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Hematogenous metastases are rarely present at diagnosis of ovarian clear cell carcinoma (OCC). Instead dissemination of these tumors is characteristically via direct extension of the primary tumor into nearby organs and the spread of exfoliated tumor cells throughout the peritoneum, initially via the peritoneal fluid, and later via ascites that accumulates as a result of disruption of the lymphatic system. The molecular mechanisms orchestrating these processes are uncertain. In particular, the signaling pathways used by malignant cells to survive the stresses of anchorage-free growth in peritoneal fluid and ascites, and to colonize remote sites, are poorly defined. We demonstrate that the transmembrane glycoprotein CUB-domain-containing protein 1 (CDCP1) has important and inhibitable roles in these processes. In vitro assays indicate that CDCP1 mediates formation and survival of OCC spheroids, as well as cell migration and chemoresistance. Disruption of CDCP1 via silencing and antibody-mediated inhibition markedly reduce the ability of TOV21G OCC cells to form intraperitoneal tumors and induce accumulation of ascites in mice. Mechanistically our data suggest that CDCP1 effects are mediated via a novel mechanism of protein kinase B (Akt) activation. Immunohistochemical analysis also suggested that CDCP1 is functionally important in OCC, with its expression elevated in 90% of 198 OCC tumors and increased CDCP1 expression correlating with poor patient disease-free and overall survival. This analysis also showed that CDCP1 is largely restricted to the surface of malignant cells where it is accessible to therapeutic antibodies. Importantly, antibody-mediated blockade of CDCP1 in vivo significantly increased the anti-tumor efficacy of carboplatin, the chemotherapy most commonly used to treat OCC. In summary, our data indicate that CDCP1 is important in the progression of OCC and that targeting pathways mediated by this protein may be useful for the management of OCC, potentially in combination with chemotherapies and agents targeting the Akt pathway.

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., Competing Interests: The authors report no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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)., (Copyright © The ASCRS 2021.)

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, β-catenin, and E-cadherin, to the nucleus. Of functional importance, disruption of CDCP1 reduces nuclear localized, chromatin-associated β-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 β-catenin and E-cadherin.

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.

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

MUC13 is a transmembrane mucin glycoprotein that is over produced by many cancers, although its functions are not fully understood. Nuclear factor-κB (NF-κB) is a key transcription factor promoting cancer cell survival, but therapeutically targeting this pathway has proved difficult because NF-κB has pleiotropic functions. Here, we report that MUC13 prevents colorectal cancer cell death by promoting two distinct pathways of NF-kB activation, consequently upregulating BCL-X L . MUC13 promoted tumor necrosis factor (TNF)-induced NF-κB activation by interacting with TNFR1 and the E3 ligase, cIAP1, to increase ubiquitination of RIPK1. MUC13 also promoted genotoxin-induced NF-κB activation by increasing phosphorylation of ATM and SUMOylation of NF-κB essential modulator. Moreover, elevated expression of cytoplasmic MUC13 and NF-κB correlated with colorectal cancer progression and metastases. Our demonstration that MUC13 enhances NF-κB signaling in response to both TNF and DNA-damaging agents provides a new molecular target for specific inhibition of NF-κB activation. As proof of principle, silencing MUC13 sensitized colorectal cancer cells to killing by cytotoxic drugs and inflammatory signals and abolished chemotherapy-induced enrichment of CD133 + CD44 + cancer stem cells, slowed xenograft growth in mice, and synergized with 5-fluourouracil to induce tumor regression. Therefore, these data indicate that combining chemotherapy and MUC13 antagonism could improve the treatment of metastatic cancers.

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.

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.

Many cancers are dependent on inappropriate activation of epidermal growth factor receptor (EGFR), and drugs targeting this receptor can improve patient survival, although benefits are generally short-lived. We reveal a novel mechanism linking EGFR and the membrane-spanning, cancer-promoting protein CDCP1 (CUB domain-containing protein 1). Under basal conditions, cell surface CDCP1 constitutively internalizes and undergoes palmitoylation-dependent degradation by a mechanism in which it is palmitoylated in at least one of its four cytoplasmic cysteines. This mechanism is functional in vivo as CDCP1 is elevated and palmitoylated in high-grade serous ovarian tumors. Interestingly, activation of the EGFR system with EGF inhibits proteasome-mediated, palmitoylation-dependent degradation of CDCP1, promoting recycling of CDCP1 to the cell surface where it is available to mediate its procancer effects. We also show that mechanisms inducing relocalization of CDCP1 to the cell surface, including disruption of its palmitoylation and EGF treatment, promote cell migration. Our data provide the first evidence that the EGFR system can function to increase the lifespan of a protein and also promote its recycling to the cell surface. This information may be useful for understanding mechanisms of resistance to EGFR therapies and assist in the design of treatments for EGFR-dependent cancers.

