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1.
Ann Surg ; 277(3): 449-455, 2023 03 01.
Article in English | MEDLINE | ID: mdl-35166265

ABSTRACT

OBJECTIVE: The aim of this study was to compare patient-reported urinary, bowel, and sexual functioning of ALaCaRT Trial participants randomized to open or laparoscopic surgery for rectal cancer. SUMMARY BACKGROUND DATA: The primary endpoint, noninferiority of laparoscopic surgical resection adequacy, was not established. METHODS: Participants completed QLQ-CR29 at baseline, 3, and 12 months post-surgery. Additionally, women completed Rosen's Female Sexual Functioning Index (FSFI). Men completed the International Index of Erectile Function (IIEF) and QLQ-PR25. We compared the proportions of participants in each group who experienced moderate/severe symptoms/dysfunction at each time-point and compared mean difference scores from baseline to 12 months between groups. All analyses were intention-to-treat. Sexual functioning analyses included only the participants who expressed sexual interest at baseline. RESULTS: Baseline PRO compliance of 475 randomized participants was 88%. At 12 months, a lower proportion of open surgery participants experienced moderate-severe fecal incontinence and sore skin, compared to Laparoscopic participants, and a lower proportion of men randomized to open surgery experienced moderate-severe urinary symptoms. There were no differences at 3 months for bowel or urinary symptoms. Sexual functioning among sexually interested participants was similar between groups at 3 and 12 months; however, a lower proportion of women reported moderate to severe sexual dissatisfaction at 3 months in the open as compared to the laparoscopic group, (Rebecca.mercieca@sydney.edu.au., 95% CI 0.03-0.39). DISCUSSION: Despite the slightly lower proportions of open surgery participants self-reporting moderate-severe symptoms for 3 of 16 urinary/bowel domains, and lack of differences in sexual domains, it remains difficult to recommend one surgical approach over another for rectal resection.


Subject(s)
Laparoscopy , Proctectomy , Rectal Neoplasms , Male , Female , Humans , Rectal Neoplasms/surgery , Rectum/surgery , Proctectomy/adverse effects , Patient Reported Outcome Measures
2.
Dis Colon Rectum ; 65(7): e698-e706, 2022 07 01.
Article in English | MEDLINE | ID: mdl-34775413

ABSTRACT

BACKGROUND: Low anterior resection syndrome has a significant impact on the quality of life in rectal cancer survivors. Previous studies comparing laparoscopic to open rectal resection have neglected bowel function outcomes. OBJECTIVE: This study aimed to assess whether there is a difference in the functional outcome between patients undergoing laparoscopic versus open resection for rectal adenocarcinoma. DESIGN: Cross-sectional prevalence of low anterior resection syndrome was assessed in a secondary analysis of the multicenter phase 3 randomized clinical trial, Australasian Laparoscopic Cancer of the Rectum Trial (ACTRN12609000663257). SETTING: There were 7 study subsites across New Zealand and Australia. PATIENTS: Participants were adults with rectal cancer who underwent anterior resection and had bowel continuity. MAIN OUTCOME MEASURES: Postoperative bowel function was evaluated using the validated low anterior resection syndrome score and Bowel Function Instrument. RESULTS: The Australasian Laparoscopic Cancer of the Rectum Trial randomized 475 patients with T1-T3 rectal adenocarcinoma less than 15 cm from the anal verge. A total of 257 participants were eligible for, and invited to, participate in additional follow-up; 163 (63%) completed functional follow-up. Overall cross-sectional prevalence of major low anterior resection syndrome was 49% (minor low anterior resection syndrome 27%). There were no differences in median overall Bowel Function Instrument score nor low anterior resection syndrome score between participants undergoing laparoscopic versus open surgery (66 vs 67, p = 0.52; 31 vs 27, p = 0.24) at a median follow-up of 69 months. LIMITATIONS: The major limitations are a result of conducting a secondary analysis; the likelihood of an insufficient sample size to detect a difference in prevalence between the groups and the possibility of selection bias as a subset of the randomized population was analyzed. CONCLUSIONS: Bowel dysfunction affects a majority of rectal cancer patients for a significant time after the operation. In this secondary analysis of a randomized trial, surgical approach does not appear to influence the likelihood or severity of low anterior resection syndrome. See Video Abstract at http://links.lww.com/DCR/B794. RESULTADO FUNCIONAL DE LA RESECCIN ASISTIDA POR LAPAROSCOPIA VERSUS RESECCIN ABIERTA EN CNCER DE RECTO ANLISIS SECUNDARIO DEL ESTUDIO DE CNCER DE RECTO LAPAROSCPICO DE AUSTRALASIA: ANTECEDENTES:El síndrome de resección anterior baja tiene un impacto significativo en la calidad de vida de los supervivientes de cáncer de recto. Los estudios anteriores que compararon la resección rectal laparoscópica con la abierta no han presentado resultados de la función intestinal.OBJETIVO:Evaluar si existe una diferencia en el resultado funcional entre los pacientes sometidos a resección laparoscópica versus resección abierta por adenocarcinoma de recto.DISEÑO:La prevalencia transversal del síndrome de resección anterior baja se evaluó en un análisis secundario del ensayo clínico aleatorizado multicéntrico de fase 3, Estudio Sobre el Cáncer de Recto Laparoscópico de Australasia (Australasian Laparoscopic Cancer of the Rectum Trial, ACTRN12609000663257).AJUSTE:Siete subsitios de estudio en Nueva Zelanda y Australia.PACIENTES:Los participantes eran adultos con cáncer de recto que se sometieron a resección anterior con anastomosis.PRINCIPALES MEDIDAS DE RESULTADO:La función intestinal posoperatoria se evaluó utilizando el previamente validado puntaje LARS y el Instrumento de Función Intestinal.RESULTADOS:El Estudio Sobre el Cáncer de Recto Laparoscópico de Australasia asignó al azar a 475 pacientes con adenocarcinoma rectal T1-T3 a menos de 15 cm del borde anal. 257 participantes fueron elegibles e invitados a participar en un seguimiento adicional. 163 (63%) completaron el seguimiento funcional. La prevalencia transversal general de LARS mayor fue del 49% (LARS menor 27%). No hubo diferencias en la puntuación media general del Instrumento de Función Intestinal ni en la puntuación LARS entre los participantes sometidos a cirugía laparoscópica versus cirugía abierta (66 frente a 67, p = 0,52; 31 frente a 27, p = 0,24) en una mediana de seguimiento de 69 meses.LIMITACIONES:Las principales limitaciones son el resultado de realizar un análisis secundario; se analizó la probabilidad de un tamaño de muestra insuficiente para detectar una diferencia en la prevalencia entre los grupos y la posibilidad de sesgo de selección como un subconjunto de la población aleatorizada.CONCLUSIONES:La disfunción intestinal afecta a la mayoría de los pacientes con cáncer de recto durante un tiempo significativo después de la operación. En este análisis secundario de un ensayo aleatorizado, el abordaje quirúrgico no parece influir en la probabilidad o gravedad del síndrome de resección anterior baja. Consulte Video Resumen en http://links.lww.com/DCR/B794. (Traducción-Dr. Felipe Bellolio).


