Neuroadaptations and TGF-ß signaling: emerging role in models of neuropsychiatric disorders.

Neuropsychiatric diseases are manifested by maladaptive behavioral plasticity. Despite the greater understanding of the neuroplasticity underlying behavioral adaptations, pinpointing precise cellular mediators has remained elusive. This has stymied the development of pharmacological interventions to combat these disorders both at the level of progression and relapse. With increased knowledge on the putative role of the transforming growth factor (TGF- ß) family of proteins in mediating diverse neuroadaptations, the influence of TGF-ß signaling in regulating maladaptive cellular and behavioral plasticity underlying neuropsychiatric disorders is being increasingly elucidated. The current review is focused on what is currently known about the TGF-ß signaling in the central nervous system in mediating cellular and behavioral plasticity related to neuropsychiatric manifestations.

TAAR1 regulates drug-induced reinstatement of cocaine-seeking via negatively modulating CaMKIIα activity in the NAc.

Relapse remains a major challenge to the treatment of cocaine addiction. Recent studies suggested that the trace amine-associated receptor 1 (TAAR1) could be a promising target to treat cocaine addiction and relapse; however, the underlying mechanism remains unclear. Here, we aimed to investigate the neural mechanism underlying the role of TAAR1 in the drug priming-induced reinstatement of cocaine-seeking behavior in rats, an animal model of cocaine relapse. We focused on the shell subregion of nucleus accumbens (NAc), a key brain region of the brain reward system. We found that activation of TAAR1 by systemic and intra-NAc shell administration of the selective TAAR1 agonist RO5166017 attenuated drug-induced reinstatement of cocaine-seeking and prevented drug priming-induced CaMKIIα activity in the NAc shell. Activation of TAAR1 dampened the CaMKIIα/GluR1 signaling pathway in the NAc shell and reduced AMPAR-EPSCs on the NAc slice. Microinjection of the selective TAAR1 antagonist EPPTB into the NAc shell enhanced drug-induced reinstatement as well as potentiated CaMKIIα activity in the NAc shell. Furthermore, viral-mediated expression of CaMKIIα in the NAc shell prevented the behavioral effects of TAAR1 activation. Taken together, our findings indicate that TAAR1 regulates drug-induced reinstatement of cocaine-seeking by negatively regulating CaMKIIα activity in the NAc. Our findings elucidate a novel mechanism of TAAR1 in regulating drug-induced reinstatement of cocaine-seeking and further suggests that TAAR1 is a promising target for the treatment of cocaine relapse.

Could meeting the standards of the National Accreditation Program for Rectal Cancer in the National Cancer Database improve patient outcomes?

AIM: The National Accreditation Program for Rectal Cancer (NAPRC) was developed to improve rectal cancer patient outcomes in the United States. The NAPRC consists of a set of process and outcome measures that hospitals must meet in order to be accredited. We aimed to assess the potential of the NAPRC by determining whether achievement of the process measures correlates with improved survival. METHODS: The National Cancer Database was used to identify patients undergoing curative proctectomy for non-metastatic rectal cancer from 2010 to 2014. NAPRC process measures identified in the National Cancer Database included clinical staging completion, treatment starting <60 days from diagnosis, carcinoembryonic antigen level measured prior to treatment, tumour regression grading and margin assessment. RESULTS: There were 48 669 patients identified with a mean age of 62 ± 12.9 years and 61.3% of patients were men. The process measure completed most often was assessment of proximal and distal margins (98.4%) and the measure completed least often was the serum carcinoembryonic antigen level prior to treatment (63.8%). All six process measures were completed in 23.6% of patients. After controlling for age, gender, comorbidities, annual facility resection volume, race and pathological stage, completion of all process measures was associated with a statistically significant mortality decrease (Cox hazard ratio 0.88, 95% CI 0.81-0.94, P < 0.001). CONCLUSION: Participating institutions provided complete datasets for all six process measures in less than a quarter of patients. Compliance with all process measures was associated with a significant mortality reduction. Improved adoption of NAPRC process measures could therefore result in improved survival rates for rectal cancer in the United States.

