B34: CD56+ immune cell infiltration is decreased in benign breast lobules with fibrocystic changes

Introduction: CD56+ lymphocytes (a defining marker of natural killer cells) have a predominantly cytotoxic phenotype and a hypothetical role in breast tumor immunosurveillance. Here we investigate whether CD56+ staining density varies in nonmalignant breast lobules according to confirmed breast cancer risk factors- age, and histologic features of fibrocystic change and lobular involution. Methods: Archived breast tissue samples were obtained from 94 women with benign breast disease (BBD). The sample set was selected as a nested case-control study (47 cases, 47 controls) from within a large BBD cohort; cases were those who developed breast cancer subsequent to their benign breast biopsy; controls were matched to cases on age at biopsy, year of biopsy, and length of breast cancer free follow-up at least as long as the time-to-cancer in the matched case. Up to 10 representative lobules in each sample were characterized by HE 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B34.

Abstract 1652: Immune infiltration of normal and benign breast lobules varies in breast tissues based on cancer risk

Introduction: Histologic characteristics of nonmalignant breast tissues (epithelial proliferation and involution) are associated with future breast cancer (BC) risk. We evaluated immune infiltration (lobulitis) in benign breast lobules and its association with features of BC risk. Methods: We analyzed archived nonmalignant breast tissue samples from 81 women in age-matched groups of varying cancer risk: 27 with benign breast disease (BBD) who later developed BC (cases), 27 with BBD without subsequent BC (controls), and 27 normal women without clinical breast disease from the Komen Tissue Bank at Indiana University (KTB). Up to 10 lobules in each sample were characterized by HE among women Conclusion: Lobulitis is common in normal and benign breast tissue lobules but varies with age, involution status, and epithelial abnormality. Further work is needed to understand the role of immune infiltrates in breast cancer risk. Citation Format: Rushin D. Brahmbhatt, Daniel W. Visscher, Tanya L. Hoskin, Derek C. Radisky, Linda M. Murphy, Melody L. Stallings Mann, Erin Miller, Vernon S. Pankratz, Lynn C. Hartmann, Marlene H. Frost, Amy C. Degnim. Immune infiltration of normal and benign breast lobules varies in breast tissues based on cancer risk. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1652. doi:10.1158/1538-7445.AM2014-1652