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1.
Ann Surg ; 269(4): 700-711, 2019 04.
Article in English | MEDLINE | ID: mdl-29315090

ABSTRACT

OBJECTIVE: To determine the incidence of anastomotic-related morbidity following Transanal Total Mesorectal Excision (TaTME) and identify independent risk factors for failure. BACKGROUND: Anastomotic leak and its sequelae are dreaded complications following gastrointestinal surgery. TaTME is a recent technique for rectal resection, which includes novel anastomotic techniques. METHODS: Prospective study of consecutive reconstructed TaTME cases recorded over 30 months in 107 surgical centers across 29 countries. Primary endpoint was "anastomotic failure," defined as a composite endpoint of early or delayed leak, pelvic abscess, anastomotic fistula, chronic sinus, or anastomotic stricture. Multivariate regression analysis performed identifying independent risk factors of anastomotic failure and an observed risk score developed. RESULTS: One thousand five hundred ninety-four cases with anastomotic reconstruction were analyzed; 96.6% performed for cancer. Median anastomotic height from anal verge was 3.0 ±â€Š2.0 cm with stapled techniques accounting for 66.0%. The overall anastomotic failure rate was 15.7%. This included early (7.8%) and delayed leak (2.0%), pelvic abscess (4.7%), anastomotic fistula (0.8%), chronic sinus (0.9%), and anastomotic stricture in 3.6% of cases. Independent risk factors of anastomotic failure were: male sex, obesity, smoking, diabetes mellitus, tumors >25 mm, excessive intraoperative blood loss, manual anastomosis, and prolonged perineal operative time. A scoring system for preoperative risk factors was associated with observed rates of anastomotic failure between 6.3% to 50% based on the cumulative score. CONCLUSIONS: Large tumors in obese, diabetic male patients who smoke have the highest risk of anastomotic failure. Acknowledging such risk factors can guide appropriate consent and clinical decision-making that may reduce anastomotic-related morbidity.


Subject(s)
Anastomotic Leak/epidemiology , Rectum/surgery , Adult , Aged , Aged, 80 and over , Anal Canal , Anastomosis, Surgical/methods , Digestive System Surgical Procedures/methods , Female , Humans , Incidence , Internationality , Male , Middle Aged , Prospective Studies , Registries , Risk Factors , Young Adult
2.
Surg Innov ; 25(5): 525-535, 2018 Oct.
Article in English | MEDLINE | ID: mdl-29902950

ABSTRACT

Surgery remains the mainstay of curative treatment for primary rectal cancer. For mid and low rectal tumors, optimal oncologic surgery requires total mesorectal excision (TME) to ensure the tumor and locoregional lymph nodes are removed. Adequacy of surgery is directly linked to survival outcomes and, in particular, local recurrence. From a technical perspective, the more distal the tumor, the more challenging the surgery and consequently, the risk for oncologically incomplete surgery is higher. TME can be performed by an open, laparoscopic, robotic or transanal approach. There is a lack of consensus on the "gold standard" approach with each of these options offering specific advantages. The International Symposium on the Future of Rectal Cancer Surgery was convened to discuss the current challenges and future pathways of the 4 approaches for TME. This article reviews the findings and discussion from an expert, international panel.


Subject(s)
Colorectal Surgery/organization & administration , Colorectal Surgery/trends , Rectal Neoplasms/surgery , Digestive System Surgical Procedures , Humans , Natural Orifice Endoscopic Surgery
3.
Surg Endosc ; 32(9): 4036-4043, 2018 09.
Article in English | MEDLINE | ID: mdl-29785456

ABSTRACT

BACKGROUND: Iatrogenic ureteric injury is a serious complication of colorectal surgery. Incidence is estimated to be between 0.3 and 1.5%. Of all ureteric injuries, 9% occur during colorectal procedures. Ureteric stents are utilised as a method to reduce the risk of injury; however, these are not without risk and do not guarantee prevention of injury. Fluorescence is a safe and effective alternative for intraoperative ureteric localisation. This proof of principle study aims to assess the use of methylene blue to fluoresce the ureter during colorectal surgery. METHOD: Patients undergoing elective colorectal surgery were included in this open label, non-randomised study. Methylene blue was administered intravenously at varying doses (0.25-1 mg/kg) over 5 min, 10-15 min prior to entering 'ureteric territory.' Fluorescence was assessed using the PINPOINT Deep Red laparoscopic system at fixed time points by the surgeon and an independent observer. RESULTS: 42 patients received methylene blue; 2 patients were excluded from analysis. Of the 69 ureters assessed, 64 were seen under fluorescence. Of these, 14 were not visible under white light. 50 ureters were observed with both fluorescence and white light with 14 of these being seen earlier with fluorescence. In ten cases, fluorescence revealed the ureter to be in a different location than suspected. CONCLUSION: Fluorescence is a promising method to allow visualisation of the ureter, where it is not identified easily under standard operative conditions, thereby improving safety and reducing operative time and difficulty.


