Outcomes of Emotional Intelligence Training for Surgeons in a Real-World Setting: a Mixed Methods Study.

OBJECTIVE: The objective was to assess, improve and re-assess Emotional Intelligence (EI) in a group of junior and senior surgeons in a real-world setting. DESIGN: This was a mixed methods study. An EI education program was delivered through a series of webinars. The program drew from the central concepts of emotional intelligence: Motivation, empathy, social skills, self-knowledge, and self-control. There was also a component of professional development. EI assessment was performed pre- and post-intervention using the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) and a series of targeted questions. Qualitative assessment was performed by means of structured interviews examining uptake in techniques, understanding of EI, and its effect on personal and professional life. SETTING: The Australia and New Zealand Training Board in Colorectal Surgery administers a 2-year bi-national training program in teaching hospitals in Australia and New Zealand and runs a series of educational webinars throughout the training program. The "EI series" was part of this educational program. PARTICIPANTS: Webinars were attended by 35 junior surgeons and 8 senior surgeons RESULTS: Self-perceived knowledge and use of EI increased from a mean of 3.6 to 6.5 (p<0.0001). There was a significant difference between experiential (94) and strategic (101) scores (p=0.005). There was a nonsignificant improvement (98.04-100.6, p=0.16), in the pre-post MSCEIT among the junior surgeons and no change for senior surgeons. Seventy-eight percent (25/32) of surgeons interviewed reported using any new EI strategies. Seventy-five percent actively stopped and considered what other people in a clinical scenario may be thinking; 78% commenced metacognition; 81% practiced the process of self-regulation; 66% had begun to recognise and use emotions as data; and, 47% had actively practiced the process of self-distancing CONCLUSION: This study demonstrated the feasibility and utility of delivering EI training in an online format to a group of time-poor surgeons in a real-world setting.

The patient with obstructed defecatory symptoms: Management differs considerably between physicians and surgeons.

BACKGROUND: Patients with obstructed defecatory symptoms (ODS) are commonly referred to either gastroenterologists (GE) or colorectal surgeons (CS). Further management of these patients may be impacted by this choice of referral. METHODS: An online survey of specialist practice was disseminated to GE and CS in Australia and New Zealand. A case vignette of a patient presenting with ODS was described, with multiple subsequent scenarios designed to delineate the responder's preferred approach to management of this patient. KEY RESULTS: A total of 107 responders participated in the study, 62 CS and 45 GE. For a female patient with ODS not responding to pharmacological treatment, GE were more likely than CS to refer patients for anorectal manometry, while CS were more likely to refer for dynamic imaging. A quarter of CS and GE referred patients directly to pelvic floor physiotherapy, without any pre-treatment testing. Knowing the result of dynamic imaging, especially if a rectocele was demonstrated, substantially influenced management for both of the specialties: GE became more likely to refer the patients for CS consultation and less likely to refer directly for biofeedback or physiotherapy and CS were more likely to opt for an operative pathway over conservative management than they were prior to knowledge of the imaging findings. The majority (>75%) of GE and CS did not find it necessary to obtain a gynecological consultation, even in the presence of a rectocele. CONCLUSIONS & INFERENCES: Practice variation across medical specialties affects diagnostic and management recommendations for patients with ODS, impacting treatment pathways. Our findings provide an incentive toward establishing interdisciplinary, uniform, management guidelines.

Using a footstool does not aid simulated defecation in undifferentiated constipation: A randomized trial.

INTRODUCTION: The use of a footstool has been advocated to optimize posture when sitting on the toilet and thus facilitate bowel evacuation. We aimed to assess the alterations in defecatory posture, and the changes in simulated defecation with use of a footstool in patients with constipation. METHODS: Forty-one patients (female 93%, mean 52 year, SD 14 year) with constipation referred to a tertiary neurogastroenterology unit were enrolled. A bowel questionnaire, Hospital Anxiety and Depression Scale, and Rome questionnaire were administered prior to anorectal manometry. Each patient underwent three rectal balloon expulsion tests in randomized order with no footstool, a 7-inch, and a 9-inch footstool. Additional assessments included angle between spine and femur, and visual analogue scales assessing ease of evacuation, urge to defecate, and discomfort with expulsion. KEY RESULTS: Defecatory posture was significantly altered by footstool use, with progressive narrowing of the angle between the spine and femur as footstool height increased (p < 0.001 for all comparisons). Compared with no footstool, the use of a footstool was not associated with a change in balloon expulsion time and there was no difference between the two footstool heights. Subjectively, no significant change was identified in any of the three perceptions of balloon expulsion between no footstool and footstool use. CONCLUSIONS AND INFERENCES: Although the use of a footstool led to changes in defecatory posture, it did not improve subjective or objective measures of simulated defecation in patients with undifferentiated constipation. Therefore, the recommendation for its use during evacuation cannot be applied to all patients with constipation.