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.

Aim: The advent of rescue medical therapy (cyclosporin or infliximab) and laparoscopic surgery has shifted the paradigm in managing steroid refractory acute severe ulcerative colitis (ASUC). We investigated prospectively the impact of rescue therapy on timing and postoperative complications of urgent colectomy and subsequent restorative surgery for steroid refractory ASUC., Method: All consecutive presentations of steroid refractory ASUC at the Royal Brisbane Hospital (1996-2009) were entered in the study. Data collated included demographics, clinical and laboratory parameters on admission, medical therapy and operative and postoperative details. Steroid refractory ASUC patients undergoing immediate colectomy were compared with those failing rescue therapy and requiring same admission colectomy., Results: Of 108 steroid refractory ASUC presentations, 19 (18%) received intravenous steroids only and proceeded directly to colectomy. Rescue medical therapy was instituted in 89 (82%) patients with 30 (34%) failing to respond and proceeding to colectomy. There was no significant difference in the median time from admission to colectomy for rescue therapy compared with steroid-only cases (12 vs 10 days, P = 0.70) or 30-day complication rates (27%vs 47%, P = 0.22). The interval from colectomy to a subsequent restorative procedure was significantly longer for patients who failed rescue therapy (12 vs 5 months, P = 0.02). Furthermore 30-day complications following pouch surgery were significantly higher in patients who failed rescue therapy (32%vs 0%, P = 0.01)., Conclusion: Rescue therapy in steroid refractory ASUC is not related to delay in urgent colectomy or increased post-colectomy complications., (© 2012 The Authors. Colorectal Disease © 2012 The Association of Coloproctology of Great Britain and Ireland.)

Background: The IPAA has become established as the preferred technique for restoring intestinal continuity postproctocolectomy. The ideal pouch design has not been established. W-pouches may give better functional results owing to increased volume, whereas the J-pouch's advantage is its straightforward construction. We report short- and long-term results of an randomized control trial designed to establish the ideal pouch., Design: Ninety-four patients were randomly assigned to J- and W-pouches (49:45) and assessed at 1 and 8.7 years postoperatively. Assessment was questionnaire based and designed to assess pouch function and patient quality of life., Results: Eighty-five percent of patients were followed up at 1 year, and 68% were followed up at 8.7 years. At 1 year, there was a significant difference in 24-hour bowel movement frequency J- vs W-pouches 7 vs 5(p < 0.001) and in daytime frequency J- vs W-pouches 6 vs 4 (p < 0.001), with no difference in nocturnal function. At 9-year follow-up, function had equilibrated between the 2 groups: 24-hour bowel movement frequency J- vs W-pouches 6.5 vs 6 (p = 0.36), daytime frequency 5.5 vs 5 (p = 0.233), and nocturnal function 1 vs 1 (p = 0.987). Mean operating time of J- and W-pouches was 195 and 215 minutes (p < 0.05). All other parameters, pad usage, urgency, incontinence, and quality of life, did not differ significantly between groups., Conclusion: These data demonstrate that the theoretical functional advantage conferred on the W-pouch by its greater volume exists only in the short term and is of little consequence to patients' long-term quality of life. This advantage is attenuated as the pouches mature, resulting in no disparity in pouch function. This, combined with the more consistent, efficient, and easily taught construction of the J-pouch, should conclusively establish it as the optimum ileal-pouch design.

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.

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.

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.

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.