Subject(s)
Fluorescence , Iatrogenic Disease/prevention & control , Intraoperative Complications/prevention & control , Methylene Blue , Ureter/diagnostic imaging , Adult , Aged , Aged, 80 and over , Colon/surgery , Female , Humans , Laparoscopy , Male , Middle Aged , Rectum/surgery
4.
Surg Endosc ; 32(2): 1073-1076, 2018 02.
Article in English | MEDLINE | ID: mdl-28643063

ABSTRACT

BACKGROUND: Standard surgical practice for colorectal cancer involves resection of the primary lesion and all draining lymph nodes. Accurate intraoperative assessment of nodal status could allow stratified resectional extent. One-step nucleic acid (OSNA) can provide a rapid method of interrogating nodal tissue, whilst near-infrared (NIR) laparoscopy together with indocyanine green (ICG) can identify relevant nodal tissue intraoperatively. METHODS: ICG was administered around the tumour endoscopically prior to the operation. Fluorescent nodes identified by NIR were marked and submitted for whole-node OSNA analysis. Further fresh lymph nodes dissected from the standard resection specimen were examined and analysed by both conventional histology and OSNA. In addition, the status of the fluorescent nodes was compared to that of non-ICG nodes to assess their predictive value. RESULTS: Sixteen patients were recruited with a total final lymph node count of 287. 78 fresh lymph nodes were identified on fresh dissection for both histological and OSNA assessment with an analytical concordance rate of 98.7% (77/78). OSNA sensitivity was 1 (0.81-1, 95% CI) and specificity 0.98 (0.91-1, 95% CI). Six patients had a total of nine nodes identified intraoperatively by ICG fluorescence. Of these nine nodes, one was positive for metastasis on OSNA. OSNA analysis of the ICG-labelled node matched the final histological nodal stage in 3/6 patients (two being N0 and one N1). The final pathological nodal stage of the other three was N1 or N2, while the ICG nodes were negative. CONCLUSION: OSNA is highly concordant with standard histology, although only a minority of nodes identifiable by full pathological analysis were found for OSNA on fresh dissection. OSNA can be combined with NIR and ICG lymphatic mapping to provide intraoperative assessment of nodal tissue in patients with colorectal cancer.


Subject(s)
Colorectal Neoplasms/surgery , Indocyanine Green/pharmacology , Laparoscopy/methods , Lymph Nodes/pathology , Nucleic Acid Amplification Techniques/methods , RNA, Neoplasm/analysis , Sentinel Lymph Node Biopsy/methods , Adult , Aged , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/secondary , Coloring Agents/pharmacology , Feasibility Studies , Female , Fluorescence , Humans , Intraoperative Period , Lymph Nodes/surgery , Lymphatic Metastasis/diagnosis , Male , Middle Aged , Pilot Projects , Prospective Studies
5.
Dis Colon Rectum ; 60(6): 577-585, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28481851

ABSTRACT

BACKGROUND: There remains a lack of international consensus on the appropriate management of lateral nodal disease. Although the East manages this more aggressively with lateral lymph node dissections, the West aims to eradicate small-volume disease with neoadjuvant chemoradiotherapy and lateral nodal disease is not considered for routine surgical treatment. However, recent studies have shown that, despite neoadjuvant treatment, a significant number of patients with lateral nodal disease develop local recurrence in the lateral compartment after total mesorectal excision. OBJECTIVE: The aim of this study is to assess the role of the pretreatment features of lateral nodes on MRI in regard to local recurrence. DESIGN: All patients operated on for low locally advanced rectal cancer over a 5-year period were evaluated retrospectively. SETTINGS: This study was conducted at a single expert center. PATIENTS: The MRIs of a total of 313 patients were reviewed, and only those with rectal cancers up to 8 cm from the anorectal junction, measured on MRI, were selected. This left 185 patients; of these, 58 patients had clinical T1 or T2 tumors as assessed on MRI, identifying 127 patients who had cT3/T4 tumors that were included in this study. MAIN OUTCOME MEASURES: The primary outcomes measured were lateral local recurrence and multivariate analyses. RESULTS: The lateral local recurrence rate was significantly higher (33.3% 4-year rate) in patients with nodes larger than 10 mm than in patients with smaller nodes (10.1%, p = 0.03), despite patients being irradiated in the lateral compartment. LIMITATIONS: Because this is a relatively uncommon disease, patient numbers are low, and a multicenter study is needed to further address lateral nodal disease in low rectal cancer. CONCLUSIONS: Chemoradiotherapy with total mesorectal excision might not be sufficient in a selected group of patients. Further research is needed about which pretreatment features of the lateral nodes predict local recurrence and what is needed to prevent these from developing. See Video Abstract at http://links.lww.com/DCR/A338.