Flatus Incontinence and Fecal Incontinence: A Case-Control Study.

BACKGROUND: Incontinence to gas can be a troublesome symptom impacting quality of life for patients even in the absence of fecal incontinence. Whether isolated flatus incontinence represents part of the spectrum of true fecal incontinence or a separate condition with a different pathophysiology remains unclear. OBJECTIVE: This study aimed to evaluate the clinical features and anorectal physiology in women presenting with severe isolated flatus incontinence compared to women with fecal incontinence and healthy asymptomatic women. DESIGN: This was a retrospective case-control study of prospectively collected data. SETTINGS: Data from participants were obtained from a single tertiary Neurogastroenterology Unit in Sydney, Australia. PATIENTS: Data from 34 patients with severe isolated flatus incontinence, 127 women with fecal incontinence' and 44 healthy women were analyzed. MAIN OUTCOME MEASURES: The primary outcomes were clinical (including demographic, obstetric, and symptom variables) and physiological differences across the 3 groups. RESULTS: Patients with flatus incontinence were significantly younger (mean 39 versus 63 years; p = 0.0001), had a shorter history of experiencing their symptoms ( p = 0.0001), and had harder stool form than patients with fecal incontinence ( p = 0.02). Those with flatus incontinence had an adverse obstetric history and impaired anorectal physiology (motor and sensory, specifically rectal hypersensitivity) but to a lesser extent than patients with fecal incontinence. LIMITATIONS: This study was limited by its retrospective design and modest sample size. CONCLUSIONS: Anorectal physiology was impaired in patients with flatus incontinence compared to healthy controls, but to a lesser extent than in those with fecal incontinence, raising the possibility that flatus incontinence could be a precursor to fecal incontinence. As clinical and physiological findings are different from healthy controls (including the presence of visceral hypersensitivity), isolated flatus incontinence should be considered a distinct clinical entity (like other functional GI disorders), or possibly part of an incontinence spectrum rather than purely a normal phenomenon. See Video Abstract at http://links.lww.com/DCR/B946 . INCONTINENCIA DE FLATOS E INCONTINENCIA FECAL UN ESTUDIO DE CASOS Y CONTROLES: ANTECEDENTES:La incontinencia de gases puede ser un síntoma molesto que afecta la calidad de vida de los pacientes incluso en ausencia de incontinencia fecal. Aún no está claro si la incontinencia de flatos aislada representa parte del espectro de la incontinencia fecal verdadera o una condición separada con una fisiopatología poco clara.OBJETIVO:Evaluar las características clínicas y la fisiología anorrectal en mujeres que presentan incontinencia grave aislada de flatos, en comparación con la incontinencia fecal y mujeres sanas asintomáticas.DISEÑO:Este fue un estudio retrospectivo de casos y controles de datos recolectados prospectivamente.AJUSTE:Los datos de los participantes se obtuvieron de una sola Unidad de Neurogastroenterología terciaria en Sydney, Australia.PACIENTES:Se analizaron los datos de 34 pacientes con incontinencia grave aislada de flatos, junto con 127 mujeres con incontinencia fecal y 44 mujeres sanas.PRINCIPALES MEDIDAS DE RESULTADO:Los resultados primarios fueron clínicos (incluidas las variables demográficas, obstétricas y de síntomas), así como las diferencias fisiológicas entre los tres grupos.RESULTADOS:Los pacientes con incontinencia de flatos eran significativamente más jóvenes (media de 39 años frente a 63 años, p = 0,0001), tenían un historial más corto de experimentar sus síntomas (p = 0,0001) y tenían heces más duras que los pacientes con incontinencia fecal (p = 0,02). Aquellos con incontinencia de flatos tenían antecedentes obstétricos adversos y fisiología anorrectal alterada (motora y sensorial, específicamente hipersensibilidad rectal); aunque en menor medida que las pacientes con incontinencia fecal.LIMITACIONES:Este estudio estuvo limitado por su diseño retrospectivo y tamaño de muestra modesto.CONCLUSIONES:La fisiología anorrectal se vio afectada en las pacientes con incontinencia de flatos en comparación con las controles sanos, pero en menor medida que en aquellas con incontinencia fecal, lo que plantea la posibilidad de que la incontinencia de flatos pueda ser un precursor de la incontinencia fecal. Dado que los hallazgos clínicos y fisiológicos son diferentes a los de los controles sanos (incluida la presencia de hipersensibilidad visceral), la incontinencia de flatos aislada debe considerarse como una entidad clínica distinta (al igual que otros trastornos gastrointestinales funcionales), o posiblemente como parte de un espectro de incontinencia en lugar de un trastorno puramente a un fenómeno normal. Consulte Video Resumen en http://links.lww.com/DCR/B946 . (Traducción-Dr Yolanda Colorado ).

