Anne Marie Boller

Effect of Laparoscopic-Assisted Resection vs Open Resection of Stage II or III Rectal Cancer on Pathologic Outcomes: The ACOSOG Z6051 Randomized Clinical Trial

IMPORTANCE Evidence about the efficacy of laparoscopic resection of rectal cancer is incomplete, particularly for patients with more advanced-stage disease. OBJECTIVE To determine whether laparoscopic resection is noninferior to open resection, as determined by gross pathologic and histologic evaluation of the resected proctectomy specimen. DESIGN, SETTING, AND PARTICIPANTS A multicenter, balanced, noninferiority, randomized trial enrolled patients between October 2008 and September 2013. The trial was conducted by credentialed surgeons from 35 institutions in the United States and Canada. A total of 486 patients with clinical stage II or III rectal cancer within 12 cm of the anal verge were randomized after completion of neoadjuvant therapy to laparoscopic or open resection. INTERVENTIONS Standard laparoscopic and open approaches were performed by the credentialed surgeons. MAIN OUTCOMES AND MEASURES The primary outcome assessing efficacy was a composite of circumferential radial margin greater than 1 mm, distal margin without tumor, and completeness of total mesorectal excision. A 6% noninferiority margin was chosen according to clinical relevance estimation. RESULTS Two hundred forty patients with laparoscopic resection and 222 with open resection were evaluable for analysis of the 486 enrolled. Successful resection occurred in 81.7% of laparoscopic resection cases (95% CI, 76.8%-86.6%) and 86.9% of open resection cases (95% CI, 82.5%-91.4%) and did not support noninferiority (difference, -5.3%; 1-sided 95% CI, -10.8% to ∞; P for noninferiority = .41). Patients underwent low anterior resection (76.7%) or abdominoperineal resection (23.3%). Conversion to open resection occurred in 11.3% of patients. Operative time was significantly longer for laparoscopic resection (mean, 266.2 vs 220.6 minutes; mean difference, 45.5 minutes; 95% CI, 27.7-63.4; P < .001). Length of stay (7.3 vs 7.0 days; mean difference, 0.3 days; 95% CI, -0.6 to 1.1), readmission within 30 days (3.3% vs 4.1%; difference, -0.7%; 95% CI, -4.2% to 2.7%), and severe complications (22.5% vs 22.1%; difference, 0.4%; 95% CI, -4.2% to 2.7%) did not differ significantly. Quality of the total mesorectal excision specimen in 462 operated and analyzed surgeries was complete (77%) and nearly complete (16.5%) in 93.5% of the cases. Negative circumferential radial margin was observed in 90% of the overall group (87.9% laparoscopic resection and 92.3% open resection; P = .11). Distal margin result was negative in more than 98% of patients irrespective of type of surgery (P = .91). CONCLUSIONS AND RELEVANCE Among patients with stage II or III rectal cancer, the use of laparoscopic resection compared with open resection failed to meet the criterion for noninferiority for pathologic outcomes. Pending clinical oncologic outcomes, the findings do not support the use of laparoscopic resection in these patients. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00726622.

Expression of RORγt Marks a Pathogenic Regulatory T Cell Subset in Human Colon Cancer

