Alan J. Herline

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.

Use of Endoscopic Ultrasound to Guide Combination Medical and Surgical Therapy for Patients with Crohn's Perianal Fistulas

Background: This study was performed to assess if using endoscopic ultrasound (EUS) to assess and guide combination medical and surgical therapy during fistula healing will lead to a high rate of durable fistula closure and a low or absent incidence of perianal abscess formation in patients with Crohns perianal fistulas. Methods: This is a retrospective analysis of 21 patients who presented with a symptomatic Crohns perianal fistula. Patients were enrolled in a clinical practice protocol of serial EUS exams. All patients underwent a baseline rectal EUS and were placed on maximal medical treatment with 6‐mercaptopurine (6‐MP) or azathioprine, Cipro, and infliximab (5 mg/kg at 0, 2, and 6 wk and then every 8 wk). Patients were also assessed at baseline by a colorectal surgeon who was aware of the EUS findings. Seton placement and incision and drainage were performed when appropriate. Serial EUS examinations were performed, and the findings were used to guide therapy (i.e., the presence of fistula healing on EUS was used to guide seton removal, discontinuation of infliximab, and Cipro). Results: In the 21 patients enrolled, the median duration of active perianal symptoms was 9 wks (1‐36). 10 patients (48%) had previous perianal surgery and 5 (24%) had received infliximab previously. The fistulas treated included 8 trans‐sphincteric, 2 superficial, 3 recto‐vaginal, and 7 with multiple and horseshoe fistulas. 13 patients (62%) had associated abscesses at presentation. Eighteen of 21 patients (86%) had complete cessation of drainage initially. Median time to cessation of drainage was 10.6 weeks (range, 4‐32 wk). Sixteen of 21 patients (76%) maintained long‐term cessation of drainage. The median length of follow‐up was 68 weeks (range, 35‐101 wk). No abscess developed during treatment in any patient. EUS evidence of persistent fistula activity was seen in 10 patients (48%). Of the 11 patients (52%) in whom EUS showed no persistent fistula activity, 7 (64%) have maintained fistula closure off of infliximab and Cipro. Median duration from last infliximab infusion was 47 weeks (range, 20‐80 wk). The remaining 4 patients continued infliximab to maintain remission of their luminal disease. Only 1 patient with a horseshoe fistula showed complete healing on EUS. Conclusion: In conclusion, using EUS to guide therapy for Crohns perianal fistulas with infliximab, an immunosuppressive, and an antibiotic is associated with a high short and long‐term fistula response rate. EUS may identify a subset of patients who can discontinue infliximab without recurrence of fistula drainage.

A Randomized Prospective Trial of Endoscopic Ultrasound to Guide Combination Medical and Surgical Treatment for Crohn's Perianal Fistulas

AIMS:To prospectively determine if rectal endoscopic ultrasound (EUS) can guide combination medical and surgical therapy and improve outcomes for patients with perianal fistulizing Crohns disease.METHODS:Ten patients with perianal Crohns disease were prospectively enrolled in a randomized prospective pilot study. The patients were randomized to either the EUS cohort or the control group. All patients underwent a rectal EUS to delineate fistula anatomy followed by an examination under anesthesia by a colorectal surgeon with seton placement and/or incision and drainage, as indicated. The surgeon was blinded to the initial EUS results of patients in the control group. Medical treatment was maximized with 6-mercaptopurine (1.0–1.5 mg/kg) or azathioprine (2.0–2.5 mg/kg), ciprofloxacin (1,000 mg a day) or metronidazole (1,500 mg a day), and infliximab (5 mg/kg at 0, 2, and 6 wk and then every 8 wk). For patients in the control group, additional interventions (seton removal and repeat surgery) were at the discretion of the surgeon (without EUS guidance). Patients in the EUS cohort had EUS performed at weeks 22 and 38, with additional surgical interventions based on EUS findings. The primary end point was complete cessation of drainage at week 54. All patients had a repeat EUS performed at week 54 to determine the fistula status on EUS (secondary end point). The need for additional surgery was defined as a treatment failure.RESULTS:Ten patients were enrolled in the study. One of 5 (20%) in the control group and 4 of 5 (80%) in the EUS group had complete cessation of drainage. From the control group, 3 patients failed due to repeat surgery (2 for persistent/recurrent fistula and 1 for abscess), and 1 had a persistent drainage at week 54. In the EUS cohort, 1 patient had a recurrent abscess after his seton fell out prematurely.In the EUS cohort, the median time to cessation of drainage was 99 days, and the time to EUS evidence of fistula inactivity was 229 days.CONCLUSION:This pilot study suggests that using EUS to guide combination medical and surgical therapy for perianal fistulizing Crohns disease improves the outcomes.

