Surgeon-Level Variation in Utilization of Local Staging and Neoadjuvant Therapy for Stage II-III Rectal Adenocarcinoma.

INTRODUCTION: Neoadjuvant therapy (NT) is the standard of care for clinical stage II-III rectal adenocarcinoma, but utilization remains suboptimal. We aimed to determine the underlying reasons for omission of local staging and NT. METHODS: We conducted a retrospective study of patients with clinical stage II-III or undocumented clinical stage/pathologic stage II-III rectal adenocarcinoma who were treated in 2010-2016 in one of nine Intermountain Healthcare hospitals. The outcomes of omission of local staging and NT were examined with multivariable models. Risk- and reliability-adjusted rates of local staging and NT were calculated for surgeons who treated ≥ 3 patients. Pathologic and long-term outcomes were examined after excluding patients who were not resected or who underwent local excision (N = 11). RESULTS: Local staging was omitted in 43/240 (17.9%) patients and NT was omitted in 41/240 (17.1%). The strongest risk factors for local staging and NT omission were upper rectal tumors and surgeons who treated ≤ 3 cases/year. Thirty-six of 41 (87.8%) cases of omitted NT had local staging omitted. Adjusted surgeon-specific local staging rates varied 1.6-fold (56.3-92.4%) and NT rates varied 2.8-fold (34.1-97.1%). Surgeon local staging and NT rates were strongly correlated (r = 0.92). NT was associated with lower rates of positive circumferential radial margins (7.9 vs. 20.0%; P = 0.02), node positivity (33.3 vs. 55.0%; P = 0.01), and local recurrences (7.6 vs. 14.9% at 5 years; P = 0.0176). CONCLUSIONS: NT omission should be understood as a consequence of surgeon failure to perform local staging in most cases. Quality improvement efforts should focus on improving utilization of local staging.

Vulvar Recurrences After Intensity-modulated Radiation Therapy for Squamous Cell Carcinoma of the Anus.

OBJECTIVES: The objective is to determine localregional control (LRC), distant metastasis free survival, disease-free survival, overall survival (OS), and toxicity for patients with squamous cell carcinoma of the anus treated with definitive chemotherapy and intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS: We conducted a retrospective review of patients treated using IMRT for squamous cell carcinoma of the anus at our institution since 2005. Patients with local recurrences were identified and reviewed. The Kaplan-Meier curves were used for LRC and OS. RESULTS: From 2005 to 2014, 52 patients were treated with IMRT-based chemoradiation for squamous cell carcinoma of the anus. Median dose to the primary tumor was 54 Gy. LRC, distant metastasis free survival, OS, and disease-free survival were 92.3%, 88.5%, 86.5%, and 84.6%, respectively, with a median follow-up of 20 months. Two local failures occurred at the anal primary site and 2 in the vulva. Despite subsequent palliative radiotherapy and chemotherapy, neither patient with a vulvar recurrence achieved disease control. CONCLUSIONS: In a cohort of patients treated with IMRT-based chemoradiation, 2 vulvar recurrences were identified within the avoided external genitalia despite limited recurrence rates within the cohort overall. This experience suggests that for patients with a locally advanced primary tumor and bulky bilateral inguinal or pelvic disease, the in-transit vulvar dermal lymphatics may be at risk for subclinical involvement and subsequent recurrence. If substantiated by a similar pattern of recurrence at other institutions, the external genitalia may need to be reclassified from an avoidance structure to a clinical treatment volume in patients with locally advanced anal cancer.

Stage III & IV colon and rectal cancers share a similar genetic profile: a review of the Oregon Colorectal Cancer Registry.

