Role of Molecular Profiling of Pancreatic Cancer After Neoadjuvant Therapy: Does it Change Practice?

INTRODUCTION: Tumor profiling can improve the selection of oncologic therapies in patients with pancreatic cancer (PC). The impact of neoadjuvant therapy on tumor testing is unknown. METHODS: Molecular profiling using commercially available 53-, 315-, or 472-gene next generation sequencing (NGS) panels was performed on surgical specimens following neoadjuvant therapy. All specimens with 472-gene sequencing also had immunohistochemical (IHC) testing. Treatment recommendations were based on somatic variants and IHC staining. RESULTS: NGS was performed on 74 patient specimens: 42 (57%) with a 472-gene panel, 28 (38%) with a 315-gene panel, 3 (4%) had 472- and 315-gene panels, and 1 (1%) patient had 53- and 472-gene panels (78 total tests). Likely pathogenic/pathogenic variants were identified in 73 (94%) of the 78 tests. Of the 73 samples with variants identified, 13 (18%) variants were associated with an actionable treatment: ATM (n = 10), BRCA1 (n = 1), PIK3CA (n = 1), and BRCA2 (n = 1). No patient had more than one actionable variant. Based on NGS results, the most commonly recommended therapy was a platinum agent (n = 12/78, 15%). Of the 46 specimens that underwent IHC analysis, overlapping chemotherapeutic treatment recommendations were identified in 40 (87%) specimens. CONCLUSION: Using current multigene NGS panels, actionable variants were identified in 13 (18%) of 74 surgical specimens and primarily involved genes of the DNA repair pathway. Anecdotal reproducibility of test concordance was low.

Successful Pallidal Deep Brain Stimulation Treatment in a Case of Generalized Dystonia due to a Novel ANO3 Mutation.

BACKGROUND: Dystonia is a ubiquitous syndrome, with a growing number of genes being continually identified. Mutations in the anoctamin-3 gene have been described to cause dystonia but the management and long-term outcomes are still largely unknown. METHODS: We present here a long term, longitudinal follow up of a patient with generalized dystonia, who was treated with bilateral pallidal deep brain stimulation and was found to harbor a mutation in the anoctamin-3 gene. RESULTS: Ongoing adjustment of stimulation settings and medications led to good and sustained dystonia control; however the patient did suffer short term relapses, manifested as dystonic crisis, which necessitated inpatient admission. CONCLUSION: This only the second patient to be reported with pallidal stimulation and an anoctamin-3 gene mutation. Long term outcomes seem to be favorable but larger case series are needed to confirm our findings.

Surgical resectability of multisite metastatic colorectal cancer: Pushing the limits while appropriately selecting patients.

Management of multisite colorectal metastases is expanding to make curative resection possible for more patients who present with advanced disease. Patient selection, tumor biology, meticulous surgical technique, and thoughtful perioperative care are essential to extending the benefit to patients previously treated with palliative goals of care.

Neoadjuvant therapy versus upfront surgery for resected pancreatic adenocarcinoma: A nationwide propensity score matched analysis.

BACKGROUND: Neoadjuvant therapy is an emerging paradigm in pancreatic cancer care; however, its role for resectable disease remains controversial in the absence of conclusive randomized controlled trials. The purpose of the present study is to assess the impact of neoadjuvant therapy on survival in resected pancreatic cancer patients by clinical stage. METHODS: A retrospective cohort study using the National Cancer Data Base from 2004 to 2012 including nonmetastatic pancreatic adenocarcinoma patients who underwent pancreatectomy and initiated chemotherapy. Propensity score matching within each stage was used to account for potential selection bias between patients undergoing neoadjuvant therapy and upfront surgery. Overall survival was compared by the Kaplan-Meier method. RESULTS: In the study, 1,541 and 7,159 patients received neoadjuvant therapy followed by surgery and upfront surgery succeeded by adjuvant therapy, respectively. In clinical stage III pancreatic cancer (n = 486), neoadjuvant therapy was associated with significant survival benefit after matching (median survival 22.9 vs 17.3 months; log-rank P < .0001) compared with conventional upfront surgery followed by adjuvant therapy; however, no survival difference was found between the 2 treatment sequences in patients with clinical stage I (n = 3,149; median survival, 26.2 vs 25.7 months; P = .4418) and II (n = 5,065; median survival, 23.5 vs 23.0 months; P = .7751) disease after matching. CONCLUSION: The survival impact of neoadjuvant therapy is stage-dependent. Neoadjuvant therapy does not disadvantage survival compared with conventional upfront surgery followed by adjuvant therapy in any stage, and is associated with a significant survival advantage in stage III pancreatic cancer.