Subject(s)
Adenocarcinoma/pathology , Adenocarcinoma/therapy , Lymph Nodes/pathology , Neoplasm Recurrence, Local/pathology , Rectal Neoplasms/pathology , Rectal Neoplasms/therapy , Adenocarcinoma/mortality , Adult , Aged , Aged, 80 and over , Chemoradiotherapy , Female , Humans , Lymphatic Metastasis , Magnetic Resonance Imaging , Male , Middle Aged , Multivariate Analysis , Rectal Neoplasms/mortality , Retrospective Studies
6.
Ann Surg ; 266(1): 111-117, 2017 07.
Article in English | MEDLINE | ID: mdl-27735827

ABSTRACT

OBJECTIVE: This study aims to report short-term clinical and oncological outcomes from the international transanal Total Mesorectal Excision (taTME) registry for benign and malignant rectal pathology. BACKGROUND: TaTME is the latest minimally invasive transanal technique pioneered to facilitate difficult pelvic dissections. Outcomes have been published from small cohorts, but larger series can further assess the safety and efficacy of taTME in the wider surgical population. METHODS: Data were analyzed from 66 registered units in 23 countries. The primary endpoint was "good-quality TME surgery." Secondary endpoints were short-term adverse events. Univariate and multivariate regression analyses were used to identify independent predictors of poor specimen outcome. RESULTS: A total of 720 consecutively registered cases were analyzed comprising 634 patients with rectal cancer and 86 with benign pathology. Approximately, 67% were males with mean BMI 26.5 kg/m. Abdominal or perineal conversion was 6.3% and 2.8%, respectively. Intact TME specimens were achieved in 85%, with minor defects in 11% and major defects in 4%. R1 resection rate was 2.7%. Postoperative mortality and morbidity were 0.5% and 32.6% respectively. Risk factors for poor specimen outcome (suboptimal TME specimen, perforation, and/or R1 resection) on multivariate analysis were positive CRM on staging MRI, low rectal tumor <2 cm from anorectal junction, and laparoscopic transabdominal posterior dissection to <4 cm from anal verge. CONCLUSIONS: TaTME appears to be an oncologically safe and effective technique for distal mesorectal dissection with acceptable short-term patient outcomes and good specimen quality. Ongoing structured training and the upcoming randomized controlled trials are needed to assess the technique further.


Subject(s)
Digestive System Surgical Procedures/methods , Minimally Invasive Surgical Procedures/methods , Rectal Neoplasms/surgery , Rectum/surgery , Adolescent , Adult , Aged , Aged, 80 and over , Anal Canal/surgery , Body Mass Index , Digestive System Surgical Procedures/adverse effects , Female , Humans , Intraoperative Complications , Male , Middle Aged , Minimally Invasive Surgical Procedures/adverse effects , Neoadjuvant Therapy , Neoplasm Staging , Postoperative Complications , Rectal Neoplasms/pathology , Registries , Risk Factors , Treatment Outcome , Young Adult
8.
World J Gastrointest Surg ; 7(11): 313-8, 2015 Nov 27.
Article in English | MEDLINE | ID: mdl-26649154

ABSTRACT

While diverticular disease is extremely common, the natural history (NH) of its most frequent presentation (i.e., sigmoid diverticulitis) is poorly investigated. Relevant information is mostly restricted to population-based or retrospective studies. This comprehensive review aimed to evaluate the NH of simple sigmoid diverticulitis. While there is a clear lack of uniformity in terminology, which results in difficulties interpreting and comparing findings between studies, this review demonstrates the benign nature of simple sigmoid diverticulitis. The overall recurrence rate is relatively low, ranging from 13% to 47%, depending on the definition used by the authors. Among different risk factors for recurrence, patients with C-reactive protein > 240 mg/L are three times more likely to recur. Other risk factors include: Young age, a history of several episodes of acute diverticulitis, medical vs surgical management, male patients, radiological signs of complicated first episode, higher comorbidity index, family history of diverticulitis, and length of involved colon > 5 cm. The risk of developing a complicated second episode (and its corollary to require an emergency operation) is less than 2%-5%. In fact, the old rationale for elective surgery as a preventive treatment, based mainly on concerns that recurrence would result in a progressively increased risk of sepsis or the need for a colostomy, is not upheld by the current evidence.