Subject(s)
Adenocarcinoma , Laparoscopy , Rectal Neoplasms , Adenocarcinoma/surgery , Adult , Cross-Sectional Studies , Humans , Laparoscopy/adverse effects , Postoperative Complications/diagnosis , Quality of Life , Rectal Neoplasms/diagnosis , Rectal Neoplasms/surgery , Syndrome
3.
Ann Surg ; 269(4): 596-602, 2019 04.
Article in English | MEDLINE | ID: mdl-30247332

ABSTRACT

OBJECTIVE: The aim of the study was to determine the efficacy of laparoscopic rectal resection (Lap) versus open laparotomy and rectal resection (Open) for rectal cancer on locoregional recurrence (LRR) and disease-free survival (DFS) at 2 years. SUMMARY BACKGROUND DATA: Although a Lap approach to colon cancer surgery may offer similar oncological outcomes to Open with potentially less morbidity, this remains to be clearly established for the treatment of rectal cancer. METHODS: A randomized, multicenter noninferiority phase 3 trial of 475 patients with T1 to T3 rectal adenocarcinoma <15 cm from anal verge, given Lap or Open and followed for a minimum 2 years to assess LRR, DFS, and overall survival (OS). RESULTS: Secondary endpoint analyses included 450 patients (95%) without metastases at baseline (mean age 64; 34% women) who received Lap (n = 225) or Open (n = 225). Median follow-up was 3.2 years (range: 0.1-5.4 yrs). LRR cumulative incidence at 2 years: Lap 5.4%; Open 3.1% [difference, 2.3%; 95% confidence interval (CI), -1.5% to 6.1%; hazard ratio (HR) 1.7; 95% CI, 0.74-3.9]. DFS at 2 years: Lap 80%; Open 82% (difference, 2.0%; 95% CI, -9.3% to 5.4%; HR for recurrence or death, 1.17; 95% CI, 0.81-1.68; P = 0.41). After adjustment for baseline factors HR = 1.07 (95% CI, 0.7-1.6). OS at 2 years: Lap 94%; Open 93% (difference 0.9%; 95% CI, -3.6% to 5.4%). CONCLUSIONS: Laparoscopic surgery for rectal cancer did not differ significantly from open surgery in effects on 2-year recurrence or DFS and OS. Confidence intervals included potentially clinically important differences favoring open resection, so that the combination of primary and secondary study endpoints may not support laparoscopic resection of rectal cancer as a routine standard of care and further follow-up is required.