Background: Palliative resection of the primary tumour in asymptomatic patients with stage IV colorectal cancer is associated with improved survival and fewer complications. Laparoscopic surgery is widely employed in the curative treatment of colorectal cancer, but its value in advanced colorectal cancer remains unclear., Methods: All patients who underwent laparoscopic resection of primary colorectal cancer in this unit between June 1991 and Jan 2010 were entered into a prospective computerized database. Outcomes for patients with laparoscopic resection of stage IV colorectal cancer were compared with those of patients who had laparoscopic surgery for stage I disease., Results: Some 185 patients with stage IV colorectal cancer who underwent laparoscopic resection were compared with 310 patients who had stage I colorectal cancer. Some 94·1 and 98·4 per cent of operations respectively were completed laparoscopically. Hospital stay was slightly longer in the group with stage IV disease (mean 6·2 versus 5·3 days; P = 0·091). The 30-day mortality rate was 2·7 per cent in patients with stage IV disease and 0·6 per cent in those with stage I tumours (P = 0·061). There was no difference in complications. One-year survival rates were 77·8 and 99·0 per cent respectively (P < 0·001)., Conclusion: Short-term outcomes after laparoscopic surgery for stage IV colorectal cancer in selected patients are equivalent to those for stage I cancers., (Copyright © 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

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., (© 2010 The Authors. ANZ Journal of Surgery © 2010 Royal Australasian College of Surgeons.)

Background: There have recently been reports of higher levels of bladder and sexual dysfunction in men after laparoscopic rectal surgery when compared with those undergoing open surgery. This has led some surgeons to question the role of the laparoscopic approach to rectal surgery., Method: This study represents a retrospective analysis of a prospectively collected database for a single unit, comprising 2406 patients undergoing laparoscopic colorectal surgery. Bladder function, potency and ejaculation were assessed at postoperative clinic visits for men undergoing laparoscopic low or ultra-low anterior resection and abdominoperineal excision of the rectum., Results: A total of 101 males were identified (median age 62 years: range 20-90 years). Urinary dysfunction was reported by six (6%) patients. Six (6%) patients had sexual dysfunction, manifesting as retrograde ejaculation in four patients and erectile dysfunction in a further two patients., Conclusions: The low rates of sexual dysfunction in this unit may be attributable to pelvic dissection only being undertaken by experienced, dedicated laparoscopic colorectal surgeons. Laparoscopic restorative surgery for rectal cancer has been performed here only since 2001 after considerable experience accrued in operating on benign rectal disease and colon cancer. Studies from elsewhere reporting poorer functional outcomes have probably included a significant number of patients on the surgeons''learning curve'.

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.

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.

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.

Purpose: Perioperative hypothermia has been shown to be an important determinant of outcome after open colorectal resections. The degree of hypothermia occurring with laparoscopic-assisted colorectal surgery is, however, unknown, and the effectiveness of standard warming measures is untested. This study was designed to assess hypothermia in open and laparoscopic-assisted colonic resections using a standardized warming protocol., Methods: A prospective, nonrandomized study was performed with temperature measurements recorded every ten minutes. Statistical analysis was based on repeated measures analysis of variance models with significance set at the conventional 95 percent (two tailed)., Results: A total of 107 patients were entered into the trial; 68 had open and 39 had laparoscopic colectomies. The groups were well matched for age, weight, and duration of surgery, with a median operating time of 180 minutes in each group. The average drop in temperature from commencement of surgery to lowest point was 0.68 degrees C (standard deviation, 0.08) in the open group, compared with 0.53 degrees C (standard deviation, 0.06) in the laparoscopic group (P = 0.126)., Conclusions: Laparoscopic-assisted colorectal surgery is not associated with a higher incidence of perioperative hypothermia than open colorectal surgery using a standard warming regimen for both groups. On the basis of these results, standard temperature conservation is adequate, even for long, complex laparoscopic procedures.

Introduction: Open colorectal surgery in elderly patients is associated with increased morbidity and mortality rates compared with those in younger age groups. It also requires more intensive postoperative support, longer hospitalization, and in many cases leads to prolonged rehabilitation or institutionalization. Because of its less invasive nature, laparoscopically assisted colorectal surgery may lead to a reduced period of convalescence. However, the safety of advanced laparoscopic surgical techniques in the elderly has not been established, so this prospective comparative study was undertaken., Methods: All patients aged 80 years or more who were undergoing an elective laparoscopic or open colorectal procedure between 1 January 1992 and 30 June 1997 were assessed prospectively. Patients having simple stoma formation were excluded. Perioperative care, operative results and subsequent function were analysed., Results: There were 42 patients in the laparoscopic group and 35 in the open group, with a median age of 84 years in each group. Five patients undergoing laparoscopic surgery required conversion to an open procedure. No complications related to laparoscopy occurred. Three patients died after operation in the laparoscopic group and four in the open group, with morbidity in seven and 15 patients respectively. Median hospital stay was 9 (range 4-21) days for patients having the laparoscopic operation, and 17 (range 7-28) days in the open cases. At 4 weeks after operation 30 of the 35 independent patients surviving the operation in the laparoscopic group and 16 of 28 in the open group were back to preoperative activity levels., Conclusion: In this series laparoscopically assisted colorectal surgery was safe and was associated with a low incidence of complications, short hospitalization and a rapid return to preoperative activity levels when compared with open colorectal resections in this age group.