9.
World J Gastroenterol ; 21(41): 11700-8, 2015 Nov 07.
Article in English | MEDLINE | ID: mdl-26556997

ABSTRACT

Low anterior resection can be a challenging operation, especially in obese male patients and in particular after radiotherapy. Transanal total mesorectal excision (TaTME) might offer technical advantages over laparoscopic or open approaches particularly for tumors in the distal third of the rectum. The aim of this article is to review the current experience with TaTME. The limits and future developments are also explored. Although the experience with TaTME is still limited, it might be a promising alternative to laparoscopic TME, especially for difficult cases where laparoscopy is too demanding. The preliminary data on complications and short-term oncological outcomes are good, but also emphasize the importance of careful patient selection. Finally, there is a need for large-scale trials focusing on long-term outcomes and oncological safety before widespread adoption can be recommended.


Subject(s)
Adenocarcinoma/surgery , Rectal Neoplasms/surgery , Rectum/surgery , Transanal Endoscopic Surgery/methods , Adenocarcinoma/pathology , Diffusion of Innovation , Humans , Laparoscopy , Patient Selection , Postoperative Complications/etiology , Rectal Neoplasms/pathology , Rectum/pathology , Risk Factors , Robotic Surgical Procedures , Transanal Endoscopic Surgery/adverse effects , Treatment Outcome
10.
Clin Colon Rectal Surg ; 28(3): 158-64, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26491408

ABSTRACT

Colorectal surgery is one of the most common procedures performed around the world with more than 600,000 operations each year in the United States, and more than a million worldwide. In the past two decades, there has been a clear trend toward minimal access and surgeons have embraced this evolution. Widespread adoption of advanced minimally invasive procedures is often limited by procedural complexity and the need for specific technical skills. Furthermore, the loss of 3D vision, limited overview of the surgical field, and diminished tactile sensation make major colorectal procedures more challenging and have an impact on the surgeons' learning curves. New technologies are emerging that can compensate for some of the sensory losses associated with laparoscopy. High-definition picture acquisition, 3D camera systems, and the use of biomarkers will allow improved identification of the target structures and help differentiate them from surrounding tissues. In this article, we describe some of the new technologies available and, in particular, focus on the possible implications of biomarkers and fluorescent laparoscopic imaging.

11.
Dis Colon Rectum ; 58(10): 938-42, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26347965

ABSTRACT

BACKGROUND: Noninflammatory masses in the ischiorectal fossa are rare. OBJECTIVE: This study aimed to review our experience with ischiorectal fossa tumors and to address the question of whether percutaneous biopsy should be undertaken. DESIGN: This is a retrospective study. SETTINGS: This study was conducted at a tertiary institution. PATIENTS: From April 2007 to November 2014, all consecutive ischiorectal fossa masses treated in a referral center were retrospectively reviewed. They were all presented and discussed in a multidisciplinary team meeting. Magnetic resonance imaging was performed in all the patients. Inflammatory pathologies, such as abscess, were excluded from the analysis. INTERVENTIONS: Percutaneous biopsy and surgical excision of ischiorectal fossa tumors were reviewed. MAIN OUTCOME MEASURES: Perioperative, pathological, and oncological outcomes were measured. RESULTS: Eleven patients were identified (8 female; median age, 50 years; range, 25-90). Percutaneous biopsy was undertaken in 8 patients. All biopsies were diagnostic and altered preoperative management in 3 cases (aggressive angiomyxoma (n = 2), desmoid fibromatosis (n = 1)). Overall final diagnosis was benign in 3 patients, locally aggressive neoplasm in 3, and malignant in 5 cases (leiomyosarcomas (n = 2), liposarcomas (n = 2), and angiomyosarcoma (n = 1)). Surgical approaches were perineal in 8 patients, abdominoperineal in 1 patient, and totally abdominal in 1 patient. One patient (age 90 years) was managed nonsurgically. After resection, 2 positive margins were observed (R1 rate, 20%). After a mean follow-up of 24.3 months, 3 patients have experienced local recurrence, which required further surgery in 2 cases. LIMITATIONS: This study is limited by the small number of patients. CONCLUSIONS: Noninflammatory masses in the ischiorectal fossa are rare, but they are commonly malignant and should be imaged by MRI. Unless the radiological appearances are diagnostic, percutaneous biopsy is recommended and alters management in about one-third of cases.