A novel combined anorectal biofeedback and percutaneous tibial nerve stimulation protocol for treating fecal incontinence.

BACKGROUND/AIMS: Fecal incontinence (FI) is a common, debilitating condition that causes major impact on quality of life for those affected. Non-surgical treatment options include anorectal biofeedback therapy (BF) and percutaneous tibial nerve stimulation (PTNS), usually performed separately. The aims of the current study were to determine the feasibility, tolerability, safety, and efficacy of performing a combined BF and PTNS treatment protocol. METHODS: Female patients with urge FI were offered a novel pilot program combining BF with PTNS. The treatment protocol consisted of 13 weekly sessions: an educational session, followed by 5 combined BF and PTNS sessions, 6 PTNS and a final combined session. Anorectal physiology and clinical outcomes were assessed throughout the program. For efficacy, patients were compared with BF only historical FI patients matched for age, parity, and severity of symptoms. RESULTS: A total of 12/13 (93%) patients completed the full program. Overall attendance rate was 93% (157/169 sessions). Patient comfort score with treatment was rated high at 9.8/10 (SD 0.7) for PTNS and 8.6/10 (SD 1.7) for the BF component. No major side effects were reported. A reduction of at least 50% in FI episodes/week was achieved by 58% of patients by visit 6, and 92% by visit 13. No physiology changes were evident immediately following PTNS compared with before, but pressure during sustained anal squeeze improved by the end of the treatment course. Comparing outcomes with historical matched controls, reductions in weekly FI episodes were more pronounced in the BF only group at visit 6, but not week 13. CONCLUSIONS: In this pilot study, concurrent PTNS and anorectal biofeedback therapy has been shown to be feasible, comfortable, and low risk. The combined protocol is likely to be an effective treatment for FI, but future research could focus on optimizing patient selection.

Appendicectomy during pregnancy and the risk of preterm birth: A population data linkage study.

BACKGROUND: Suspected appendicitis is a common non-obstetric indication for emergency abdominal surgery during pregnancy. AIMS: Assess the risk of preterm birth and other maternal and neonatal adverse birth outcomes following appendicectomy during pregnancy. MATERIALS AND METHODS: Population-based data linkage study of women with singleton births in New South Wales, Australia, 2002-2014. Pregnancies with appendicitis and appendicectomy were compared to pregnancies without appendicitis. Crude and adjusted hazard ratios (aHR) with 95% confidence intervals (CI) for preterm birth were estimated. Modified Poisson regression with robust variance was used to estimate crude and adjusted risk ratios (aRR) with 99% CI for other outcomes. RESULTS: Of 1 124 551 eligible pregnancies, 1024 (0.9/1000 pregnancies) had appendicitis and appendicectomy. Of these, 566 (55.3%) had laparoscopic and 458 (44.7%) had open appendicectomy. Appendicectomy at later gestational ages was associated with increasing rates of preterm birth. After adjustment for maternal and pregnancy factors, appendicectomy was associated with increased risk of preterm birth (overall aHR 1.73, 95% CI 1.42-2.09; planned aHR 2.08, 95% CI 1.60-2.72), maternal morbidity (aRR 2.68, 99% CI 1.88-3.83) and neonatal morbidity (aRR 1.42, 99% CI 1.03-1.94). However, there was no difference in perinatal mortality rates. CONCLUSION: Appendicectomy during pregnancy is associated with increased risk of spontaneous and planned preterm birth, maternal and neonatal morbidity. Availability of resources to prevent or manage preterm labour should be considered when appendicectomy is performed at gestational ages of 20 weeks or more.

Outcomes of Gallstone Disease during Pregnancy: a Population-based Data Linkage Study.