Percutaneous versus Cut-Down Technique for Indwelling Port Placement.

The superiority of surgical cut-down of the cephalic vein versus percutaneous catheterization of the subclavian vein for the insertion of totally implantable venous access devices (TIVADs) is debated. To compare the safety and efficacy of surgical cut-down versus percutaneous placement of TIVADs. This is a single-institution retrospective cohort study of oncologic patients who had TIVADs implanted by 14 surgeons. Primary outcomes were inability to place TIVAD by the primary approach and postoperative complications within 30 days. Multivariate analysis was performed by logistic regression. Secondary outcomes included operative time. Two hundred and forty-seven (55.9%) percutaneous and 195 (44.1%) cephalic cut-down patients were identified. The 30-day complication rate was 5.2 per cent: 14 patients (5.7%) in the percutaneous and nine (4.6%) in the cut-down group. The technique was not a significant predictor of having a 30-day complication (odds ratio = 0.820; 95% confidence interval 0.342-1.879). Implantation failure was observed in 16 percutaneous patients (6.5%) and 28 cut-down patients (14.4%) (adjusted odds ratio for cephalic vs cut-down = 2.387; 95% confidence interval 1.275-4.606). The median operative time for percutaneous patients was 46 minutes (interquartile range = 35, 59) versus 37.5 minutes (interquartile range = 30, 49) for cut-down patients(P < 0.0001). Both the percutaneous and cut-down technique are safe and effective for TIVAD implantation. Operative times were shorter and the odds of implantation failure higher for cephalic cut-down. As implantation failure is common, surgeons should familiarize themselves with both techniques.

Massachusetts Healthcare Reform and Trends in Emergent Colon Resection.

BACKGROUND: Insurance impacts access to therapeutic options, yet little is known about how healthcare reform might change the pattern of surgical admissions. OBJECTIVE: We compared rates of emergent admissions and outcomes after colectomy before and after reform in Massachusetts with a nationwide control group. DESIGN: This study is a retrospective cohort analysis in a natural experiment. Prereform was defined as hospital discharge from 2002 through the second quarter of 2006 and postreform from the third quarter of 2006 through 2012. Categorical variables were compared by χ. Piecewise functions were used to test the effect of healthcare reform on the rate of emergent surgeries. SETTINGS: The study included acute care hospitals in the Massachusetts Healthcare Cost and Utilization Project State Inpatient Database (2002-2012) and the Nationwide Inpatient Sample (2002-2011). PATIENTS: Patients aged 18 to 64 years with public or no insurance who underwent inpatient colectomy (via International Classification of Diseases, Ninth Revision, Clinical Modification procedural code) were included and patients with Medicare were excluded. INTERVENTION: Massachusetts health care reform was the study intervention. MAIN OUTCOME MEASURES: We measured the rate of emergent colectomy, complications, and mortality. RESULTS: The unadjusted rate of emergent colectomies was lower in Massachusetts after reform but did not change nationally over the same time period. For emergent surgeries in Massachusetts, a piecewise model with an inflection point (peak) in the third quarter of 2006, coinciding with implementation of healthcare reform in Massachusetts, had a lower mean squared error than a linear model. In comparison, the national rate of emergent surgeries demonstrated no change in pattern. Postreform, length of stay decreased by 1 day in Massachusetts; however, there were no significant improvements in other outcomes. LIMITATIONS: The study was limited by its retrospective design and unadjusted analysis. CONCLUSIONS: There was a unique and sustained decline in the rate of emergent colon resection among publically insured and uninsured patients after 2006 in Massachusetts, in contradistinction to the national pattern, suggesting improved access to care associated with health insurance expansion. The reasons for lack of improvement in outcomes are multifactorial.

Keeping it in the family: the impact of marital status and next of kin on cancer treatment and survival.

BACKGROUND: This study examines the impact of marriage and next of kin identity on timing of diagnosis, treatment, and survival in cancer patients. METHODS: Retrospective review of patients with 5 solid tumor types treated at an academic medical center from 2002 to 2012. Exposures of interest were marriage status at time of diagnosis and familial relationship with next of kin (NOK). Association with overall survival determined via Cox regressions and with early diagnosis (stage I to II) and receipt of surgery via logistic regressions. RESULTS: Marriage was not associated with early diagnosis for any cancer type. After adjustment, being married was associated with significantly higher odds of receiving surgery only for pancreatic cancer and with improved survival for breast and lung cancers. Having a nuclear relationship with NOK was not associated with any outcomes. CONCLUSIONS: Marriage status was associated with improved outcomes for certain cancers whereas familial relationship with NOK was not.