Subject(s)
Biopsy/methods , Fibromatosis, Aggressive , Myxoma , Neoplasm Recurrence, Local/prevention & control , Pelvic Neoplasms , Diagnosis, Differential , Dissection/adverse effects , Dissection/methods , Female , Fibromatosis, Aggressive/pathology , Fibromatosis, Aggressive/surgery , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Myxoma/pathology , Myxoma/surgery , Outcome Assessment, Health Care , Pelvic Neoplasms/diagnosis , Pelvic Neoplasms/pathology , Pelvic Neoplasms/surgery , Reoperation , Reproducibility of Results , Retrospective Studies , United Kingdom
12.
Dis Colon Rectum ; 58(9): 857-61, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26252847

ABSTRACT

BACKGROUND: The Internet is a vast resource for patients to search for health information on the treatment of Crohn's disease. OBJECTIVE: This study examines the quality of Web sites that provide information to adults regarding Crohn's disease, including treatment options and surgery. DESIGN: Two search engines (Google and Yahoo) and the search terms "surgery for Crohn's disease" were used. The first 50 sites of each search were assessed. Sites that fulfilled the inclusion criteria were evaluated for content and scored by using the DISCERN instrument, which evaluates the quality of health information on treatment choices. RESULTS: One hundred sites were examined, of which 13 were duplicates. Sixty-two sites provided patient-orientated information. The other sites included 7 scientific articles, 3 blogs, 2 links, 6 forums, 3 video links, and 4 dead links. Of the 62 Web sites that provided patient information for adults, only 15 (24.2%) had been updated within the past 2 years. Only 9 (14.5%) were affiliated with hospitals and clinics. The majority of sites (33, 53.2%) were associated with private companies with commercial interests. Only half of the Web sites provided details on treatment options, and most Web sites did not provide any information on symptoms and procedure details. Just 5 Web sites (8.1%) described the risks of surgery, and only 7 (11.3%) provided any information on the timescale for recovery. Overall, only 1 Web site (1.6%) was identified as being "good" or "excellent" with the use of the DISCERN criteria. LIMITATIONS: Although the internet is constantly evolving, this study captures data at a specific time point. Search results may vary depending on geographical location. This study only assessed English language websites. CONCLUSIONS: The quality of patient information on surgery for Crohn's disease is highly variable and generally poor. There is potential for the Internet to provide valuable information, and clinicians should identify high-quality Web sites to guide their patients.


Subject(s)
Consumer Health Information/standards , Crohn Disease/therapy , Internet , Quality of Health Care/statistics & numerical data , Adult , Consumer Health Information/statistics & numerical data , Humans , Search Engine
13.
Cell Rep ; 9(5): 1781-1797, 2014 Dec 11.
Article in English | MEDLINE | ID: mdl-25464844

ABSTRACT

Loss of heterozygosity (LOH) of the adenomatous polyposis coli (APC) gene triggers a series of molecular events leading to intestinal adenomagenesis. Haploinsufficiency of the cohesin Rad21 influences multiple initiating events in colorectal cancer (CRC). We identify Rad21 as a gatekeeper of LOH and a ß-catenin target gene and provide evidence that Wnt pathway activation drives RAD21 expression in human CRC. Genome-wide analyses identified Rad21 as a key transcriptional regulator of critical CRC genes and long interspersed element (LINE-1 or L1) retrotransposons. Elevated RAD21 expression tracks with reactivation of L1 expression in human sporadic CRC, implicating cohesin-mediated L1 expression in global genomic instability and gene dysregulation in cancer.


Subject(s)
Adenomatous Polyposis Coli/genetics , Haploinsufficiency , Nuclear Proteins/physiology , Phosphoproteins/physiology , Adenomatous Polyposis Coli/metabolism , Adult Stem Cells/physiology , Animals , Cell Cycle Proteins , Cell Proliferation , Chromosomal Instability , Colon/pathology , DNA Damage , DNA-Binding Proteins , Gene Expression , Gene Expression Regulation, Neoplastic , HCT116 Cells , Humans , Mice , Mice, Transgenic , Retroelements/genetics , Up-Regulation
14.
Surg Endosc ; 28(7): 2221-6, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24566744

ABSTRACT

BACKGROUND: Anastomotic leakage is a devastating complication of colorectal surgery. However, there is no technology indicative of in situ perfusion of a laparoscopic colorectal anastomosis. METHODS: We detail the use of near-infrared (NIR) laparoscopy (PinPoint System, NOVADAQ, Canada) in association with fluorophore [indocyanine green (ICG), 2.5 mg/ml] injection in 30 consecutive patients who underwent elective minimally invasive colorectal resection using the simultaneous appearance of the cecum or distal ileum as positive control. RESULTS: The median (range) age of the patients was 64 (40-81) years with a median (range) BMI of 26.7 (20-35.5) kg/m(2). Twenty-four patients had left-sided resections (including six low anterior resections) and six had right-sided resections. Of the total, 25 operations were cancer resections and five were for benign disease [either diverticular strictures (n = 3) or Crohn's disease (n = 2)]. A high-quality intraoperative ICG angiogram was achieved in 29/30 patients. After ICG injection, median (range) time to perfusion fluorescence was 35 (15-45) s. Median (range) added time for the technique was 5 (3-9) min. Anastomotic perfusion was documented as satisfactory in every successful case and encouraged avoidance of defunctioning stomas in three patients with low anastomoses. There were no postoperative anastomotic leaks. CONCLUSION: Perfusion angiography of colorectal anastomosis at the time of their laparoscopic construction is feasible and readily achievable with minimal added intraoperative time. Further work is required to determine optimum sensitivity and threshold levels for assessment of perfusion sufficiency, in particular with regard to anastomotic viability.