Subject(s)
Adenocarcinoma/epidemiology , Adenocarcinoma/surgery , Laparoscopy , Neoplasm Recurrence, Local/epidemiology , Rectal Neoplasms/epidemiology , Rectal Neoplasms/surgery , Aged , Digestive System Surgical Procedures/methods , Disease-Free Survival , Female , Humans , Laparotomy/methods , Male , Middle Aged
4.
JAMA ; 314(13): 1356-63, 2015 Oct 06.
Article in English | MEDLINE | ID: mdl-26441180

ABSTRACT

IMPORTANCE: Laparoscopic procedures are generally thought to have better outcomes than open procedures. Because of anatomical constraints, laparoscopic rectal resection may not be better because of limitations in performing an adequate cancer resection. OBJECTIVE: To determine whether laparoscopic resection is noninferior to open rectal cancer resection for adequacy of cancer clearance. DESIGN, SETTING, AND PARTICIPANTS: Randomized, noninferiority, phase 3 trial (Australasian Laparoscopic Cancer of the Rectum; ALaCaRT) conducted between March 2010 and November 2014. Twenty-six accredited surgeons from 24 sites in Australia and New Zealand randomized 475 patients with T1-T3 rectal adenocarcinoma less than 15 cm from the anal verge. INTERVENTIONS: Open laparotomy and rectal resection (n = 237) or laparoscopic rectal resection (n = 238). MAIN OUTCOMES AND MEASURES: The primary end point was a composite of oncological factors indicating an adequate surgical resection, with a noninferiority boundary of Δ = -8%. Successful resection was defined as meeting all the following criteria: (1) complete total mesorectal excision, (2) a clear circumferential margin (≥1 mm), and (3) a clear distal resection margin (≥1 mm). Pathologists used standardized reporting and were blinded to the method of surgery. RESULTS: A successful resection was achieved in 194 patients (82%) in the laparoscopic surgery group and 208 patients (89%) in the open surgery group (risk difference of -7.0% [95% CI, -12.4% to ∞]; P = .38 for noninferiority). The circumferential resection margin was clear in 222 patients (93%) in the laparoscopic surgery group and in 228 patients (97%) in the open surgery group (risk difference of -3.7% [95% CI, -7.6% to 0.1%]; P = .06), the distal margin was clear in 236 patients (99%) in the laparoscopic surgery group and in 234 patients (99%) in the open surgery group (risk difference of -0.4% [95% CI, -1.8% to 1.0%]; P = .67), and total mesorectal excision was complete in 206 patients (87%) in the laparoscopic surgery group and 216 patients (92%) in the open surgery group (risk difference of -5.4% [95% CI, -10.9% to 0.2%]; P = .06). The conversion rate from laparoscopic to open surgery was 9%. CONCLUSIONS AND RELEVANCE: Among patients with T1-T3 rectal tumors, noninferiority of laparoscopic surgery compared with open surgery for successful resection was not established. Although the overall quality of surgery was high, these findings do not provide sufficient evidence for the routine use of laparoscopic surgery. Longer follow-up of recurrence and survival is currently being acquired. TRIAL REGISTRATION: anzctr.org Identifier: ACTRN12609000663257.


Subject(s)
Adenoma/surgery , Digestive System Surgical Procedures/methods , Laparoscopy/methods , Laparotomy , Rectal Neoplasms/surgery , Adenoma/pathology , Adult , Disease-Free Survival , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local , Neoplasm, Residual , Quality of Life , Rectal Neoplasms/pathology , Single-Blind Method , Treatment Outcome
5.
Surg Endosc ; 28(5): 1515-21, 2014 May.
Article in English | MEDLINE | ID: mdl-24337191

ABSTRACT

BACKGROUND: Previous cost analyses of laparoscopic resection for colorectal cancer (CRC) reported slightly higher or similar costs to those of open resection. These analyses were based on randomised controlled trials when the laparoscopic approach was newly adopted. This study compared costs for laparoscopic versus open resection in a region of high uptake where adoption is mature. METHODS: Hospital cost data were obtained for elective resections for CRC that occurred between June 2009 and June 2011 in public hospitals in Queensland, Australia. The primary outcome was total cost and secondary outcomes were length-of-stay, operating time, and ICU admission. Multivariate least-squares regression was used to adjust for potential confounders: age, sex, comorbidities, procedure, and hospital volume. RESULTS: The crude mean cost for laparoscopic resection was euro 20,036 compared with that for open resection of euro 22,780 (difference = euro 2,744). Patients who underwent laparoscopic resection (744/1,397; 53 %) were slightly younger and had fewer comorbidities (decreasing costs) but more had rectal surgery (increasing costs). The adjusted mean cost for laparoscopic resection was euro 20,396 compared with euro 22,442 for open resection (difference = euro 2,054). Compared with open resection, when adjusted for potential confounders, laparoscopic resection resulted in similar operating time (216 vs. 214 min), shorter length-of-stay (difference = -1.1 days, 95 % CI -1.9, -0.3), and shorter admission to ICU (difference = -7.3 h, 95 % CI -11.9, -2.7). CONCLUSIONS: This non-randomised study in a region of high uptake found a similar operating time and lower cost for laparoscopic resection for CRC compared with those of open resection due to a shorter length-of-stay and shorter time in ICU. Laparoscopic resection for CRC saves money when the procedure is widely adopted and surgeons are experienced in the technique.


