Consequences of Increasing Complexity in Anorectal Surgery Performed at an Academic Center.

BACKGROUND: Anorectal surgery encompasses a wide range of procedures with varying complexity. The Accreditation Council for Graduate Medical Education Review Committee for Colon and Rectal Surgery recommends minimum case numbers (60) for 1-year specialty trainees in 6 categories of anorectal surgery, with definitions for procedural complexity. OBJECTIVE: The purpose of this study was to assess the scope of anorectal procedures and propose a stratification of procedures based on a consensus of levels of difficulty, as well as to identify a predictive charge cutoff suggestive of procedural complexity. DESIGN: This was a retrospective review. SETTINGS: The study was conducted at a tertiary academic center. PATIENTS: Patients undergoing anorectal procedures between January 2011 and December 2014 identified by Current Procedural Terminology coding were entered into 6 categories. Codes were stratified as routine or complex based on an assessment of perioperative care and technical expertise required. Patients with an abdominal portion to any procedure were excluded. MAIN OUTCOMES MEASURES: The study measured distribution of complexity in anorectal surgical procedures and procedural charge associated with differentiating routine from complex procedures. RESULTS: Seven colorectal surgeons performed 2483 anorectal procedures (mean = 620 per year). Mean age was 48 ± 16 years. Forty six (64%) of 71 procedures were classified as routine and 25 (36%) of 71 as complex. Most disease processes had subsets with routine or complex procedures, whereas all of the procedures performed for fecal incontinence or advanced anorectal techniques were considered complex. Fistula procedures and transanal excisions were most heterogeneous, with a high procedural complexity rate (37% and 50%). After a procedural complexity rating, intraclass correlation by 6 surgeons was 0.70, demonstrating good correlation. Receiver operating curve assessments of consensus categorization according to billing codes revealed $553 as the optimal cutoff between routine and complex procedures. LIMITATIONS: This was a single-institution retrospective review. CONCLUSIONS: Colorectal residents may benefit from anorectal case stratification, because it serves as a dialogue for those interested in complex anorectal surgery during training. Surgeon categorization of procedures correlates well with a charge-based model of complexity. See Video Abstract at http://links.lww.com/DCR/A806.

p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation.

Glioblastoma (GBM) is a highly lethal brain tumour presenting as one of two subtypes with distinct clinical histories and molecular profiles. The primary GBM subtype presents acutely as a high-grade disease that typically harbours mutations in EGFR, PTEN and INK4A/ARF (also known as CDKN2A), and the secondary GBM subtype evolves from the slow progression of a low-grade disease that classically possesses PDGF and TP53 events. Here we show that concomitant central nervous system (CNS)-specific deletion of p53 and Pten in the mouse CNS generates a penetrant acute-onset high-grade malignant glioma phenotype with notable clinical, pathological and molecular resemblance to primary GBM in humans. This genetic observation prompted TP53 and PTEN mutational analysis in human primary GBM, demonstrating unexpectedly frequent inactivating mutations of TP53 as well as the expected PTEN mutations. Integrated transcriptomic profiling, in silico promoter analysis and functional studies of murine neural stem cells (NSCs) established that dual, but not singular, inactivation of p53 and Pten promotes an undifferentiated state with high renewal potential and drives increased Myc protein levels and its associated signature. Functional studies validated increased Myc activity as a potent contributor to the impaired differentiation and enhanced renewal of NSCs doubly null for p53 and Pten (p53(-/-) Pten(-/-)) as well as tumour neurospheres (TNSs) derived from this model. Myc also serves to maintain robust tumorigenic potential of p53(-/-) Pten(-/-) TNSs. These murine modelling studies, together with confirmatory transcriptomic/promoter studies in human primary GBM, validate a pathogenetic role of a common tumour suppressor mutation profile in human primary GBM and establish Myc as an important target for cooperative actions of p53 and Pten in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal and tumorigenic potential.

CXCR4 as a predictive marker for locally advanced breast cancer post-neoadjuvant therapy.