Subject(s)
Colon/blood supply , Colon/surgery , Fluorescein Angiography/methods , Laparoscopy , Rectum/blood supply , Rectum/surgery , Adult , Aged , Aged, 80 and over , Anastomosis, Surgical , Colonic Diseases/surgery , Coloring Agents , Female , Humans , Indocyanine Green , Male , Middle Aged , Rectal Diseases/surgery , Regional Blood Flow
15.
Dis Colon Rectum ; 57(3): 370-7, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24509462

ABSTRACT

BACKGROUND: Interstitial cells of Cajal, expressing the proto-oncogene c-kit, have been shown to regulate the spontaneous activity of the gastrointestinal tract. They have been described in the human internal anal sphincter; however, their function is still unclear. OBJECTIVE: We examined the effects of the c-kit tyrosine kinase inhibitor imatinib mesylate on sphincter strips to investigate the function of the interstitial cells. DESIGN: This was a case series study. SETTIGS: This was a single-center study conducted at the University of Oxford. PATIENTS: Internal anal sphincter strips were collected from 10 patients undergoing abdominoperineal resection or proctectomy and mounted in organ bath. Responses to electrical field stimulation and chemical agents were monitored in the absence of drugs and after the administration of increasing doses of imatinib mesylate. Immunohistochemistry was performed to identify interstitial cells. MAIN OUTCOME MEASURES: The role of the interstitial cells in the internal anal sphincter was assessed. RESULTS: Imatinib mesylate significantly reduced the tone and the spontaneous activity of the strips. In the absence of drugs, the tone generated was 147.7 ± 33.0 mg/mg of tissue. Administration of ≥5 µM of imatinib mesylate caused a dose-dependent reduction in the tone. Strips exhibited spontaneous activity characterized by intermittent low-amplitude contractions superimposed on basal tone (135.6 ± 4.6 contractions in 10 minutes). Imatinib mesylate significantly reduced the number of contractions at concentration >5 µM. No differences were observed in the responses to electrical field stimulation, carbachol, or phenylephrine. Immunohistochemistry showed c-kit-positive cells. LIMITATIONS: This study was limited by the relatively small number of patients enrolled and thus the difficulty of finding human tissue for laboratory studies. CONCLUSIONS: Our results suggest that the interstitial cells modulate the tone and the spontaneous activity of the internal anal sphincter. This provides a foundation for new approaches to preclinical and clinical research. Moreover, these cells may represent a target for drugs inhibiting the c-kit receptor and provide a new approach for treating anorectal diseases.


Subject(s)
Anal Canal/cytology , Anal Canal/drug effects , Benzamides/pharmacology , Interstitial Cells of Cajal/physiology , Piperazines/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Adult , Aged , Aged, 80 and over , Electric Stimulation , Female , Humans , Imatinib Mesylate , Immunoenzyme Techniques , Male , Middle Aged , Muscle Contraction/drug effects , Proto-Oncogene Mas , Proto-Oncogene Proteins c-kit/physiology
16.
Proc Natl Acad Sci U S A ; 109(51): 21046-51, 2012 Dec 18.
Article in English | MEDLINE | ID: mdl-23213241

ABSTRACT

A significant proportion of colorectal cancer (CRC) patients are resistant to anti-ERBB1 [avian erythroblastic leukemia viral (v-erb-b) oncogene homolog, receptor for EGF] monoclonal antibodies (Mabs). We evaluated both immune and nonimmune effects of cetuximab (anti-ERBB1 Mab), trastuzumab (anti-ERBB2 Mab), pertuzumab (anti-ERBB2 Mab), and lapatinib (dual ERBB1 and ERBB2 tyrosine kinase inhibitor) in a large well-characterized panel of 64 CRC cell lines to find response predictive tumor characteristics. There was a significant correlation between the direct effects of cetuximab and lapatinib. Both agents were associated (P = 0.0004) with "triple' wild-type status in KRAS, BRAF, and PIK3CA exon 20. Most cell lines were resistant to the direct effects of anti-ERBB2 Mabs, suggesting that the effects of lapatinib might mainly be through ERBB1. Microarray mRNA expression profiles of sensitive and resistant cell lines showed that although ERBB1 receptor or ligand levels did not associate with cetuximab sensitivity, high levels of ERBB2 (P = 0.036) and amphiregulin (P = 0.026) predicted sensitivity to lapatinib. However, higher ERBB1 expression predicted susceptibility to cetuximab-induced antibody-dependent cellular cytotoxicity and occurred independently of KRAS/BRAF/PIK3CA mutations (P = 0.69). Lapatinib may be an effective alternative therapy to cetuximab in triple wild-type tumors. Microarray analysis provides suggestive biomarkers for resistance. ERBB1 levels, independent of mutation status, predict immune killing. Therefore, anti-ERBB1 antibodies may be considered in CRC tumors with higher ERBB1 expression and favorable FcγR polymorphisms.