Adolescent exposure to sucrose increases cocaine-mediated behaviours in adulthood via Smad3.

Adolescence, a critical period of developmental period, is marked by neurobiological changes influenced by environmental factors. Here, we show how exposure to sucrose, which is ubiquitously available in modern diets, results in changes in behavioural response to cocaine as an adult. Rats were given daily access to either 10% sucrose or water during the adolescent period (PND28-42). Following this period, rats are left undisturbed until they reach adulthood. In adulthood, rats were tested for (i) acquisition of a low dose of cocaine, (ii) progressive ratio (PR) test, and (iii) resistance to punished cocaine taking. Sucrose exposure resulted in significant alterations in all behavioural measures. To determine the neurobiological mechanisms leading to such behavioural adaptations, we find that adolescent sucrose exposure results in an upregulation of the transcription factor Smad3 in the nucleus accumbens (NAc) when compared with water-exposed controls. Transiently blocking the active form of this transcription factor (HSV-dnSmad3) during adolescence mitigated the enhanced cocaine vulnerability-like behaviours observed in adulthood. These findings suggest that prior exposure to sucrose during adolescence can heighten the reinforcing effects of cocaine. Furthermore, they identify the TGF-beta pathway and Smad3 as playing a key role in mediating enduring and long-lasting adaptations that contribute to sucrose-induced susceptibility to cocaine. Taken together, these results have important implications for development and suggest that adolescent sucrose exposure may persistently enhance the susceptibility to substance abuse.

Neuroadaptations in the dorsal hippocampus underlie cocaine seeking during prolonged abstinence.

Relapse vulnerability in substance use disorder is attributed to persistent cue-induced drug seeking that intensifies (or "incubates") during drug abstinence. Incubated cocaine seeking has been observed in both humans with cocaine use disorder and in preclinical relapse models. This persistent relapse vulnerability is mediated by neuroadaptations in brain regions involved in reward and motivation. The dorsal hippocampus (DH) is involved in context-induced reinstatement of cocaine seeking but the role of the DH in cocaine seeking during prolonged abstinence has not been investigated. Here we found that transforming growth factor-ß (TGF-ß) superfamily member activin A is increased in the DH on abstinence day (AD) 30 but not AD1 following extended-access cocaine self-administration compared to saline controls. Moreover, activin A does not affect cocaine seeking on AD1 but regulates cocaine seeking on AD30 in a bidirectional manner. Next, we found that activin A regulates phosphorylation of NMDA receptor (NMDAR) subunit GluN2B and that GluN2B-containing NMDARs also regulate expression of cocaine seeking on AD30. Activin A and GluN2B-containing NMDARs have both previously been implicated in hippocampal synaptic plasticity. Therefore, we examined synaptic strength in the DH during prolonged abstinence and observed an increase in moderate long-term potentiation (LTP) in cocaine-treated rats compared to saline controls. Lastly, we examined the role of DH projections to the lateral septum (LS), a brain region implicated in cocaine seeking and found that DH projections to the LS govern cocaine seeking on AD30. Taken together, this study demonstrates a role for the DH in relapse behavior following prolonged abstinence from cocaine self-administration.

Interleukin-1 receptor-associated kinase 4 (IRAK4) in the nucleus accumbens regulates opioid-seeking behavior in male rats.

Opioid addiction remains a severe health problem. While substantial insights underlying opioid addiction have been yielded from neuron-centric studies, the contribution of non-neuronal mechanisms to opioid-related behavioral adaptations has begun to be recognized. Toll-like receptor 4 (TLR4), a pattern recognition receptor, has been widely suggested in opioid-related behaviors. Interleukin-1 receptor-associated kinase 4 (IRAK4) is a kinase essential for TLR4 responses, However, the potential role of IRAK4 in opioid-related responses has not been examined. Here, we explored the role of IRAK4 in cue-induced opioid-seeking behavior in male rats. We found that morphine self-administration increased the phosphorylation level of IRAK4 in the nucleus accumbens (NAc) in rats; the IRAK4 signaling remained activated after morphine extinction and cue-induced reinstatement test. Both systemic and local inhibition of IRAK4 in the NAc core attenuated cue-induced morphine-seeking behavior without affecting the locomotor activity and cue-induced sucrose-seeking. In addition, inhibition of IRAK4 also reduced the cue-induced reinstatement of fentanyl-seeking. Our findings suggest an important role of IRAK4 in opioid relapse-like behaviors and provide novel evidence in the association between innate immunity and drug addiction.