BACKGROUND: CXCR4 is a G-protein coupled receptor that has been linked with metastasis in several cancers, including breast cancer. We recently demonstrated that high CXCR4 levels in primary tumors of patients with breast cancer had a prognostic significance. We hypothesize that patients whose tumors had a low CXCR4 overexpression level following neoadjuvant chemotherapy will have a lower recurrence rate than those whose tumors remained high. METHODS: Seventeen locally advanced breast cancer (LABC) patients were accrued, and tumor specimens were obtained before and after neoadjuvant therapy. CXCR4 levels were quantified by Western blots against 1 µg of protein from HeLa cells. The primary end-point was cancer recurrence. Statistical tests utilized include Kaplan-Meier survival analysis and log-rank test. A P value ≤ 0.05 was considered significant. RESULTS: We previously defined low CXCR4 overexpression as ≤6-fold elevation and high overexpression as >6-fold elevation over HeLa cells. Of 17 LABC tumors evaluated, 10 (59%) remained in the low group, 5 (29%) reduced from high to low overexpression, and 2 (12%) maintained a high overexpression after neoadjuvant therapy. With a median follow-up of 28 mo, patients whose tumors maintained a high CXCR4 overexpression level after neoadjuvant therapy had a significantly higher rate of cancer recurrence (P = 0.0068). CONCLUSIONS: CXCR4 was a predictive molecular marker of response to neoadjuvant chemotherapy for patients with LABC. Patients whose tumors had a persistently high CXCR4 overexpression level after neoadjuvant therapy are at a significant risk for recurrence, and therefore, should be targeted for more intensive and/or novel therapy.

Predictive value of eIF4E reduction after neoadjuvant therapy in breast cancer.

INTRODUCTION: Initiation factor 4E (eIF4E) overexpression has prognostic significance in breast cancer. Up-regulation of downstream gene products associated with high eIF4E overexpression has been linked to chemoresistance. We hypothesize patients whose tumors had eIF4E reduction after neoadjuvant chemotherapy will have lower cancer recurrence compared with those who did not. METHODS: Seventeen locally advanced breast cancer patients were accrued, and tumor specimens were obtained before and after neoadjuvant therapy. eIF4E was quantified by Western blots. Primary end-point was cancer recurrence. RESULTS: Low eIF4E was defined as < or =7.5-fold elevation and high eIF4E was >7.5-fold elevation. Of 17 patients, six tumors remained low after neoadjuvant therapy, six dropped from high to low eIF4E, and five remained high. With a median follow-up of 29 mo, four of five patients with tumors that remained high have recurred while only three of 12 patients in the low eIF4E post-therapy group have recurred (P=0.05, chi(2)). Survival analysis using the Kaplan-Meier method showed a higher rate of cancer recurrence in patients with post-treatment high eIF4E overexpression (P=0.026, log rank test). CONCLUSIONS: Breast cancer patients whose tumors had low eIF4E overexpression after neoadjuvant chemotherapy had lower cancer recurrence compared with those who did not.

Robotic Rectopexy for Rectal Prolapse in Pediatric Patients.

Rectal prolapse is the protrusion of the rectum out of the anus. Surgical correction can be accomplished via open and minimally invasive abdominal approaches, as well as from the perineum. Robotic rectopexy is an option for minimally invasive treatment of rectal prolapse. There are no studies that have established the efficacy of robotic rectopexy for rectal prolapse in the pediatric population. The aim of this study was to review the experience of robotic rectopexy at a single institution. This is a retrospective review of our pediatric robotic rectopexy experience from 2012 to 2015. Information was obtained from chart review of both operative notes and clinic visits. Four pediatric patients underwent a robotic rectopexy for rectal prolapse from 2012 to 2015. Three patients were male and one was female. The mean age was 15.5 years (range 13-17). Two patients had rectal prolapse with chronic constipation. One patient had rectal prolapse from Ehlers Danlos syndrome, and the last had rectal prolapse after imperforate anus repair as an infant. Three patients received a bowel preparation. Three patients were completed robotically, and one patient required conversion to an open procedure. The average postoperative length of stay was 3.25 days (range 2-4). There were no episodes of recurrent prolapse. Two patients had improvement in constipation, one had no improvement, and one had no documented change. Average postoperative follow-up was 11.5 months (range 3-29). This study was a review of one institution's experience with pediatric robotic rectopexy. With short-term follow-up, there was no recurrence of prolapse. Robotic rectopexy provided a safe, reliable, and short-term resolution of rectal prolapse in pediatric patients.