Subject(s)
Colorectal Neoplasms/metabolism , ErbB Receptors/metabolism , Gene Expression Regulation, Neoplastic , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized/pharmacology , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cetuximab , Genes, ras , Humans , Immune System , Lapatinib , Models, Genetic , Oligonucleotide Array Sequence Analysis , Polymorphism, Genetic , Quinazolines/pharmacology , Trastuzumab
17.
Lancet Oncol ; 13(12): e525-36, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23182193

ABSTRACT

Elderly people represent almost all patients diagnosed with and treated for rectal cancer, and this trend is likely to become more apparent in the future. Surgical management and treatment decisions for this disease are becoming increasingly complex, but only a few reports deal specifically with older patients. In this systematic review, we provide an overview of published studies of outcomes after curative surgery for rectal cancer in elderly people (>70 years). We identified 48 studies providing information about postoperative results, survival, surgical approach, stoma formation, functional results, and quality of life after rectal resection for cancer. We found that advanced chronological age should not, by itself, exclude patients from curative rectal surgery or from other surgical options that are available for younger patients. Although overall survival is lower in elderly patients than in younger patients, cancer-specific survival does not decrease with age. However, the level of evidence for most studies was weak, emphasising the need for high-quality clinical trials for this population.


Subject(s)
Rectal Neoplasms/surgery , Age Factors , Aged , Aged, 80 and over , Anastomotic Leak , Humans , Laparoscopy , Postoperative Complications , Quality of Life , Rectal Neoplasms/mortality , Survival Rate , Treatment Outcome
18.
Dis Colon Rectum ; 55(4): 465-72, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22426272

ABSTRACT

BACKGROUND: Neoadjuvant chemoradiotherapy is recommended in the treatment of locally advanced rectal cancer. Studies have suggested that chemoradiotherapy adversely affects anorectal function. However, the functional implication and the underlying neuromyogenic changes involved in radiation-induced damage are poorly understood. OBJECTIVE: This study evaluated the functional changes following chemoradiotherapy on the internal anal sphincter. DESIGN AND PATIENTS: This article describes an in vitro study on the internal anal sphincter collected from patients undergoing abdominoperineal resection or proctectomy. Five patients were treated by surgery alone (control group), and 6 received preoperative chemoradiotherapy (treatment group). Sphincter strips were mounted in organ bath, and the responses to electrical field stimulation and drugs were monitored. SETTINGS: The study was performed at the University of Oxford. MAIN OUTCOME MEASURES: The end points of this study were to investigate whether chemoradiotherapy has any significant effects on internal anal sphincter function and, subsequently, to establish the type of injury induced. RESULTS: Chemoradiotherapy strips developed similar tone, but significantly lower spontaneous activity (p = 0.001) than controls. Electrical field stimulation induced relaxation, followed by contraction. At 50 Hz, electrical field stimulation produced 25.6 ± 4.9% (mean ± SE) of maximum relaxation followed by a contraction of 5.5 ± 0.9% of basal tone in chemoradiotherapy strips i9n comparison with 47.0 ± 6.2% (p = 0.009) and 17.7 ± 4.0% (p = 0.007) in controls. Relaxation was significantly attenuated by N-nitro-L-arginine. Significant differences were found in responses to carbachol (p = 0.018) and phenylephrine (p = 0.022), but not to sodium nitroprusside. LIMITATIONS: This work was limited by the relatively small number of patients enrolled, because of the difficulty of finding human tissue for laboratory studies, and the lack of long-term results. CONCLUSIONS: Chemoradiotherapy significantly impairs internal anal sphincter function and intrinsic nerves seem more susceptible than smooth muscle. The exclusion of anal canal from the radiation field is recommended, when oncologically safe.