DNA Methyltransferase 3A Is Involved in the Sustained Effects of Chronic Stress on Synaptic Functions and Behaviors.

Emerging evidence suggests that epigenetic mechanisms regulate aberrant gene transcription in stress-associated mental disorders. However, it remains to be elucidated about the role of DNA methylation and its catalyzing enzymes, DNA methyltransferases (DNMTs), in this process. Here, we found that male rats exposed to chronic (2-week) unpredictable stress exhibited a substantial reduction of Dnmt3a after stress cessation in the prefrontal cortex (PFC), a key target region of stress. Treatment of unstressed control rats with DNMT inhibitors recapitulated the effect of chronic unpredictable stress on decreased AMPAR expression and function in PFC. In contrast, overexpression of Dnmt3a in PFC of stressed animals prevented the loss of glutamatergic responses. Moreover, the stress-induced behavioral abnormalities, including the impaired recognition memory, heightened aggression, and hyperlocomotion, were partially attenuated by Dnmt3a expression in PFC of stressed animals. Finally, we found that there were genome-wide DNA methylation changes and transcriptome alterations in PFC of stressed rats, both of which were enriched at several neural pathways, including glutamatergic synapse and microtubule-associated protein kinase signaling. These results have therefore recognized the potential role of DNA epigenetic modification in stress-induced disturbance of synaptic functions and cognitive and emotional processes.

Effects of surgical approach on short- and long-term outcomes in early-stage rectal cancer: a multicenter, propensity score-weighted cohort study.

BACKGROUND: Randomized controlled trials have been unable to demonstrate noninferiority of minimally invasive surgery for rectal cancer. The aim of this study was to assess oncologic resection success, short- and long-term morbidity, and overall survival by operative approach in a homogenous early-stage rectal cancer cohort. METHODS: This is a multicenter, propensity score-weighted cohort study utilizing deidentified data from the National Cancer Database. Individuals who underwent a formal proctectomy for early-stage rectal cancer (T1-2, N0, M0) from 2010 to 2015 were included. The primary outcome was a composite variable indicating successful oncologic resection stratified by operative approach, defined as negative margins with at least 12 lymph nodes evaluated. RESULTS: Among 3649 proctectomies for rectal adenocarcinoma, 1660 (45%) were approached open, 1461 (40%) laparoscopically, and 528 (15%) robotically. After propensity score weighting, compared to open approach, there were no differences in odds of successful oncologic resection (ORadj = 1.07, 95% CI 0.9, 1.28 and ORadj = 1.28, 95% CI 0.97, 1.7). Open approach was associated with longer mean (± SD) length of stay compared to laparoscopic (7.7 ± 0.18 vs. 6.5 ± 0.25 days, p < 0.001) and robotic (7.7 ± 0.18 vs. 6.3 ± 0.35 days, p < 0.001) approaches. In regard to 90-day mortality, compared to open approach, laparoscopic (ORadj = 0.56, 95% CI 0.36, 0.88) and robotic (ORadj = 0.45, 95% CI 0.22, 0.94) approaches were associated with a reduced odd of 90-day mortality. This mortality benefit persists in the long-term for laparoscopic approach (p = 0.003). CONCLUSION: For individuals with early-stage rectal cancer treated with proctectomy, successful oncologic resection can be achieved irrespective of technical approach. Minimally invasive approaches provide short-term reduction in morbidity. Surgical approach must be tailored to each patient based on surgeon experience and judgement in collaboration with a multi-disciplinary team.