BACKGROUND: Gallstone disease is a leading indication for non-obstetric abdominal surgery during pregnancy. There are limited whole population data on maternal and neonatal outcomes. This population-based study aims to describe the outcomes of gallstone disease during pregnancy in an Australian setting. METHODS: Linked hospital, birth, and mortality data for all women with singleton pregnancies in New South Wales, Australia, 2001-2012 were analysed. Exposure of interest was gallstone disease (acute biliary pancreatitis, gallstones with/without cholecystitis). Outcomes including preterm birth (spontaneous and planned), readmission, morbidity and mortality (maternal and neonatal) were compared between pregnancies with and without gallstone disease. Adjusted risk ratios (aRRs) and 99% confidence intervals were estimated using modified Poisson regression and adjusted for maternal and pregnancy factors. RESULTS: Among 1 064 089 pregnancies, 1882 (0.18%) had gallstone disease. Of these, 239 (12.7%) had an antepartum cholecystectomy and 1643 (87.3%) were managed conservatively. Of those managed conservatively, 319 (19.0%) had a postpartum cholecystectomy. Gallstone disease was associated with increased risk of preterm birth (aRR 1.3, 99% CI 1.1, 1.6), particularly planned preterm birth (aRR 1.6, 99% CI 1.2, 2.1), maternal morbidity (aRR 1.6, 99% CI 1.1, 2.3), maternal readmission (aRR 4.7, 99% CI 4.2, 5.3), and neonatal morbidity (aRR 1.4, 99% CI 1.1, 1.7). Surgery was associated with decreased risk of maternal readmission (aRR 0.4, 99% CI 0.2, 0.7). CONCLUSIONS: Gallstone disease during pregnancy was associated with adverse maternal and neonatal outcomes. Most women with gallstone disease during pregnancy are managed conservatively. Surgical management was associated with decreased risk of readmission.

Medullary colorectal carcinoma revisited: a clinical and pathological study of 102 cases.

AIM: Medullary carcinoma is a recently described subtype of mismatch repair deficient (MMRd) colorectal carcinoma (CRC) which, despite being poorly differentiated by traditional morphological criteria, has been reported to have a good prognosis. We investigated the pathological and clinical features of medullary CRC in an unselected cohort of CRCs undergoing surgical resection. METHODS: All CRCs resected within a single health district database from 1998 to 2012 were categorized prospectively and underwent retrospective review to identify 91 medullary CRCs, with 11 additional cases from 2013 to 2014. Strict criteria were employed to diagnose medullary carcinoma requiring both MMRd and greater than 90 % of the tumor to demonstrate typical morphology, including solid growth. The demographic and pathological features, as well as all-cause survival, were compared with other CRCs, and specifically to other MMRd CRCs. RESULTS: From 1998 to 2012, 91 of 3,295 CRCs (2.8 %) were of the medullary type. Medullary CRC was more likely to arise in females than males (3.3:1; p < 0.0001), the elderly (mean age 77 vs. 71 years; p < 0.001), and the right colon (86 %; p < 0.0001). All medullary CRCs demonstrated MMR deficiency (considered an inclusion criteria) and 86 % were BRAFV600E-mutated (p < 0.0001). Thirty-day mortality after resection was higher in medullary CRC (4.6 vs. 1.7 %; p = 0.049). On univariate analysis, survival was not better than well-differentiated or other MMRd tumors. However, using a multivariate model, a medullary phenotype was protective (hazard ratio of death 0.54, 95 % CI 0.30-0.96; p = 0.037). CONCLUSIONS: Medullary CRC is more common than previously reported, frequently presents with locally advanced disease, and may be associated with higher mortality at 30 days after resection. Despite this, when strict criteria are used for diagnosis, the overall survival is favorable when compared with CRCs with equivalent demographic and pathological characteristics.

Incisional hernia repair after caesarean section: a population-based study.

BACKGROUND: Incisional hernias occur at surgical abdominal incision sites, but the association with caesarean section (CS) has not been examined. AIM: To determine whether CS is a risk factor for incisional hernia repair. MATERIALS AND METHODS: Population-based cohort study in Australia using linked birth and hospital data for women who gave birth from 2000 to 2011. Survival analysis was used to explore the association between CS and subsequent incisional hernia repair. Analyses were adjusted for confounding factors, including other abdominal surgery. The main outcome measure was surgical repair of an incisional hernia. RESULTS: Of 642,578 women, 217,555 (33.9%) had at least one CS and 1,554 (0.2%) women had a subsequent incisional hernia repair. The rate of incisional hernia repair in women who had ever had a caesarean section was 0.47%, compared to 0.12% in women who never had a caesarean section. After controlling for the duration of follow-up and known explanatory variables (eg other abdominal surgery, parity and multiple pregnancy), the adjusted hazard ratio (aHR) was 2.73 (95% confidence interval (CI) 2.45-3.06, P < 0.001). Incisional hernia repair risk increased with number of caesarean sections: women with two CS had a threefold increased risk of incisional hernia repair, which increased to sixfold after five CS (aHR = 6.29, 95% CI 3.99-9.93, P < 0.001) compared to women with no CS. CONCLUSIONS: There was a strong association between maternal CS and subsequent incisional hernia repair, which increased as the number of CSs increased, but the absolute risk of incisional hernia repair was low.