Is routine pouch surveillance for dysplasia indicated for ileoanal pouches

AbstractPURPOSE: Isolated accounts of neoplastic pouch transformation suggest the need to perform routine ileoanal pouch surveillance with biopsy. These reports imply a model of dysplasia to cancer transformation of the pouch mucosa. More recent reports studying “high risk” ulcerative colitis patients concluded that the development of pouch dysplasia is indeed a rare event. This study was designed to evaluate our institutional incidence of dysplasia in ileoanal pouch during long-term follow-up. METHODS: A prospective database of all patients undergoing ileoanal pouch construction (n = 767) was queried for all patients undergoing pouch biopsy between 1983 and 2001. All patients with ulcerative colitis who underwent pouch biopsy were included. This excluded patients with Crohn’s disease, indeterminate colitis, and familial adenomatous polyposis. Pathology reports were reviewed for histologic evidence of inflammation, atypia, metaplasia, dysplasia, or cancer. Patient age at biopsy, pouch age at time of biopsy, and pathology were analyzed. RESULTS: The ileoanal pouches of 160 patients were surveyed with biopsies a total of 222 times. The average length of follow-up from pouch construction to time of surveillance and biopsy was 8.4 ± 4.6 years. There were 83 patients (52 percent) whose pouches were older than 10 years (mean, 12.7 ± 2) at time of surveillance. With over 1,800 pouch-years of surveillance, only 1 patient had focal, low-grade dysplasia in the pouch. This patient demonstrated no evidence of dysplasia on further surveillance. CONCLUSION: Even with long-term follow-up of ileoanal pouch patients, there is little evidence to support routine biopsy of the ileal mucosa in ulcerative colitis patients.

Carcinoid tumors are 15 times more common in patients with Crohn's disease.

Background: The coexistence of intestinal neoplasms with Crohns disease (CD) has been reported, but the evidence of an increased risk of carcinoid tumor with Crohns disease has been mixed. We present 4 patients with CD with associated carcinoid tumor. Methods: The charts of 111 patients with CD who had undergone resection between June 2001 and March 2005 were reviewed. The number of incidental carcinoid tumors in patients who underwent an appendectomy was used as a control. Results: Four cases of carcinoid tumor discovered in patients at resection for CD were identified. None had metastatic disease or carcinoid syndrome. These included 1 cecal (1 mm), 2 appendiceal (3 and 7mm), and 1 transverse colon (7 mm) carcinoid tumors. None of the carcinoid tumors were identified in regions of active Crohns disease. The incidence of carcinoid tumor in patients with Crohns disease was 4 of 111 (3.6%). In comparison, 3 of 1199 patients (0.25%) who had appendectomies were identified as having appendiceal carcinoid tumor. Crohns disease was associated with an increased incidence of carcinoid tumor; OR 14.9 (95% CI 2.5–102.5), P < 0.0001. Conclusions: There was a significantly increased incidence of carcinoid tumor in our Crohns patients compared to the control patients. None of the carcinoid tumors developed in areas of Crohns disease. This suggests that the development of carcinoid tumors may be secondary to distant proinflammatory mediators, rather than a local inflammatory effect from adjacent Crohns disease. Patients with CD may be at increased risk of developing a carcinoid tumor.

Proteomic profiling of mucosal and submucosal colonic tissues yields protein signatures that differentiate the inflammatory colitides

Background: Differentiating ulcerative colitis (UC) from Crohns colitis (CC) can be difficult and may lead to inaccurate diagnoses in up to 30% of inflammatory bowel disease (IBD) patients. Much of the diagnostic uncertainty arises from the overlap of clinical and histologic features. Matrix‐assisted laser desorption/ionization mass spectrometry (MALDI‐MS) permits a histology‐directed cellular protein analysis of tissues. As a pilot study, we evaluated the ability of histology‐directed MALDI‐MS to determine the proteomic patterns for potential differences between CC and UC specimens. Methods: Mucosal and submucosal layers of CC and UC colon resection samples were analyzed after histologic assessment. To determine whether MALDI‐MS would distinguish inflammation, the uninflamed (n = 21) versus inflamed submucosa (n = 22) were compared in UC and the uninflamed (n = 17) versus inflamed submucosa (n = 20) in CC. To determine whether there were proteomic differences between the colitides, the uninflamed UC submucosa (n = 21) was compared versus the uninflamed CC submucosa (n = 17), the inflamed UC submucosa (n = 22) was compared versus the inflamed CC submucosa (n = 20), and inflamed UC mucosa versus inflamed CC mucosa. Pairwise statistics comparisons of the subsets were performed. Results: Pairwise comparative analyses of the clinical groups allowed identifying subsets of features important for classification. Comparison of inflamed versus uninflamed CC submucosa showed two significant peaks: m/z 6445 (P = 0.0003) and 12692 (P = 0.003). In the case of inflamed versus uninflamed UC submucosa, several significant differentiating peaks were found, but classification was worse. Comparisons of the proteomic spectra of inflamed submucosa between UC and CC identified two discrete significant peaks: m/z 8773 (P = 0.006) and 9245 (P = 0.0009). Comparisons of the proteomic spectra of uninflamed submucosa between UC and CC identified three discrete significant peaks: m/z 2778 (P = 0.005), 9232 (P = 0.005), and 9519 (P = 0.005). No significantly different features were found between UC and CC inflamed mucosa. Conclusions: MALDI‐MS was able to distinguish CC and UC specimens while profiling the colonic submucosa. Further analyses and protein identification of the differential protein peaks may aid in accurately diagnosing IBD and developing appropriate personalized therapies. (Inflamm Bowel Dis 2011;)