The Evolution of Pelvic Pouch Surgery: Optimal Pouch Design for an Ileal Pouch Anal Anastomosis.

The history of pouch surgery is rooted in surgical innovation to improve quality of life in patients requiring surgical extirpation of the colon and rectum. From the early straight ileoanal anastomosis to the continent ileostomy to the modern ileal pouch anal anastomosis (IPAA), techniques have evolved in response to pitfalls in design. Optimal IPAA design and construction have changed in response to functional outcomes. Nowadays, restorative proctocolectomy with IPAA is the optimal treatment for patients with ulcerative colitis or familial adenomatous polyposis. The J-pouch with stapled anastomosis has become the preferred procedure. Historical configurations and technical pearls, as described in this article, should be considered by surgeons who regularly care for patients requiring ileal pouch surgery.

Evaluating disparities in delivery of neoadjuvant guideline-based chemoradiation for rectal cancer: A multicenter, propensity score-weighted cohort study.

BACKGROUND: Despite guideline recommendations, some patients still receive care inappropriate for their clinical stage of disease. Identification of factors that contribute to variation in guideline base care may help eradicate disparities in the treatment of early and locally advanced rectal cancer. METHODS: The American College of Surgeons National Cancer Database from 2010 to 2015 was analyzed with propensity score weighting to identify factors associated with delivery and omission of neoadjuvant guideline-based chemoradiation (GBC) for those with early and locally advanced rectal cancer. RESULTS: Only 74% of patients with rectal cancer received stage-appropriate neoadjuvant chemoradiation; 4544 (88%) of those with early stage disease and 8675 (68%) in locally advanced disease. Chemotherapy and radiotherapy were not planned in 27% and 34% respectively, of those who did not receive GBC. Factors associated with receipt of non-guideline-based neoadjuvant chemoradiation were age >65 years, Medicare insurance, treatment at a community facility, West-South-Central geography, having locally advanced disease, and Charlson-Deyo score >3. Receipt of ideal guideline-based neoadjuvant chemoradiation conferred a survival benefit at 5 years. CONCLUSION: Patient and non-patient factors contribute to disparities in guideline-based delivery of neoadjuvant chemoradiation in the treatment of rectal cancer. Identification of these risk factors are important to help standardize care and improve survival outcomes.

A role for the endocannabinoid enzymes monoacylglycerol and diacylglycerol lipases in cue-induced cocaine craving following prolonged abstinence.

Following exposure to drugs of abuse, long-term neuroadaptations underlie persistent risk to relapse. Endocannabinoid signaling has been associated with drug-induced neuroadaptations, but the role of lipases that mediate endocannabinoid biosynthesis and metabolism in regulating relapse behaviors following prolonged periods of drug abstinence has not been examined. Here, we investigated how pharmacological manipulation of lipases involved in regulating the expression of the endocannabinoid 2-AG in the nucleus accumbens (NAc) influence cocaine relapse via discrete neuroadaptations. At prolonged abstinence (30 days) from cocaine self-administration, there is an increase in the NAc levels of diacylglycerol lipase (DAGL), the enzyme responsible for the synthesis of the endocannabinoid 2-AG, along with decreased levels of monoacylglycerol lipase (MAGL), which hydrolyzes 2-AG. Since endocannabinoid-mediated behavioral plasticity involves phosphatase dysregulation, we examined the phosphatase calcineurin after 30 days of abstinence and found decreased expression in the NAc, which we demonstrate is regulated through the transcription factor EGR1. Intra-NAc pharmacological manipulation of DAGL and MAGL with inhibitors DO-34 and URB-602, respectively, bidirectionally regulated cue-induced cocaine seeking and altered the phosphostatus of translational initiation factor, eIF2α. Finally, we found that cocaine seeking 30 days after abstinence leads to decreased phosphorylation of eIF2α and reduced expression of its downstream target NPAS4, a protein involved in experience-dependent neuronal plasticity. Together, our findings demonstrate that lipases that regulate 2-AG expression influence transcriptional and translational changes in the NAc related to drug relapse vulnerability.