BACKGROUND: Determining the molecular profile of colon and rectal cancers offers the possibility of personalized cancer treatment. The purpose of this study was to determine whether known genetic mutations associated with colorectal carcinogenesis differ between colon and rectal cancers and whether they are associated with survival. METHODS: The Oregon Colorectal Cancer Registry is a prospectively maintained, institutional review board-approved tissue repository with associated demographic and clinical information. The registry was queried for any patient with molecular analysis paired with clinical data. Patient demographics, tumor characteristics, microsatellite instability status, and mutational analysis for p53, AKT, BRAF, KRAS, MET, NRAS, and PIK3CA were analyzed. Categorical variables were compared using chi-square tests. Continuous variables between groups were analyzed using Mann-Whitney U tests. Kaplan-Meier analysis was used for survival studies. Comparisons of survival were made using log-rank tests. RESULTS: The registry included 370 patients: 69% with colon cancer and 31% with rectal cancer. Eighty percent of colon cancers and 68% of rectal cancers were stages III and IV. Mutational analysis found no significant differences in detected mutations between colon and rectal cancers, except that there were significantly more BRAF mutations in colon cancers compared with rectal cancers (10% vs 0%, P < .008). No differences were seen in 5-year survival rates of patients with colon versus rectal cancers when stratified by the presence of KRAS, PIK3CA, and BRAF mutations. CONCLUSIONS: Stage III and IV colon and rectal cancers share similar molecular profiles, except that there were significantly more BRAF mutations in colon cancers compared with rectal cancers.

Resection and primary anastomosis with proximal diversion instead of Hartmann's: evolving the management of diverticulitis using NSQIP data.

BACKGROUND: The emergency surgical treatment of acute diverticulitis with feculent or purulent peritonitis has traditionally been the Hartmann's procedure (HP). Debate continues over whether primary resection with anastomosis and proximal diversion may be performed in the setting of a high-risk anastomosis in complicated diverticular disease. In contrast to a loop ileostomy takedown, the morbidity of a Hartmann's reversal is preventative for many patients, leaving them with a permanent stoma. Our study compared the surgical outcomes of patients with perforated diverticulitis who underwent a HP to primary anastomosis with proximal diversion (PAPD). METHODS: The National Surgical Quality Improvement Program (NSQIP) database was queried from 2005 to 2009 to identify all cases of perforated diverticulitis classified as contaminated or dirty/infected. Patients were stratified into HP or PAPD, and logistic regression models were created to control for patient demographics, comorbidities, perioperative risk, and illness severity to determine the impact of surgical procedure on outcome. RESULTS: There were 2,018 patients meeting the inclusion criteria of which 340 (17%) underwent PAPD and the remainder underwent HP. Significant independent predictors of infectious outcomes were alcohol use, preoperative sepsis, and operative time. There was no significant difference in risk of infectious complications, return to the operating room, prolonged ventilator use, death, or hospital length of stay between the two procedures. When considering only dirty/infected cases, the mortality risk was twofold greater when PAPD was performed. CONCLUSION: The treatment of acute diverticulitis in the setting of contamination can be safely treated with resection, primary anastomosis, and proximal diversion as opposed to a HP in certain circumstances. Given the decreased morbidity of subsequent loop ileostomy takedown compared with a Hartmann's reversal, this procedure should be given consideration in the management of acute, perforated diverticulitis but may not be warranted in cases of feculent peritonitis.

Success in sentinel lymph node procedures in obese patients with breast cancer.

BACKGROUND: Sentinel lymph node (SLN) biopsy for axillary staging in breast cancer is technically more demanding but of added benefit in obese patients. This retrospective review compares variables and outcomes of SLN staging in obese and nonobese women. METHODS: From 235 total SLN cases, demographics and clinical and procedural variables were collected and compared in obese (body mass index [BMI] of ≥ 35, n = 28) and nonobese (BMI ≤ 25 [n = 84]) patients. RESULTS: Overall, the intraoperative false-negative rate was 13.6% and failure to identify SLN occurred in 2 cases (.85%). Although no differences in patient or tumor characteristics were found, obese patients had significantly lower external hotspot counts, first sentinel node counts, and fewer sentinel nodes recovered when compared with the nonobese. CONCLUSIONS: SLN procedures are successful and accurate for axillary staging in obese women and avoid the added morbidity of axillary lymph node dissection in this higher risk population.

Antibiotic prophylaxis in the placement of totally implanted central venous access ports.