Ultrasound-to-computer-tomography registration for image-guided laparoscopic liver surgery

BackgroundThe application of image-guided surgery (IGS) to laparoscopic liver resection and ablation is currently limited, but it would assist in intraoperative decision making regarding oncologic margins, ablation probe placement, and ablation tracking.MethodsEight spherical surface targets on a liver phantom were imaged with an optically tracked laparoscopic ultrasound (US) probe. Ten US images of each target were registered to computer tomography (CT) images of the phantoms and then mapped to the CT scans. Accuracy of the registration was assessed by comparing the distance between the predicted target location and the position obtained directly from CT.ResultsThe average localization error was 5.3 mm. The errors resulted primarily from inaccurate US probe tracking but were otherwise insensitive to the variability that arises from manually identifying targets in US and CT images.ConclusionsThe results obtained for US-to-CT registration in a phantom model suggest that further investigations into its clinical use are warranted and that other IGS technologies could be applied to laparoscopic liver surgery as well.

Design and implementation of a PC-based image-guided surgical system

In interactive, image-guided surgery, current physical space position in the operating room is displayed on various sets of medical images used for surgical navigation. We have developed a PC-based surgical guidance system (ORION) which synchronously displays surgical position on up to four image sets and updates them in real time. There are three essential components which must be developed for this system: (1) accurately tracked instruments; (2) accurate registration techniques to map physical space to image space; and (3) methods to display and update the image sets on a computer monitor. For each of these components, we have developed a set of dynamic link libraries in MS Visual C++ 6.0 supporting various hardware tools and software techniques. Surgical instruments are tracked in physical space using an active optical tracking system. Several of the different registration algorithms were developed with a library of robust math kernel functions, and the accuracy of all registration techniques was thoroughly investigated. Our display was developed using the Win32 API for windows management and tomographic visualization, a frame grabber for live video capture, and OpenGL for visualization of surface renderings. We have begun to use this current implementation of our system for several surgical procedures, including open and minimally invasive liver surgery.

A prototype ultrasound-guided laparoscopic radiofrequency ablation system

BackgroundAdvanced laparoscopic procedures, particularly laparoscopic liver resection and ablation, may benefit from image-guided surgery techniques that involve interactive three-dimensional imaging and instrument tracking.MethodsA prototype system for laparoscopic ultrasound-guided radiofrequency ablation was designed and implemented. This system uses an infrared camera to track instruments and runs on a personal computer. Features of the system include spatially registered ultrasound visualization, volume reconstruction, and interactive targeting. Targeting of accuracy studies was performed by directing a tracked needle to a phantom target.ResultsUltrasound data collection and volume reconstruction can be achieved within minutes and interactively reviewed by the surgeon. Early results with phantom experiments demonstrate a targeting accuracy of 5 to 10 mm.ConclusionsThese results support the further development of this and similar image-guided surgery systems for specific laparoscopic procedures. Eventually, rigorous clinical evaluation will be necessary to prove their value.

Development of spectral markers for the discrimination of ulcerative colitis and Crohn's disease using Raman spectroscopy.

BACKGROUND: Ulcerative colitis and Crohns disease are 2 distinct forms of IBD that can overlap radiologically, endoscopically, and pathologically. This difficulty complicates surgical options. The development of new technologies providing accurate diagnosis of IBD is needed. Raman spectroscopy is a noninvasive method that uses the intrinsic properties of tissue and that tissues vibrational energy in reaction to light. PURPOSE: We hypothesize that Raman spectroscopy can detect the structural and compositional changes that occur in the tissue during the development of inflammatory bowel disease, and thus may offer increased diagnostic certainty in the differentiation between Crohns disease and ulcerative colitis. METHODS: Fresh frozen colon tissue biopsies from patients with ulcerative colitis (n = 12) and with Crohns disease (n = 9) were measured in vitro using a custom-designed Raman fiber-optic probe. For spectra collection, the probe was placed in gentle contact with the mucosa surface for 3 seconds, with excitation power at 150 mW. Five spectra were acquired from each biopsy to increase the signal-to-noise ratio and to ensure repeatability of data collection. Mean spectra were analyzed for peak difference and molecular origin. RESULTS: Significant difference was observed between the spectra from each disease in the spectral regions assigned to nucleic acid, phenylalanine, and lipids. Tissue samples from patients with ulcerative colitis demonstrated higher content of lipid and lower amount of phenylalanine and nucleic acid. These characteristic Raman features could serve as spectral markers that can potentially be applied to distinguish ulcerative colitis and Crohns disease. CONCLUSIONS: This study presents the only application of Raman spectroscopy in the diagnosis of inflammatory bowel disease. The feasibility of this technique in differentially detecting molecular alterations in ulcerative colitis and Crohns disease has been demonstrated, indicating the potential to improve diagnostic accuracy of inflammatory bowel disease.