Tregs that expand in human colon cancer have proinflammatory properties and contribute to tumor progression. A Treg Melting Pot Some things are not what they seem. Like the allegorical wolf in sheep’s clothing, cell populations that may seem homogeneous may actually contain subsets with different functions. Indeed, such hidden subpopulations may result in contradictory findings in different systems. Blatner et al. now find a subset of regulatory T cells (Tregs) in human colon cancer that may explain disparate clinical outcomes between studies. The authors found preferential expansion in human colon cancer of Tregs that can suppress T cells but are not anti-inflammatory like more classic Tregs. They then looked in a mouse model of hereditary polyposis and found that these cells, which express Foxp3 and RORγt, express the proinflammatory cytokine IL-17 and are directly associated with inflammation and disease progression. The balance between anti-inflammatory Tregs and these “pathogenic” proinflammatory Tregs may play a role in regulating cancer inflammation. Targeting these RORγt+ Tregs may influence disease outcome in colon cancer. The role of regulatory T cells (Tregs) in human colon cancer (CC) remains controversial: high densities of tumor-infiltrating Tregs can correlate with better or worse clinical outcomes depending on the study. In mouse models of cancer, Tregs have been reported to suppress inflammation and protect the host, suppress T cells and protect the tumor, or even have direct cancer-promoting attributes. These different effects may result from the presence of different Treg subsets. We report the preferential expansion of a Treg subset in human CC with potent T cell–suppressive, but compromised anti-inflammatory, properties; these cells are distinguished from Tregs present in healthy donors by their coexpression of Foxp3 and RORγt. Tregs with similar attributes were found to be expanded in mouse models of hereditary polyposis. Indeed, ablation of the RORγt gene in Foxp3+ cells in polyp-prone mice stabilized Treg anti-inflammatory functions, suppressed inflammation, improved polyp-specific immune surveillance, and severely attenuated polyposis. Ablation of interleukin-6 (IL-6), IL-23, IL-17, or tumor necrosis factor–α in polyp-prone mice reduced polyp number but not to the same extent as loss of RORγt. Surprisingly, loss of IL-17A had a dual effect: IL-17A–deficient mice had fewer polyps but continued to have RORγt+ Tregs and developed invasive cancer. Thus, we conclude that RORγt has a central role in determining the balance between protective and pathogenic Tregs in CC and that Treg subtype regulates inflammation, potency of immune surveillance, and severity of disease outcome.

Fecal Incontinence: Epidemiology, Impact, and Treatment.

Fecal incontinence (FI) is a chronic and debilitating condition that carries a significant health, economic, and social burden. FI has a considerable psychosocial and financial impact on patients and their families. A variety of treatment modalities are available for FI including behavioral and dietary modifications, pharmacotherapy, pelvic floor physical therapy, bulking agents, anal sphincteroplasty, sacral nerve stimulation, artificial sphincters, magnetic sphincters, posterior anal sling, and colostomy.

Mesh—Is Less More?

Due to safety concerns, the US Food and Drug Administration has placed a warning on the use of transvaginal mesh in pelvic organ prolapse (POP) repair.1 Studies like the one by Chughtai et al2 in this issue of JAMA Surgery are important because they provide important information regarding the incidence and timing of complications. Compared with other studies, their work is unique for 2 reasons. First, it focuses on clinically important mesh complications (those that require an intervention as opposed to asymptomatic erosions). Second, it includes a statewide database, which minimizes underreporting that occurs when patients change clinicians secondary to perceived complications. The authors compare the following 4 groups of surgical procedures that use varying amounts of mesh: (1) POP repair with transvaginal mesh and mesh stress urinary incontinence (SUI) sling, (2) POP repair with transvaginal mesh and no concurrent sling, (3) POP repair without mesh but with mesh sling, and (4) mesh sling alone. They conclude that there is a dose-response relationship between the amount of mesh used and the need for surgical intervention secondary to mesh erosion. This conclusion seems logical and is supported by the data, but its clinical applicability is limited because patients with SUI and POP often desire surgical correction for both problems. In other words, the population of groups 1 and 3 differs from that of groups 2 and 4. The authors’ hypothesis about the dose-dependent risk of mesh erosions is intriguing and warrants further investigation. Patients undergoing surgery for POP who have occult SUI would be a more ideal population in which to study this theory. These patients have underlying SUI that is unmasked when POP is reduced (ie, the urethra is unkinked) and are given the option of a concomitant vs staged procedure (the placement of mesh sling at the time of POP repair vs delayed placement in those who develop symptomatic SUI after POP repair). Does placing a sling at the same time as opposed to later increase the risk of mesh-related complications? A study answering this question would guide treatment decisions and reflect a scenario in which the dose response would be clinically important. The data reported in this article are limited by the contents of its database. The Current Procedural Terminology codes used to identify transvaginal prolapse repairs with mesh include other prosthetic grafts (biologic implants and nonmesh devices) that would dilute the denominator, underestimating the overall rate of mesh complications. In addition, the authors note that the number of laparoscopic sacrocolpopexies in the database was too few to include in the analysis. This limitation poses serious concern for the generalizability of the database. It has been well established that sacrocolpopexies have greater success than transvaginal mesh and fewer complications.3-5 The number of sacrocolpopexies has almost doubled yearly from 2008 to 2011, while the number of transvaginal mesh procedures has declined.6 Studying a population of patients undergoing sacrocolpopexies and midurethral slings for a dose-response mesh risk may be more reflective of current standards of practice.