Subject(s)
Colectomy/economics , Colorectal Neoplasms/surgery , Cost Savings , Elective Surgical Procedures/economics , Hospital Costs , Hospitals, Public/economics , Laparoscopy/economics , Aged , Colectomy/methods , Colorectal Neoplasms/economics , Female , Humans , Length of Stay/economics , Male , Queensland , Retrospective Studies
6.
J Biol Chem ; 287(13): 9792-9803, 2012 Mar 23.
Article in English | MEDLINE | ID: mdl-22315226

ABSTRACT

Epidermal growth factor (EGF) activation of the EGF receptor (EGFR) is an important mediator of cell migration, and aberrant signaling via this system promotes a number of malignancies including ovarian cancer. We have identified the cell surface glycoprotein CDCP1 as a key regulator of EGF/EGFR-induced cell migration. We show that signaling via EGF/EGFR induces migration of ovarian cancer Caov3 and OVCA420 cells with concomitant up-regulation of CDCP1 mRNA and protein. Consistent with a role in cell migration CDCP1 relocates from cell-cell junctions to punctate structures on filopodia after activation of EGFR. Significantly, disruption of CDCP1 either by silencing or the use of a function blocking antibody efficiently reduces EGF/EGFR-induced cell migration of Caov3 and OVCA420 cells. We also show that up-regulation of CDCP1 is inhibited by pharmacological agents blocking ERK but not Src signaling, indicating that the RAS/RAF/MEK/ERK pathway is required downstream of EGF/EGFR to induce increased expression of CDCP1. Our immunohistochemical analysis of benign, primary, and metastatic serous epithelial ovarian tumors demonstrates that CDCP1 is expressed during progression of this cancer. These data highlight a novel role for CDCP1 in EGF/EGFR-induced cell migration and indicate that targeting of CDCP1 may be a rational approach to inhibit progression of cancers driven by EGFR signaling including those resistant to anti-EGFR drugs because of activating mutations in the RAS/RAF/MEK/ERK pathway.


Subject(s)
Antigens, CD/biosynthesis , Cell Adhesion Molecules/biosynthesis , Cell Movement , ErbB Receptors/metabolism , Gene Expression Regulation, Neoplastic , Neoplasm Proteins/biosynthesis , Ovarian Neoplasms/metabolism , Antigens, CD/genetics , Antigens, Neoplasm , Antineoplastic Agents/pharmacology , Cell Adhesion Molecules/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Epidermal Growth Factor/genetics , Epidermal Growth Factor/metabolism , ErbB Receptors/genetics , Female , Humans , Intercellular Junctions/genetics , Intercellular Junctions/metabolism , Intercellular Junctions/pathology , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Mutation , Neoplasm Proteins/genetics , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Pseudopodia/genetics , Pseudopodia/metabolism , Pseudopodia/pathology , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , RNA, Neoplasm/biosynthesis , RNA, Neoplasm/genetics , Up-Regulation
7.
J Biol Chem ; 286(49): 42303-42315, 2011 Dec 09.
Article in English | MEDLINE | ID: mdl-21994943

ABSTRACT

Reciprocal interactions between Src family kinases (SFKs) and focal adhesion kinase (FAK) are critical during changes in cell attachment. Recently it has been recognized that another SFK substrate, CUB-domain-containing protein 1 (CDCP1), is differentially phosphorylated during these events. However, the molecular processes underlying SFK-mediated phosphorylation of CDCP1 are poorly understood. Here we identify a novel mechanism in which FAK tyrosine 861 and CDCP1-Tyr-734 compete as SFK substrates and demonstrate cellular settings in which SFKs switch between these sites. Our results show that stable CDCP1 expression induces robust SFK-mediated phosphorylation of CDCP1-Tyr-734 with concomitant loss of p-FAK-Tyr-861 in adherent HeLa cells. SFK substrate switching in these cells is dependent on the level of expression of CDCP1 and is also dependent on CDCP1-Tyr-734 but is independent of CDCP1-Tyr-743 and -Tyr-762. In HeLa CDCP1 cells, engagement of SFKs with CDCP1 is accompanied by an increase in phosphorylation of Src-Tyr-416 and a change in cell morphology to a fibroblastic appearance dependent on CDCP1-Tyr-734. SFK switching between FAK-Tyr-861 and CDCP1-Tyr-734 also occurs during changes in adhesion of colorectal cancer cell lines endogenously expressing these two proteins. Consistently, increased p-FAK-Tyr-861 levels and a more epithelial morphology are seen in colon cancer SW480 cells silenced for CDCP1. Unlike protein kinase Cδ, FAK does not appear to form a trimeric complex with Src and CDCP1. These data demonstrate novel aspects of the dynamics of SFK-mediated cell signaling that may be relevant during cancer progression.