Purpose: The objectives of this study were to refine the technique of laparoscopically assisted anterior resection (LAR) for diverticular disease and to analyze the morbidity and mortality rates, and longer term follow-up of the first 100 consecutive patients., Methods: Data were collected prospectively, and follow-up was performed by an independent assessor using a standardized questionnaire., Results: The median duration of surgery was 180 minutes, the median time for passage of flatus was 2 days after surgery, and the median length of hospital stay was 4 days. Overall, the morbidity rate was 21%, and the wound infection rate was 5%. There were no deaths. Eight patients underwent open laparotomy. The rate of complications was significantly greater in the latter group of patients (75%) than in those who underwent laparoscopy (16%, p = 0.002). The comparison between the first 20 cases and the last 20 patients revealed a significantly shorter duration of surgery (median 225 min. vs. 150 min.; p < 0.0001) and decreased length of stay (6 days vs. 4 days, p < 0.0001). Apart from a nonsignificant increase in the length of surgery, there were no differences in other study parameters when comparisons were made between those patients who underwent LAR for complicated diverticular disease and those patients who underwent uncomplicated diverticular disease., Follow-Up: Ninety patients were available for follow-up at a median time of 37 months. Ninety-three percent of the patients reported that the surgery had improved their symptoms. No patient required hospitalization, and no one was treated with antibiotics for recurrent symptoms., Conclusion: Laparoscopically assisted anterior resection for diverticular disease has acceptable morbidity and mortality rates and a median postoperative hospital stay of only 4 days. Follow-up investigations revealed no recurrence of diverticulitis, and patients reported satisfaction regarding cosmetic and functional results.

Purpose: Objectives of this study were to describe the technique of laparoscopic-assisted resection rectopexy and audit the clinical outcomes, including review of functional results., Methods: Data were prospectively collected for duration of operation, time to passage of flatus and feces postoperatively, hospital stay, morbidity, and mortality. Follow-up was performed by an independent assessor using a standardized questionnaire. Patients were also assessed by clinical review or telephone interview., Results: During a four-year period, 34 patients underwent laparoscopic repair for rectal prolapse, of which 30 patients underwent laparoscopic-assisted resection rectopexy. Median duration of the operations was 185 minutes, median time for passage of flatus was two days postoperatively, and median length of hospital stay was five days. Morbidity was 13 percent and mortality rate was 3 percent. Comparison between the first ten patients who underwent laparoscopic-assisted resection rectopexy and the last ten revealed a significant reduction in both median duration of operating time (224 vs. 163 minutes; P < 0.005) and length of stay (6 vs. 4 days; P < 0.015). Follow-up study conducted at a median time of 18 months revealed that most patients (92 percent) felt that the operation had improved their symptoms, that incontinence was improved in 14 of 20 patients with impaired continence (70 percent), and that constipation was improved in 64 percent. Symptoms of incomplete emptying and the need to strain at stool were both improved in 62 and 59 percent of patients, respectively. No full-thickness recurrences have occurred, but two patients have had mucosal prolapse detected (7 percent) and treated., Conclusion: Laparoscopic-assisted resection rectopexy is feasible and safe, with acceptable recurrence rates and functional results compared with the open procedure in the surgical literature. There is rapid return of intestinal function associated with an early discharge from hospital.