Synaptic Microtubule-Associated Protein EB3 and SRC Phosphorylation Mediate Structural and Behavioral Adaptations During Withdrawal From Cocaine Self-Administration.

Addictive behaviors, including relapse, are thought to depend in part on long-lasting drug-induced adaptations in dendritic spine signaling and morphology in the nucleus accumbens (NAc). While the influence of activity-dependent actin remodeling in these phenomena has been studied extensively, the role of microtubules and associated proteins remains poorly understood. We report that pharmacological inhibition of microtubule polymerization in the NAc inhibited locomotor sensitization to cocaine and contextual reward learning. We then investigated the roles of microtubule end-binding protein 3 (EB3) and SRC kinase in the neuronal and behavioral responses to volitionally administered cocaine. In synaptoneurosomal fractions from the NAc of self-administering male rats, the phosphorylation of SRC at an activating site was induced after 1 d of withdrawal, while EB3 levels were increased only after 30 d of withdrawal. Blocking SRC phosphorylation during early withdrawal by virally overexpressing SRCIN1, a negative regulator of SRC activity known to interact with EB3, abolished the incubation of cocaine craving in both male and female rats. Conversely, mimicking the EB3 increase observed after prolonged withdrawal increased the motivation to consume cocaine in male rats. In mice, the overexpression of either EB3 or SRCIN1 increased dendritic spine density and altered the spine morphology of NAc medium spiny neurons. Finally, a cocaine challenge after prolonged withdrawal recapitulated most of the synaptic protein expression profiles observed at early withdrawal. These findings suggest that microtubule-associated signaling proteins such as EB3 cooperate with actin remodeling pathways, notably SRC kinase activity, to establish and maintain long-lasting cellular and behavioral alterations following cocaine self-administration.SIGNIFICANCE STATEMENT Drug-induced morphological restructuring of dendritic spines of nucleus accumbens neurons is thought to be one of the cellular substrates of long-lasting drug-associated memories. The molecular basis of these persistent changes has remained incompletely understood. Here we implicate for the first time microtubule function in this process, together with key players such as microtubule-bound protein EB3 and synaptic SRC phosphorylation. We propose that microtubule and actin remodeling cooperate during withdrawal to maintain the plastic structural changes initially established by cocaine self-administration. This work opens new translational avenues for further characterization of microtubule-associated regulatory molecules as putative drug targets to tackle relapse to drug taking.

Sarcopenia is associated with worse overall survival in patients with anal squamous cell cancer.

BACKGROUND AND OBJECTIVES: Sarcopenia is associated with poor long-term outcomes in many gastrointestinal cancers, but its role in anal squamous cell carcinoma (ASCC) is not defined. We hypothesized that patients with sarcopenic ASCC experience worse long-term outcomes. METHODS: A retrospective review of patients with ASCC treated at an academic medical center from 2006 to 2017 was performed. Of 104 patients with ASCC, 64 underwent PET/computed tomography before chemoradiation and were included in the analysis. The skeletal muscle index was calculated as total L3 skeletal muscle divided by height squared. Sarcopenia thresholds were 52.4 cm2 /m2 for men and 38.5 cm2 /m2 for women. Cox regression analysis was performed to assess overall and progression-free survival. RESULTS: Twenty-five percent of the patients were sarcopenic (n = 16). Demographics were similar between groups. There was no difference in the clinical stage or comorbidities between groups. On multivariate analysis, factors associated with worse overall survival were male gender (hazard ratio [HR] 3.7, P = .022) and sarcopenia (HR 3.6, P = .019). Male gender was associated with worse progression-free survival (HR 2.6, P = .016). CONCLUSIONS: Sarcopenia is associated with worse overall survival in patients with anal cancer. Further studies are indicated to determine if survival can be improved with increased attention to nutritional status in sarcopenic patients.

WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine.