Subject(s)
Antigens, CD/chemistry , Cell Adhesion Molecules/chemistry , Focal Adhesion Protein-Tyrosine Kinases/chemistry , Neoplasm Proteins/chemistry , Tyrosine/chemistry , src-Family Kinases/metabolism , Antigens, Neoplasm , Binding Sites , Cell Adhesion , Cell Line, Tumor , Cell Membrane/metabolism , Disease Progression , Fibroblasts/metabolism , Gene Silencing , HeLa Cells , Humans , Microscopy, Confocal/methods , Phosphorylation
8.
Int J Colorectal Dis ; 26(6): 755-9, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21271344

ABSTRACT

PURPOSE: Patients undergoing colorectal resections are considered high risk for developing thromboembolic disease. We postulate, however, that the rapid recovery and swift mobilization after laparoscopic resections reduce this risk and that these patients therefore do not need prolonged thromboprophylaxis. This hypothesis was tested in this paper. METHODS: All patients who underwent laparoscopic colorectal surgery in our Colorectal Surgical Unit in the period from June 1991 until January 2010 were entered into a prospective database. The entire database was reviewed, and incidence of thromboembolic disease and significant bleeding complications were noted. RESULTS: Three thousand, three hundred sixty-four patients were laparoscopically operated on for colorectal disease and were entered in the database. Two thousand, one hundred twenty-seven patients were operated on for benign disease; 1,230, for colorectal cancer, and four, for other malignancies. Two deep venous thromboses were encountered (0.059%), and ten patients had pulmonary embolism (0.30%). The combined venous thromboembolism (VTE) risk for the overall group of patients undergoing laparoscopic colorectal operations is 0.36%. The combined VTE risk was 0.57% (7/1,230) in patients with colorectal cancer and 0.24% (5/2,127) in patients with benign disease (p = 0.118). Bleeding complications occurred in 44 patients (1.3%). CONCLUSIONS: In our group, the combined VTE risk for the overall group of patients undergoing laparoscopic colorectal operations is 0.36%. Therefore, we postulate that the prolonged use of thromboprophylaxis is not indicated in the vast majority of patients undergoing laparoscopic colorectal surgery. In particular, patients undergoing laparoscopic resections for benign disease and without other risk factors have such a low VTE risk that prolonged prophylaxis is probably not warranted.


Subject(s)
Colorectal Surgery/adverse effects , Laparoscopy/adverse effects , Thromboembolism/etiology , Thromboembolism/prevention & control , Humans , Postoperative Complications/etiology
9.
Med J Aust ; 194(9): 443-7, 2011 May 02.
Article in English | MEDLINE | ID: mdl-21534898

ABSTRACT

OBJECTIVE: To examine the trends in the uptake of laparoscopic resection for colorectal cancer. DESIGN AND SETTING: Retrospective analysis of Australia-wide data on elective resections for colorectal cancer over the 8 financial years 2000-01 to 2007-08, obtained from the National Hospital Morbidity Database. MAIN OUTCOME MEASURES: National trends in annual percentage of colorectal resections for cancer that were conducted laparoscopically for each year, stratified by hospitals conducting a high volume of elective resections (40 or more/year) versus a low volume, and by public versus private hospitals. RESULTS: For all Australian hospitals combined, the percentage of resections for colon cancer conducted laparoscopically increased from 2.4% in 2000-01 to 27.5% in 2007-08. For rectal cancer, this increase was from 1.1% to 21.5%. The largest increases were seen in high-volume private hospitals (colon cancer, 2.7% to 34.1%; rectal cancer, 1.5% to 26.2%), but increases also occurred in high-volume public hospitals (colon cancer, 2.7% to 32.2%; rectal cancer, 0.5% to 20.3%), low-volume private (colon cancer, 3.8% to 27.1%; rectal cancer, 2.4% to 25.5%) and low-volume public (colon cancer, 1.1% to 17.0%; rectal cancer, 0.5% to 13.8%) hospitals. CONCLUSIONS: The use of laparoscopic resection for colorectal cancer has increased throughout Australian hospitals. Our findings provide the data necessary to ensure adequate resource allocation by the appropriate medical bodies to achieve optimal success in the uptake of laparoscopic resection for colorectal cancer in Australia.