Laparoscopic colorectal surgery is being assessed in many centres worldwide. This paper looks at the authors' experiences of 320 laparoscopic colorectal procedures and discusses modifications of technique, new instruments and changes in outcomes as experience is attained. Operating times are now approaching that of open surgery as the "learning curve" levels out. For example, the median operating time for the last 20 patients undergoing a laparoscopic right hemicolectomy was 2.1 hours and anterior resection was 2.2 hours. Of the 320 laparoscopic colorectal procedures performed, the conversion rate of 8.1% (26 patients) and perioperative death rate of 2.2% (7 patients) appear to be acceptable for the extent of surgery performed. The median inpatient stay for the last 20 patients undergoing a laparoscopic-assisted right hemicolectomy or high anterior resection was 5 days (range 3 to 11 days) and 4 days (range 3 to 18 days) respectively. Outcomes for cancer patients are encouraging. Of 106 selected patients having a potentially curative resection for colorectal and anal cancer, there have been 10 recurrences (9.4%) to date. Sixty-four patients have now been followed-up for more than 2 years. It is our belief that with appropriate patient selection a laparoscopic approach can give outcomes similar to open surgery with a slightly decreased hospital stay and convalescence. Laparoscopic colorectal surgery, particularly for benign disease, should be encouraged.

Purpose: To audit the development and outcomes of laparoscopic colorectal surgery at the Royal Brisbane Hospital., Methods: Since July 1991, laparoscopic-assisted colectomy for benign and malignant colorectal disease has been performed on more than 300 patients at the Royal Brisbane Hospital. This paper summarizes the outcome for the first 240 patients who underwent a laparoscopic colorectal procedure. All laparoscopic data were collected prospectively, and for selected studies, data were compared with open surgical controls., Results: Nineteen patients required open conversion (7.9 percent). There was a significant decrease in wound infection rates in patients having a laparoscopic-assisted colectomy (3.6 percent) compared with historical controls (7.9 percent) (P < 0.05; chi-squared). There were five anastomotic leaks, five laparotomies for postoperative adhesive obstruction, and four perioperative deaths. A total of 103 patients had a procedure for colorectal cancer. Of the 79 potentially curative procedures, there have been 5 (6.3 percent) recurrences to date., Conclusion: The overall morbidity and mortality in this series seem to be acceptable compared with that of open procedures.

Laparoscopic colectomy for both benign and malignant conditions has been performed in many institutions worldwide. Because of its recent inception, there has been little data available about follow-up in cancer patients. This prospective study assesses the operating statistics, postoperative complications, and long-term outcomes for 128 patients with colorectal cancer who were treated selectively with laparoscopic surgery. Median operating times for right hemicolectomy, anterior resection, and abdominoperineal resection were 3 hours, 3.3 hours, 3.5 hours, respectively. For right hemicolectomy and anterior resection patients, the median postoperative stay was 6 days. This stay was 9 days for abdominoperineal patients. Open conversion occurred in 9 patients (7%). 30 patients suffered from some postoperative morbidity (23%). Of 102 potentially curative procedures, there have been 9 recurrences (8,8%) to date. Fifteen patients have died. There is a low incidence of intestinal ileus (3%) and wound infection (1.8%).

During the period May 1986 to July 1989, a prospective, double blind, randomized trial of antibiotic prophylaxis in colorectal surgery was undertaken at the Royal Brisbane Hospital. Three hundred and thirty patients were considered eligible for the trial. Three regimens were compared: a combination of 2 g ceftriaxone and 1 g metronidazole; a single dose of 2 g ceftriaxone; or 1 g cefazolin and 1 g metronidazole, as antibacterial prophylaxis in colorectal surgery. Fifty patients were excluded from analysis. The overall incidence of wound sepsis was 7.9% (22 patients). There was no statistical difference in the incidence of wound infections between the three groups. The presence of drains and the non-performance of a bowel anastomosis at the time of surgery predisposed patients to wound infection. Staphylococcus aureus or Staphylococcus epidermidis were the cause of wound infection in 16 cases. Patients in the cefazolin and metronidazole group had a significantly higher number of postoperative urinary tract and respiratory tract infections than the other two groups combined (P less than 0.01). There did not appear to be any change in sensitivity patterns to ceftriaxone during the 3 year trial. During the 3 year period of the study, ceftriaxone was found to be a safe and effective drug in antibacterial prophylaxis in colorectal surgery.

We believe this is the first Australian reported case of anal carcinoma complicating Crohn's disease. The opportunity has been taken to present a detailed case report and review the increasing overseas literature about this problem.