Validation of a Clinical-Grade Assay to Measure Donor-Derived Cell-Free DNA in Solid Organ Transplant Recipients.

The use of circulating cell-free DNA (cfDNA) as a biomarker in transplant recipients offers advantages over invasive tissue biopsy as a quantitative measure for detection of transplant rejection and immunosuppression optimization. However, the fraction of donor-derived cfDNA (dd-cfDNA) in transplant recipient plasma is low and challenging to quantify. Previously reported methods to measure dd-cfDNA require donor and recipient genotyping, which is impractical in clinical settings and adds cost. We developed a targeted next-generation sequencing assay that uses 266 single-nucleotide polymorphisms to accurately quantify dd-cfDNA in transplant recipients without separate genotyping. Analytical performance of the assay was characterized and validated using 1117 samples comprising the National Institute for Standards and Technology Genome in a Bottle human reference genome, independently validated reference materials, and clinical samples. The assay quantifies the fraction of dd-cfDNA in both unrelated and related donor-recipient pairs. The dd-cfDNA assay can reliably measure dd-cfDNA (limit of blank, 0.10%; limit of detection, 0.16%; limit of quantification, 0.20%) across the linear quantifiable range (0.2% to 16%) with across-run CVs of 6.8%. Precision was also evaluated for independently processed clinical sample replicates and is similar to across-run precision. Application of the assay to clinical samples from heart transplant recipients demonstrated increased levels of dd-cfDNA in patients with biopsy-confirmed rejection and decreased levels of dd-cfDNA after successful rejection treatment. This noninvasive clinical-grade sequencing assay can be completed within 3 days, providing the practical turnaround time preferred for transplanted organ surveillance.

Incidence and Operative Excision of Presacral Masses: An Institutional Analysis.

Presacral masses are rare lesions that encompass a broad range of pathologic findings. Most presacral masses are benign. The aim of this study was to analyze the clinical presentation, pathology, and surgical treatment of presacral masses at a single academic institution over a decade. In this retrospective study, we reviewed all surgically excised presacral tumors between 2003 and 2013. Clinical and pathologic data were recorded. Thirteen patients had surgical excision of a presacral mass. The median age was 42 years (standard deviation ± 19.7) and average follow-up was 11.9 months (standard deviation ± 17.5). The majority of patients were symptomatic. Forty-six per cent (6/13) had sacral or rectal pain. Thirty-eight per cent (5/13) of patients had a palpable mass on digital rectal examination. Sixty-nine per cent of patients had an MRI, 84.6 per cent a CT, and 61.5 per cent multimodality imaging. Most presacral masses were benign (10/13, 77%). Twenty-three per cent (3/13) were malignant. A majority were excised via posterior approach (9/13, 69%), but 31 per cent (4/13) required an anterior or combined approach. Presacral masses are rare, even at a high-volume tertiary care center. They are commonly evaluated with a multiple imaging modalities, are most likely benign, and can be excised via posterior approach.

Current Status of Poly(ADP-ribose) Polymerase Inhibitors as Novel Therapeutic Agents for Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer that is clinically defined as lacking estrogen and progesterone receptors, as well as being ERBB2 (HER-2) negative. Without specific therapeutic targets, TNBC carries a worse prognosis than other types of breast cancer in the absence of therapy. Research has now further differentiated breast cancer into subtypes based on genetic expression patterns. One of these subtypes, basal-like, frequently overlaps with the clinical picture of TNBC. Additionally, both TNBC and basal-like breast cancer link to BRCA mutations. Recent pharmaceutical advances have created a class of drugs, poly(ADP-ribose) polymerase (PARP) inhibitors, which are showing potential to effectively treat these patients. The aim of this paper is to summarize the basis behind PARP inhibitors and update the current status of their development in clinical trials for the treatment of TNBC.

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.