Subject(s)
Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/surgery , Elective Surgical Procedures/trends , Hospitalization/trends , Hospitals/statistics & numerical data , Laparoscopy/trends , Australia/epidemiology , Colorectal Neoplasms/economics , Databases, Factual , Elective Surgical Procedures/economics , Hospitalization/economics , Humans , Laparoscopy/economics , Neoplasm Staging , Operating Rooms/trends , Patient Selection
10.
Oncogene ; 39(1): 219-233, 2020 01.
Article in English | MEDLINE | ID: mdl-31471585

ABSTRACT

Elevated CUB-domain containing protein 1 (CDCP1) is predictive of colorectal cancer (CRC) recurrence and poor patient survival. While CDCP1 expression identifies stem cell populations that mediate lung metastasis, mechanisms underlying the role of this cell surface receptor in CRC have not been defined. We sought to identify CDCP1 regulated processes in CRC using stem cell populations, enriched from primary cells and cell lines, in extensive in vitro and in vivo assays. These experiments, demonstrating that CDCP1 is functionally important in CRC tumor initiation, growth and metastasis, identified CDCP1 as a positive regulator of Wnt signaling. Detailed cell fractionation, immunoprecipitation, microscopy, and immunohistochemical analyses demonstrated that CDCP1 promotes translocation of the key regulators of Wnt signaling, ß-catenin, and E-cadherin, to the nucleus. Of functional importance, disruption of CDCP1 reduces nuclear localized, chromatin-associated ß-catenin and nuclear localized E-cadherin, increases sequestration of these proteins in cell membranes, disrupts regulation of CRC promoting genes, and reduces CRC tumor burden. Thus, disruption of CDCP1 perturbs pro-cancerous Wnt signaling including nuclear localization of ß-catenin and E-cadherin.


Subject(s)
Antigens, Neoplasm/genetics , Cadherins/genetics , Cell Adhesion Molecules/genetics , Colorectal Neoplasms/genetics , beta Catenin/genetics , Active Transport, Cell Nucleus/genetics , Carcinogenesis/genetics , Cell Proliferation/genetics , Colorectal Neoplasms/pathology , Epithelial-Mesenchymal Transition/genetics , Gene Expression Regulation, Neoplastic/genetics , HCT116 Cells , Humans , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Wnt Signaling Pathway/genetics
11.
Ann Surg ; 248(6): 1092-7, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19092355

ABSTRACT

OBJECTIVE: To examine morbidity, mortality, conversion rates, and disease recurrence after laparoscopic resection of complicated and uncomplicated diverticular disease in a single center. SUMMARY BACKGROUND DATA: In contrast to colorectal cancer, there are few large studies of laparoscopic or open resection for diverticular disease. METHODS: This study represents a retrospective analysis of a prospectively collected database of all laparoscopic resections for uncomplicated and complicated diverticulitis from a single center. RESULTS: Five hundred patients (305 female) were identified (median age 58; range, 26-89). Recurrent diverticulitis was the most common indication for surgery (77%), followed by perforation (10%) and fistulation (9%). Median operating time was 120 minutes (range, 45-285) and median length of hospital stay was 4 (2-33) days. The splenic flexure was routinely mobilized. There was 1 (0.2%) 30-day and in-hospital death and 55 (11%) patients had major morbidity after the procedure. Conversion to an open operation was performed in 14 (2.8%) cases. Dense adhesions were the most common cause for conversion (6 patients). Among patients with complicated diverticulitis, the conversion rate was 5.3%, whereas for those with uncomplicated disease, it was 2.1% (P = ns). Operating time and length of hospital stay do not differ significantly between patients with complicated and uncomplicated diverticulitis. The conversion rate has come down from 8% for the first 100 cases to 1.5% for the last 400 cases (P = 0.002). To our knowledge, there have been no cases of recurrent diverticulitis. CONCLUSIONS: Laparoscopic resection even in complicated cases of diverticulitis is safe and effective. It can be achieved with short operating times and length of stay in conjunction with very low rates of morbidity and mortality. Adherence to surgical principles including routine mobilization of the splenic flexure and anastomosis onto the rectum may explain the absence of disease recurrence in our experience.