BACKGROUND: Antibiotic prophylaxis during placement of implanted central venous access ports (CVAP) has not been studied. This retrospective review compared the rate of catheter-related infections (CRIs) with and without perioperative antibiotics. METHODS: This was a single-center study that compared patients treated with and without a single dose of antibiotics during CVAP placement. CRIs were defined as a patient treated with antibiotics for port site induration, positive blood cultures, or suspicion of infection that led to port removal within 30 days of placement. RESULTS: CVAP were placed in 459 patients, 103 of whom (22.4%) received antibiotic prophylaxis. Surgical technique and patient demographics were similar to those patients not receiving antibiotics (356). All 9 (2%) CRIs occurred in the non-prophylactic antibiotic group (P = .218), with 5 infections resulting in port removal. CONCLUSIONS: Single-dose perioperative antibiotics may decrease CVAP infection rates and should be studied further in a prospective randomized trial.

Selective use of intraoperative sentinel lymph node pathological evaluation in breast cancer.

BACKGROUND: In breast cancer staging, the need for intraoperative sentinel lymph (SLN) evaluation is not well established. This study compares intraoperative use of touch preparation (TP), frozen section (FS), and factors that may influence the selective use of intraoperative SLN analysis. METHODS: Breast cancer patients (1998-2007) undergoing SLN evaluation were retrospectively reviewed. RESULTS: Of 205 SLN procedures, 157 cases underwent intraoperative evaluation, 43% (FS) and 57% (TP) with positive pathology in 21% and 20%, respectively. The false negative case rate was 16% for TP versus 12% for FS. Of T1, low-grade tumors, 9% were intraoperatively positive, versus 43% of T2-3, moderate- to high-grade tumors (P = .006). Additional positive axillary nodes were found in 43% of the higher risk patients versus 0% in the lower risk groups. CONCLUSIONS: Both TP and FS are accurate for intraoperative SLN evaluation and can be selectively applied to breast cancer staging in low- and high-risk groups.

A conjugate of a tumor-targeting ligand and a T cell costimulatory antibody to treat brain tumors.

T cell immunotherapy is a potential strategy for the treatment of brain tumors because it offers a high degree of specificity, the ability to extravasate into solid tumors, and the potential for eliciting a long-term protective immune response. Various approaches have been developed to overcome T cell immune tolerance to cancer, including the use of cytokines and bispecific antibodies. T cell stimulation with the proinflammatory cytokine IL-12 can elicit antitumor immunity. T cell activation can be increased using bispecific antibodies against activating molecules on the surface of T cells and a tumor antigen. We studied the effects of systemic IL-12 administration in combination with a conjugate of an anti-CD28 antibody and a ligand for the folate receptor. The high affinity folate receptor is expressed on endogenously arising choroid plexus tumors of SV11 mice, which are transgenic for large T antigen under the control of the SV40 promoter. SV11 mice are immunocompetent, yet immunologically tolerant to large T antigen expressed by choroid plexus tumors. MRI analysis showed that the administration of IL-12 and anti-CD28 Fab/folate significantly slowed tumor growth. Proliferating CD8(+) T cells were found in choroid plexus tumors of treated animals. Treatment of animals with IL-12 + anti-CD28 Fab/folate prolonged survival compared to IL-12 alone. Cytokine treatment combined with tumor-targeted costimulation may be a useful adjunct treatment.

Folate-mediated targeting of T cells to tumors.

Recently various strategies have been developed to exploit in a clinical setting the well established finding that T cells can specifically recognize and destroy tumor cells. Several independent approaches to the targeting of T cells against cancer have been explored, including the use of bispecific antibodies (anti-T cell/anti-tumor cell) to redirect T cells, vaccines to induce tumor-reactive T cells, and adoptive transfer of ex vivo activated, tumor-reactive T cells. In this review, we focus on studies in which high-affinity folate receptors (FRs) on tumor cells have served as targets for redirecting or enhancing the effectiveness of activated T cells. Bispecific antibody conjugates of folate and antibodies to the T cell receptor (TCR) complex can generate tumor-reactive T cell responses. The development of folate/antibody conjugates specific for the T cell co-stimulatory molecule CD28 could yield activated T cells that recognize endogenous peptide-major histocompatibility complex (MHC) antigens on tumor cells. Finally, we discuss a less investigated area in which high-affinity FRs on macrophages, or other antigen presenting cells (APCs), may provide opportunities in the design of tumor-antigen-specific vaccines.