Early surgical bypass versus endoscopic stent placement in pancreatic cancer.

INTRODUCTION: The optimal treatment for biliary obstruction in pancreatic cancer remains controversial between surgical bypass and endoscopic stenting. METHODS: Retrospective analysis of unresected pancreatic cancer patients in the Healthcare Cost and Utilization Project Florida State Inpatient and Ambulatory Surgery databases (2007-2011). Propensity score matching by procedure. Primary outcome was reintervention, and secondary outcomes were readmission, overall length of stay (LOS), discharge home, death and cost. Multivariate analyses performed by logistic regression. RESULTS: In a matched cohort of 622, 20.3% (63) of endoscopic and 4.5% (14) of surgical patients underwent reintervention (p < 0.0001) and 56.0% (174) vs. 60.1% (187) were readmitted (p = 0.2909). Endoscopic patients had lower median LOS (10 vs. 19 days, p < 0.0001) and cost ($21,648 vs. $38,106, p < 0.0001) as well as increased discharge home (p = 0.0029). No difference in mortality on index admission. On multivariate analysis, initial procedure not predictive of readmission (p = 0.1406), but early surgical bypass associated with lower odds of reintervention (OR = 0.233, 95% CI 0.119, 0.434). DISCUSSION: Among propensity score-matched patients receiving bypass vs. stenting, readmission and mortality rates are similar. However, candidates for both techniques may experience fewer subsequent procedures if offered early biliary bypass with the caveats of decreased discharge home and increased cost/LOS.

Deconstructing the "July Effect" in Operative Outcomes: A National Study.

This study analyzes the relationship between hospital teaching status, failure to rescue, and time of year in select gastrointestinal operations. Procedure codes for laparoscopic cholecystectomy, colectomy, and pancreatectomy were queried from the Nationwide Inpatient Sample (2004-2011). Failure to rescue was defined as inpatient mortality when ≥1 complication. A total of 2,777,267 laparoscopic cholecystectomies, 2,519,903 colectomies, and 129,619 pancreatectomies were performed. Teaching hospitals had increased overall rates of failure to rescue compared to non-teaching hospitals, 10.0 vs. 9.5 % (p = 0.0187), particularly between May and August. There was greater inter-month variability in non-teaching hospitals amongst individual operations. On multivariable analysis, July was not predictive of increased odds of failure to rescue. Teaching status, hospital characteristics, and patient demographics were associated with increased odds of failure to rescue. Although teaching hospitals have a higher overall failure to rescue rate amongst the selected gastrointestinal operations, odds of failure to rescue are not increased in the month of July. Non-teaching hospitals tend to exhibit more monthly variation in failure to rescue rates, and hospital/patient demographics are predictive of failure to rescue. Further investigation targeted at identifying drivers of temporal variation is warranted to optimize patient outcomes.

A Tale of Two Cities: Reconsidering Adjuvant Radiation in Pancreatic Cancer Care.

Adjuvant chemotherapy plays a critical role in the treatment of resected pancreatic cancer patients. However, the role of adjuvant radiation remains controversial. This study compares survival between resected pancreatic cancer patients who received adjuvant radiation and no adjuvant radiation. Medical records of patients with pancreatic ductal adenocarcinoma who underwent surgical resection from January 2003 through 2013 at medical centers in Boston and Leiden were retrospectively reviewed. Propensity score matching was used to correct for potential selection bias in the allocation of adjuvant chemoradiation versus chemotherapy alone. Three hundred fifty total patients were identified, of whom 138 (39.4%) received adjuvant radiation. On pathological staging, 245 (70.0%) had positive lymph nodes, and these patients gained a significant survival benefit from adjuvant radiation (hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.56-0.99) in the complete cohort. After propensity score matching, adjuvant radiation lost its prognostic significance in the complete cohort. However, after matching, patients who survived longer than 12 months and had positive lymph nodes (n = 108) demonstrated a significant (log-rank p = 0.04) survival benefit from adjuvant radiation. This study, while non-randomized, suggests that adjuvant radiation may be associated with a survival benefit for resected pancreatic cancer patients in specific situations.

Readmission After Resections of the Colon and Rectum: Predictors of a Costly and Common Outcome.