Wiskott-Aldrich syndrome protein (WASP) family verprolin homologous protein 1 (WAVE1) regulates actin-related protein 2/3 (Arp2/3) complex-mediated actin polymerization. Our previous studies have found WAVE1 to be inhibited by Cdk5-mediated phosphorylation in brain and to play a role in the regulation of dendritic spine morphology. Here we report that mice in which WAVE1 was knocked out (KO) in neurons expressing the D1 dopamine receptor (D1-KO), but not mice where WAVE1 was knocked out in neurons expressing the D2 dopamine receptor (D2-KO), exhibited a significant decrease in place preference associated with cocaine. In contrast to wild-type (WT) and WAVE1 D2-KO mice, cocaine-induced sensitized locomotor behavior was not maintained in WAVE1 D1-KO mice. After chronic cocaine administration and following withdrawal, an acute cocaine challenge induced WAVE1 activation in striatum, which was assessed by dephosphorylation. The cocaine-induced WAVE1 dephosphorylation was attenuated by coadministration of either a D1 dopamine receptor or NMDA glutamate receptor antagonist. Upon an acute challenge of cocaine following chronic cocaine exposure and withdrawal, we also observed in WT, but not in WAVE1 D1-KO mice, a decrease in dendritic spine density and a decrease in the frequency of excitatory postsynaptic AMPA receptor currents in medium spiny projection neurons expressing the D1 dopamine receptor (D1-MSNs) in the nucleus accumbens. These results suggest that WAVE1 is involved selectively in D1-MSNs in cocaine-evoked neuronal activity-mediated feedback regulation of glutamatergic synapses.

Is Conversion of a Failed IPAA to a Continent Ileostomy a Risk Factor for Long-term Failure?

BACKGROUND: A continent ileostomy may be offered to patients in hopes of avoiding permanent ileostomy. Data on the outcomes of continent ileostomy patients with a history of a failed IPAA are limited. OBJECTIVE: This study aimed to assess whether a history of previous failed IPAA had an effect on continent ileostomy survival and the long-term outcomes. DESIGN: This was a retrospective cohort study. SETTINGS: This investigation took place in a high-volume, specialized colorectal surgery department. PATIENTS: Patients who underwent continent ileostomy construction after IPAA failure between 1982 and 2013 were evaluated and compared with patients who have no history of IPAA surgery. MAIN OUTCOME MEASURES: Functional outcomes and long-term complications were compared. RESULTS: A total of 67 patients fulfilled the case-matching criteria and were included in the analysis. Requirement of major (52% vs 61%; p = 0.756) and minor (15% vs 19%; p = 0.492) revisions were comparable between patients who had continent ileostomy after a failed IPAA and those who had continent ileostomy without having a previous restorative procedure. Intubations per day (5 vs 5; p = 0.804) and per night (1 vs 1; p = 0.700) were similar in both groups. Our data show no clear relationship between failure of continent ileostomy and history of failed IPAA (p = 0.638). The most common cause of continent ileostomy failure was enterocutaneous/enteroenteric fistula (n = 14). Six patients died during the study period because of other causes unrelated to continent ileostomy. LIMITATIONS: This study was limited by its retrospective and nonrandomized nature. CONCLUSIONS: Converting a failed IPAA to a continent ileostomy did not worsen continent ileostomy outcomes in this selected group of patients. When a redo IPAA is not feasible, continent ileostomy can be offered as an alternative to conventional end ileostomy in highly motivated patients. See Video Abstract at http://links.lww.com/DCR/A803.

Histone arginine methylation in cocaine action in the nucleus accumbens.

Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms-such as histone acetylation and methylation on Lys residues-have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motivation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction.

Reoperative Surgery in Complex Crohn's Disease.

This article provides a structured approach to the technical aspects of reoperative surgery for Crohn's disease. Specific indications for surgery including repeat ileocolic resection, Crohn's complications of ileal pouch anal anastomosis and continent ileostomy, completion proctectomy, and the role of small bowel transplant will be discussed.

Nationwide Heterogeneity in Hospital-Specific Probabilities of Rectal Cancer Understaging and Its Effects on Outcomes.