Subject(s)
Colectomy/methods , Diverticulitis, Colonic/surgery , Adult , Aged , Aged, 80 and over , Anastomosis, Surgical , Diverticulitis, Colonic/complications , Diverticulitis, Colonic/diagnosis , Female , Follow-Up Studies , Humans , Laparoscopy , Length of Stay , Male , Middle Aged , Morbidity , Recurrence , Retrospective Studies
12.
J Pharm Biomed Anal ; 139: 65-72, 2017 May 30.
Article in English | MEDLINE | ID: mdl-28279929

ABSTRACT

CUB domain containing protein 1 (CDCP1) is a transmembrane protein involved in progression of several cancers. When located on the plasma membrane, full-length 135kDa CDCP1 can undergo proteolysis mediated by serine proteases that cleave after two adjacent amino acids (arginine 368 and lysine 369). This releases from the cell surface two 65kDa fragments, collectively termed ShE-CDCP1, that differ by one carboxyl terminal residue. To evaluate the function of CDCP1 and its potential utility as a cancer biomarker, in this study we developed an enzyme-linked immunosorbent assay (ELISA) to reliably and easily measure the concentration of ShE-CDCP1 in biological samples. Using a reference standard we demonstrate that the developed ELISA has a working range of 0.68-26.5ng/ml, and the limit of detection is 0.25ng/ml. It displays high intra-assay (repeatability) and high inter-assay (reproducibility) precision with all coefficients of variation ≤7%. The ELISA also displays high accuracy detecting ShE-CDCP1 levels at ≥94.8% of actual concentration using quality control samples. We employed the ELISA to measure the concentration of ShE-CDCP1 in human serum samples with our results suggesting that levels are significantly higher in serum of colorectal cancer patients compared with serum from individuals with benign conditions (p<0.05). Our data also suggest that colorectal cancer patients with stage II-IV disease have at least 50% higher serum levels of ShE-CDCP1 compared with stage I cases (p<0.05). We conclude that the developed ELISA is a suitable method to quantify ShE-CDCP1 concentration in human serum.


Subject(s)
Antigens, CD/blood , Biomarkers, Tumor/blood , Cell Adhesion Molecules/blood , Cell Membrane/metabolism , Colorectal Neoplasms/blood , Neoplasm Proteins/blood , Aged , Antigens, Neoplasm , Colorectal Neoplasms/pathology , Enzyme-Linked Immunosorbent Assay/methods , Female , HEK293 Cells , Humans , Male , Middle Aged
13.
World J Gastroenterol ; 22(21): 4977-87, 2016 Jun 07.
Article in English | MEDLINE | ID: mdl-27275090

ABSTRACT

External and internal rectal prolapse with their affiliated rectocele and enterocele, are associated with debilitating symptoms such as obstructed defecation, pelvic pain and faecal incontinence. Since perineal procedures are associated with a higher recurrence rate, an abdominal approach is commonly preferred. Despite the description of greater than three hundred different procedures, thus far no clear superiority of one surgical technique has been demonstrated. Ventral mesh rectopexy (VMR) is a relatively new and promising technique to correct rectal prolapse. In contrast to the abdominal procedures of past decades, VMR avoids posterolateral rectal mobilisation and thereby minimizes the risk of postoperative constipation. Because of a perceived acceptable recurrence rate, good functional results and low mesh-related morbidity in the short to medium term, VMR has been popularized in the past decade. Laparoscopic or robotic-assisted VMR is now being progressively performed internationally and several articles and guidelines propose the procedure as the treatment of choice for rectal prolapse. In this article, an outline of the current status of laparoscopic and robotic ventral mesh rectopexy for the treatment of internal and external rectal prolapse is presented.


Subject(s)
Laparoscopy/instrumentation , Rectal Prolapse/surgery , Robotics/instrumentation , Surgical Mesh , Defecation , Fecal Incontinence/etiology , Fecal Incontinence/physiopathology , Humans , Laparoscopy/adverse effects , Postoperative Complications/etiology , Recovery of Function , Rectal Prolapse/complications , Rectal Prolapse/physiopathology , Risk Factors , Treatment Outcome
14.
ANZ J Surg ; 80(11): 807-12, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20969688

ABSTRACT

BACKGROUND: Laparoscopic rectal resection is now a technique that is emerging from experience with laparoscopic colonic resection. We review and present our experience with restorative proctectomy for cancer and compare those performed with a hybrid technique with those performed totally laparoscopically. METHODS: A total of 177 patients have undergone laparoscopic restorative proctectomy. All of the patients were planned to have the abdominal portion of their surgery performed laparoscopically and to convert to open for the rectal dissection as required. They were then stratified into those that had their surgery performed completely laparoscopically (laparoscopic group - LG), and to those who had their rectal dissection and or transection performed with an open incision (hybrid group - HG). RESULTS: Short-term outcomes were compared between the LG (n=103) and the HG (n=74). The overall complication rate was higher in the HG (12% versus 35% P<0.001), mainly with a significantly higher pelvic abscess rate and higher rate of post-operative ileus. There were no intraoperative or post-operative deaths. Length of stay was equivalent in both groups (five days). To date, distal recurrence has occurred in 7.7% of the patients, eight in the LG and four in the HG (NS). Two patients, one in each group, have had local recurrence only. CONCLUSIONS: Laparoscopic open or laparoscopic hybrid approaches are techniques that can be used in suitable patients. Both have acceptable morbidity and mortality.