Subject(s)
Anal Canal/physiopathology , Chemoradiotherapy/methods , Rectal Neoplasms/physiopathology , Rectal Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Anal Canal/surgery , Arginine/pharmacology , Carbachol/pharmacology , Case-Control Studies , Electric Stimulation , Female , Humans , In Vitro Techniques , Male , Middle Aged , Neoadjuvant Therapy , Phenylephrine/pharmacology , Rectal Neoplasms/surgery
19.
Surg Endosc ; 26(1): 197-204, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21853392

ABSTRACT

BACKGROUND: Appropriate lymphatic assessment is a cornerstone of definitive surgical resection for colorectal cancer. Near-infrared (NIR) laparoscopy may allow real-time intraoperative identification of territorial lymphatic drainage and sentinel nodes in patients with early-stage disease prior to radical basin resection. METHODS: With IRB approval and individual consent, consecutive patients with radiologically localized neoplasia underwent peritumoral submucosal injection of indocyanine green (ICG, a fluorophore capable of injection site tattooing and efferent lymphatic migration) prior to standard laparoscopic oncological resection. Intraoperatively, a prototype NIR laparoscope provided both white light and, by switch activation, NIR irradiation with or without discrete spectral back-filtration. Fluorescence identification of sentinel nodes prior to formal specimen dissection allowed their identification for separate histopathological analysis by in situ clipping when found within the specimen or selective lymphadenectomy by "berry-picking" when such nodes lay outside of the standard resection field. Concordance with nonsentinel nodes was then analysed. RESULTS: Eighteen patients (mean age = 66.4 years [range = 47.9-80.1], mean BMI = 29.1 [range = 20.0-39.9]) were studied. Fourteen had biopsy-proven carcinoma and four had endoscopically unresectable dysplasia. Mesocolic sentinel nodes (mean = 4.1/patient) were rendered obvious by fluorescence either solely within the standard resection field (n = 14) or both within and without the planned field (n = 4) within minutes of dye injection in every case. Laparoscopic ultrasound (n = 5) as well as histopathological analysis demonstrated oncologic correlation of mesocolic sentinel with corresponding territory nonsentinel nodes, correctly confirming the presence of mesocolic disease in 3 patients and the absence of such lymphatic spread in the remaining 15 patients. CONCLUSIONS: In this study, NIR laparoscopy with ICG mapping allowed ready and rapid confirmation of mesocolic lymphatic drainage patterns and sentinel node identification. With further validation, this technology and technique promises precise, tailored resection surgery by indicating basin pattern and status in advance of radical lymphadenectomy.


Subject(s)
Colorectal Neoplasms/surgery , Laparoscopy/methods , Aged , Aged, 80 and over , Colorectal Neoplasms/pathology , Coloring Agents , Female , Humans , Indocyanine Green , Intraoperative Care/methods , Lymphatic Metastasis , Male , Middle Aged , Sentinel Lymph Node Biopsy/methods , Spectrophotometry, Infrared/methods , Ultrasonography, Interventional
20.
Dis Colon Rectum ; 55(1): 85-9, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22156872

ABSTRACT

BACKGROUND: The Internet is a vast resource available for patients to obtain health information. OBJECTIVE: This study examines the quality of Web sites that provide information on diverticular disease, treatment options, and surgery. DESIGN: Two search engines (Google and Yahoo) and the search terms "surgery and diverticular disease" and "surgery and diverticulitis" were used. The first 50 sites of each search were assessed. Sites that fulfilled the inclusion criteria were evaluated for content and scored by using the DISCERN instrument, which evaluates the quality of health information on treatment choices. RESULTS: Two hundred sites were examined, of which 60 (30%) provided patient-orientated information. 50 sites (25%) were duplicated, 7 (3.5%) were links, 10 (5%) were advertisements, 14 (7%) were resources for clinicians, 9 (4.5%) were message forums, 27 (13.5%) were articles, and 15 (7.5%) were dead links. Of the 60 Web sites that provided patient information, only 10 (16.7%) had been updated within the past 2 years. Seventeen (28.3%) sites were affiliated with hospitals and clinics, but another 17 (28.3%) sites were associated with private companies with commercial interests. Although most Web sites contained information on symptoms, complications, investigations, and treatment options of diverticular disease, 20 (33.3%) did not describe any of the risks of surgery, and 45 (75%) did not provide information on the timescale of recovery postoperatively. Eighteen sites did not provide balanced information on treatment options; of these, 7 were biased toward medical treatment and 6 focused on laparoscopic surgery. Overall, only 22 (36.7%) were identified as being "good" or "excellent" with the use of the DISCERN criteria. CONCLUSIONS: The quality of patient information on surgery for diverticular disease is highly variable, and Web sites that are sponsored by private companies may be biased in discussing treatment options. There is potential for the Internet to provide valuable information, and clinicians should guide patients to access high-quality Web sites.


Subject(s)
Consumer Health Information/standards , Diverticulitis, Colonic/surgery , Internet , Humans , Postoperative Complications , Risk , Search Engine
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