BACKGROUND: Readmission rates are a measure of surgical quality and an object of clinical and regulatory scrutiny. Despite increasing efforts to improve quality and contain cost, 6% to 25% of patients are readmitted after colorectal surgery. OBJECTIVE: The aim of this study is to define the predictors and costs of readmission following colorectal surgery. DESIGN: This is a retrospective cohort study of patients undergoing elective and nonelective colectomy and/or proctectomy in the Healthcare Cost and Utilization Project Florida State Inpatient Database 2007 to 2011. Readmission is defined as inpatient admission within 30 days of discharge. Univariate analyses were performed of sex, age, Elixhauser score, race, insurance type, procedure, indication, readmission diagnosis, cost, and length of stay. Multivariate analysis was performed by logistic regression. Sensitivity analysis of nonemergent admissions was conducted. SETTINGS: This study was conducted in Florida acute-care hospitals. PATIENTS: Patients undergoing colectomy and proctectomy from 2007 to 2011 were included. INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURE(S): The primary outcomes measured were readmission and the cost of readmission. RESULTS: A total of 93,913 patients underwent colectomy; 14.7% were readmitted within 30 days. From 2007 to 2011, readmission rates remained stable (14.6%-14.2%, trend p = 0.1585). After multivariate adjustment, patient factors associated with readmission included nonwhite race, age <65, and a diagnosis code other than neoplasm or diverticular disease (p < 0.0001). Patients with Medicare or Medicaid were more likely to be readmitted than those with private insurance (p < 0.0001). Patients with longer index admissions, those with stomas, and those undergoing all procedures other than sigmoid or transverse colectomy were more likely to be readmitted (p < 0.0001). High-volume hospitals had higher rates of readmission (p < 0.0001). The most common reason for readmission was infection (32.9%). Median cost of readmission care was $7030 (intraquartile range, $4220-$13,247). Fistulas caused the most costly readmissions ($15,174; intraquartile range, $6725-$26,660). LIMITATIONS: Administrative data and retrospective design were limitations of this study. CONCLUSIONS: Readmissions rates after colorectal surgery remain common and costly. Nonprivate insurance, IBD, and high hospital volume are significantly associated with readmission.

Surgical management of chronic pancreatitis: current utilization in the United States.

BACKGROUND: Surgical intervention is uncommon in chronic pancreatitis. Literature largely describes single institution or international experiences. This study describes US-based chronic pancreatitis surgical management. METHODS: Retrospective analysis of chronic pancreatitis patients in the Healthcare Cost and Utilization Project Florida State Inpatient Database 2007-2011. Patients with malignancy or congenital abnormalities were excluded. Univariate analysis using the chi-square test. The number of readmissions, inpatient length of stay and cost using Wilcoxon's signed-rank test. Multivariate analysis of surgery by logistic regression. RESULTS: Twenty-one thousand four hundred and forty-five patients with chronic pancreatitis. 10.8% (2 307) underwent surgery including 1652 cholecystectomies, 564 drainage procedures and 498 pancreatectomies. Procedures decreased from 12.1% to 8.3% over time (P < 0.001), but intervention within 3 months increased (7.2% to 8.4%; P = 0.017). 15.3% (3 278) had pancreatic cysts/pseudocysts and 43.4% (9 312) had diabetes. The median numbers of admissions were 2 [interquartile range (IQR) 1,5] and 3 (IQR 2,7) among non-surgical and surgical patients, respectively (P < 0.001). Predictors of surgery were fewer co-morbidities, private insurance, and either diabetes mellitus or pancreatic cyst/pseudocyst. CONCLUSION: Chronic pancreatitis leads to numerous inpatient readmissions, but surgical intervention only occurs in a minority of cases. Complicated patients are more likely to undergo surgery. The complexities of chronic pancreatitis management warrant early multidisciplinary evaluation and ongoing consideration of surgical and non-surgical options.

A nationwide assessment of outcomes after bile duct reconstruction.