Subject(s)
Proctocolectomy, Restorative/methods , Proctoscopy/methods , Rectal Neoplasms/mortality , Rectal Neoplasms/surgery , Chi-Square Distribution , Cohort Studies , Confidence Intervals , Databases, Factual , Disease-Free Survival , Female , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Laparotomy/methods , Length of Stay , Male , Postoperative Complications/physiopathology , Proctoscopy/adverse effects , Queensland , Rectal Neoplasms/pathology , Retrospective Studies , Risk Assessment , Survival Analysis , Treatment Outcome
15.
Dis Colon Rectum ; 50(1): 50-5, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17115334

ABSTRACT

PURPOSE: This study was designed to assess the role of laparoscopic resection rectopexy for symptomatic rectal intussusception in patients who failed medical treatment. The functional outcomes of laparoscopic resection rectopexy were evaluated. METHODS: Patients who underwent laparoscopic resection rectopexy for rectal intussusception between July 1998 and November 2004 were identified. All patients with obstructed defecation failing medical treatment were included. Data were prospectively collected for the perioperative period. A follow-up questionnaire was used to assess functional outcome. RESULTS: Between 1998 and 2004, a total of 56 patients (53 females (95 percent); age range, 23-83 years) underwent laparoscopic resection rectopexy for rectal intussusception. The median operative time was 123 minutes. Morbidity was 7 percent, and there was no mortality. Fifty-two patients were available for follow-up, and of these 33 (63 percent) reported an overall improvement in their function after surgery. Of 28 patients suffering constipation, 15 (53 percent) reported an improvement in bowel frequency. Sixty-seven percent of patients incontinent before surgery improved. Symptoms of incomplete evacuation resolved in 38 percent of affected patients. Thirty-six percent of patients needing to strain at stool did not have this problem after surgery. Median follow-up was 44 (range, 15-92) months. CONCLUSIONS: The management of patients with rectal intussusception and obstructed defecation failing medical treatment is challenging. Laparoscopic resection rectopexy is an option that might offer symptomatic relief and improved function. Further studies are required to define the selection criteria to optimize the outcome in this patient group.


Subject(s)
Intussusception/surgery , Laparoscopy , Rectal Diseases/surgery , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Postoperative Complications , Prospective Studies , Treatment Outcome
16.
Dis Colon Rectum ; 48(5): 982-7, 2005 May.
Article in English | MEDLINE | ID: mdl-15785889

ABSTRACT

PURPOSE: This study has been undertaken to audit a single-center experience with laparoscopically-assisted resection rectopexy for full-thickness rectal prolapse. The clinical outcomes and long-term results were evaluated. METHODS: The data were prospectively collected for the duration of the operation, time to passage of flatus postoperatively, hospital stay, morbidity, and mortality. For follow-up, patients received a questionnaire or were contacted. The data were divided into quartiles over the study period, and the differences in operating time and length of hospital stay were tested using the Kruskal-Wallis test. RESULTS: Between March 1992 and October 2003, a total of 117 patients underwent laparoscopic resection rectopexy for rectal prolapse. The median operating time during the first quartile (representing the early experience) was 180 minutes compared with 110 minutes for the fourth quartile (Kruskal-Wallis test for operating time = 35.523, 3 df, P < 0.0001). Overall morbidity was 9 percent (ten patients), with one death (<1 percent). One patient had a ureteric injury requiring conversion. One minor anastomotic leak occurred, necessitating laparoscopic evacuation of a pelvic abscess. Altogether, 77 patients were available for follow-up. The median follow-up was 62 months. Eighty percent of the patients reported alleviation of their symptoms after the operation. Sixty-nine percent of the constipated patients experienced an improvement in bowel frequency. No patient had new or worsening symptoms of constipation after surgery. Two (2.5 percent) patients had full-thickness rectal prolapse recurrence. Mucosal prolapse recurred in 14 (18 percent) patients. Anastomotic dilation was performed for stricture in five (4 percent) patients. CONCLUSIONS: Laparoscopically-assisted resection rectopexy for rectal prolapse provides a favorable functional outcome and low recurrence rate. Shorter operating time is achieved with experience. The minimally invasive technique benefits should be considered when offering rectal prolapse patients a transabdominal approach for repair, and emphasis should now be on advanced training in the laparoscopic approach.


Subject(s)
Laparoscopy , Rectal Prolapse/surgery , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Postoperative Complications , Prospective Studies , Statistics, Nonparametric , Surveys and Questionnaires , Treatment Outcome
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