BACKGROUND: Rectal cancer patients who are understaged may not be offered the highest quality treatment modalities, which are based on an accurate assessment of preoperative staging. The objective of this study was to evaluate heterogeneity in the probability of being understaged at Commission on Cancer hospitals in the United States and to assess how this variation affects outcomes. METHODS: The 2006-2013 National Cancer Data Base was queried for clinical stage I-III rectal cancer patients who underwent resection. The initial clinical stage was compared with the "gold standard," pathological stage. A Bayesian multilevel logistic regression model was used to characterize variation in hospital-specific probabilities of being understaged (clinical stage < pathologic stage). Separate analyses assessed the impact of being understaged on positive circumferential resection margins (CRM), receipt of adjuvant chemotherapy, and 5-year overall survival. RESULTS: Among 12,684 patients who did not receive neoadjuvant chemoradiation and treated at 1176 hospitals, 3044 (24%) were understaged. After patient level risk-adjustment, a 24-fold difference in the probability of being understaged was observed between hospitals (range 3-72%, median = 15%). Understaging was independently associated with positive CRM [odds ratio (OR) 1.59, 95% confidence interval (CI) 1.39, 1.92] and receipt of adjuvant chemotherapy (OR 14.22, 95% CI 13.55, 18.88). Despite an increase in the delivery of systemic therapy after surgical resection, understaging was associated with worse survival (hazard ratio = 1.61, 95% CI 1.48, 1.95). CONCLUSIONS: Deficiencies in high-quality rectal cancer management begin with incorrect clinical staging. The risk-adjusted probability of understaging varied widely between hospitals. This institutional failure to provide optimal oncological management at the start of care was associated with worse long-term survival.

Modified Pfannenstiel Open Approach as an Alternative to Laparoscopic Total Proctocolectomy and IPAA: Comparison of Short- and Long-term Outcomes and Quality of Life.

BACKGROUND: A laparoscopic approach to total proctocolectomy with IPAA has been suggested to have better short-term outcomes and cosmesis, whereas open surgery by midline incision may result in shorter operative times. We hypothesized that a modified Pfannenstiel open approach would combine the advantages of both techniques. OBJECTIVE: The purpose of this study was to compare outcomes of open total proctocolectomy with IPAA using a modified Pfannenstiel incision versus those following the laparoscopic approach. DESIGN: This was a retrospective study comparing patients submitted to open IPAA using modified Pfannenstiel incision versus laparoscopy from 1998 to 2014. SETTINGS: The study was conducted at a high-volume tertiary referral center. PATIENTS: Among 1275 patients, 119 patients underwent the laparoscopic approach and 33 underwent the modified Pfannenstiel approach. MAIN OUTCOME MEASURES: Short- and long-term outcomes were evaluated, and quality-of-life questionnaires were assessed. RESULTS: Patients who underwent the modified Pfannenstiel approach were younger, more often women, and had lower BMI and ASA classification compared with those who underwent laparoscopy. Surgical time was lower in Pfannenstiel, and no difference was observed in length of hospital stay. No difference was observed in postoperative complications, pouch failure rate, or quality of life. Patients were then matched 1:1 by diagnosis, sex, age (±5 y) and BMI (±5 kg/m). The Pfannenstiel approach still had a shorter surgical time. No difference was observed in the length of hospital stay, complications, pouch failure, or quality of life. In long-term follow-up, pouchitis symptoms occurred more frequently in Pfannenstiel (mean follow-up = 7.3 y), and seepage was more frequently observed in the laparoscopy group (mean follow-up = 4.2 y). These differences were not observed in matched patients. LIMITATIONS: The study was limited by its retrospective design and inherent selection bias. CONCLUSIONS: The modified Pfannenstiel approach provides equivalent short- and long-term outcomes and similar quality of life compared with laparoscopy but with a significantly shorter operative time. The modified Pfannenstiel approach to total proctocolectomy with IPAA may be the most efficient method in selected patients. See Video Abstract at http://links.lww.com/DCR/A562.