BACKGROUND: Bile duct reconstruction (BDR) is used to manage benign and malignant neoplasms, congenital anomalies, bile duct injuries and other non-malignant diseases. BDR outcomes overall, by year, and by indication were compared. METHODS: Retrospective analysis of Nationwide Inpatient Sample discharges (2004-2011) including ICD-9 codes for BDR. All statistical testing was performed using survey weighting. Univariate analysis of admission characteristics by chi square testing. Multivariate modelling for inpatient complications and inpatient death by logistic regression. RESULTS: Identified 67 160 weighted patient admissions: 2.5% congenital anomaly, 37.4% malignant neoplasm, 2.3% benign neoplasm, 9.9% biliary injury, 47.9% other non-malignant disease. Most BDRs were performed in teaching hospitals (69.6%) but only 25% at centres with a BDR volume more than 35/year. 32.3% involved ≥ 1 complication, and 84.7% were discharges home. There was a 4.2% inpatient death rate. The complication rate increased but the inpatient death rate decreased over time. The rates of acute renal failure increased. Significant multivariate predictors of inpatient death include indication of biliary injury or malignancy, and predictors of any complication include public insurance and non-elective admission. CONCLUSION: This is the first national description of BDRs using a large database. In this diverse sampling, both procedure indication and patient characteristics influence morbidity and mortality.

Surgery for chronic pancreatitis: the role of early surgery in pain management.

OBJECTIVES: To examine if surgery performed for pain of chronic pancreatitis (CP) within 3 years diagnosis has greater odds of achieving complete pain relief than later surgery and to find optimal surgical timing for attaining pain relief in CP. METHODS: Retrospective review of records at a tertiary institution 2003 to 2011 for CP where the operative indication was pain. Outcomes were pain-free status, opioid use, and pancreatic insufficiency at 3-year follow-up. Univariate analysis by Fisher exact tests. Receiver operating curve to calculate cutoff threshold time for surgery. RESULTS: Outcomes for 66 patients were included. Median preoperative CP duration was 28 months (interquartile range, 12, 67). Twenty-six patients (39.4%) were free of pain at the 3-year follow-up. Thirty-four patients (51.5%) were opioid users at follow-up. Postoperatively, 34 patients (51.5%) demonstrated endocrine, and 32 patients (48.5%) demonstrated exocrine insufficiency. The optimal cutoff point for preoperative CP duration was 26.5 months (area under the curve, 0.66). Shorter duration of CP before surgery was a predictor of pain-free status and reduced postoperative opioid use at follow-up. CONCLUSIONS: Results from a single institution analysis suggest early surgical intervention of 26.5 months or less of diagnosis is associated with improved pain control, and optimal timing for surgery may be earlier than previously thought.

Appendicitis in the modern era: universal problem and variable treatment.

BACKGROUND: Acute appendicitis is the second most common gastrointestinal diagnosis mandating urgent operation in the U.S. The current state of adult appendectomy, including patient and hospital characteristics, complications, and predictors for complications, are unknown. METHODS: Retrospective review of U.S. Nationwide Inpatient Sample 2003-2011 for appendectomy in ≥18-year-olds was performed. Primary outcomes measures included postoperative complications, length of stay, and patient mortality. Categorical variables were analyzed by χ2, trend analyses by Cochran-Armitage. Multivariable logistic regression was performed to adjust for predictors of developing complications. RESULTS: 1,663,238 weighted appendectomy discharges occurred. Over the study period, complications increased from 3.2 to 3.8% (p < 0.0001), but the overall mortality decreased from 0.14 to 0.09% (p < 0.0001) and mean LOS decreased from 3.1 to 2.6 days (p < 0.0001). The proportion of laparoscopic appendectomy increased over time, 41.7-80.1% (p < 0.0001). Patients were increasingly older (≥65 years: 9.4-11.6%, p < 0.0001), more obese (3.8-8.9%, p < 0.0001), and with more comorbidities (Elixhauser score ≥3: 4.7-9.8%, p < 0.0001). After adjustment, independent predictors for postoperative complications included: open surgery (OR 1.5, 95% C.I. 1.4-1.5), male sex (OR 1.6, 95% CI 1.5-1.6), black race (vs. white: OR 1.5, 95% CI 1.4-1.6), perforated appendix (OR 2.8, 95% CI 2.7-3.0), greater comorbidity (Elixhauser ≥3 vs. 0, OR 11.3, 95% CI 10.5-12.1), non-private insurance status (vs. private: Medicaid OR 1.3, 95% CI 1.2-1.4; Medicare OR 1.7, 95% CI 1.6-1.8), increasing age (>52 years vs. ≤27: OR 1.3; 95% CI 1.2-1.4), and hospital volume (vs. high: low OR 1.2; 95% CI 1.1-1.3). Predictors of laparoscopic appendectomy were age, ethnicity, insurance status, comorbidities, and hospital location. CONCLUSIONS: Laparoscopic appendectomy is increasing but is unevenly deployed across patient groups. Appendectomy patients were increasingly older, with more comorbidities and with increasing rates of obesity. Black patients and patients with public insurance had less utilization of laparoscopy and inferior outcomes.