A further investigation of combined mismatch repair and BRAFV600E mutation specific immunohistochemistry as a predictor of overall survival in colorectal carcinoma.

Mutation specific immunohistochemistry (IHC) is a promising new technique to detect the presence of the BRAFV600E mutation in colorectal carcinoma (CRC). When performed in conjunction with mismatch repair (MMR) IHC, BRAFV600E IHC can help to further triage genetic testing for Lynch Syndrome. In a cohort of 1426 patients undergoing surgery from 2004 to 2009 we recently demonstrated that the combination of MMR and BRAFV600E IHC holds promise as a prognostic marker in CRC, particularly because of its ability to identify the poor prognosis MMR proficient (MMRp) BRAFV600E mutant subgroup. We attempted to validate combined MMR and BRAFV600E IHC as a prognostic indicator in a separate cohort comprising consecutive CRC patients undergoing surgery from 1998 to 2003. IHC was performed on a tissue microarray containing tissue from 1109 patients with CRC. The 5 year survivals stratified by staining patterns were: MMRd/BRAFwt 64%, MMRd/BRAFV600E 64%, MMRp/BRAFwt 60% and MMRp/BRAFV600E 53%. Using the poor prognosis MMRp/BRAFV600E phenotype as baseline, univariate Cox regression modelling demonstrated the following hazard ratios for death: MMRd/BRAFwt HR = 0.71 (95%CI = 0.40-1.27), p = 0.31; MMRd/BRAFV600E HR = 0.74 (95%CI = 0.51-1.07), p = 0.11 and MMRp/BRAFwt HR = 0.79 (95%CI = 0.60-1.04), p = 0.09. Although the findings did not reach statistical significance, this study supports the potential role of combined MMR and BRAF IHC as prognostic markers in CRC.

Restoring TGFbeta function in microsatellite unstable (MSI-H) colorectal cancer reduces tumourigenicity but increases metastasis formation.

BACKGROUND: TGFbeta is an important cell growth regulator which may have a role in metastasis formation. Microsatellite unstable (MSI-H) colon cancer serves as a unique model to demonstrate this as most MSI-H colon cancers have a mutation in the transforming growth factor beta receptor II (TGFbetaRII) gene and a low metastatic rate. AIMS: To demonstrate an increase in invasion and metastasis in a MSI-H colorectal cancer cell line with a known mutation in TGFbetaRII. MATERIALS AND METHODS: By restoring the wild-type TGFbetaRII gene in the KM12C MSI-H colorectal carcinoma cell line with a known mutation in TGFbetaRII, we have demonstrated that both invasion and metastasis in this cell line was significantly increased. A mouse metastatic model have shown that liver metastases were increased in mice inoculated with cells containing a wild-type TGFbetaRII gene (42% for the transfected group compared with 15% for the control group; p = 0.0379), despite a reduction in the size of primary tumours. CONCLUSIONS: This study highlights an important mechanism which may contribute to the low metastatic rate of MSI-H colon cancers and demonstrates the importance of TGFbeta signalling in metastasis formation. Previous studies involving breast cancer cell lines have shown that blocking TGFbeta signalling results in a reduction in metastasis formation. This study is the first study to use a cell line with a low metastatic rate and TGFbetaRII mutations to demonstrate that restoring TGFbeta signalling increases the metastatic rate.

Improved outcome due to increased experience and individualized management of leaks after ileal pouch-anal anastomosis.

OBJECTIVE: To assess the clinical presentation, management, and outcome of leaks after the ileal pouch-anal anastomosis (IPAA) procedure. METHODS: Of 1424 IPAA procedures performed at Mount Sinai Hospital from 1981 to 2003, 141 patients experienced leaks (9.9%). Data were reviewed retrospectively from the Inflammatory Bowel Disease database and clinic and hospital charts. Statistical comparisons were performed with the chi2 test. RESULTS: There were 81 men and 60 women with a median age of 36 years (12-69). Indication for surgery was ulcerative colitis in 93% of patients. Twenty-three leaks (16.3%) originated from the pouch whereas 118 (84.1%) arose from the ileoanal anastomosis. Of ileoanal anastomosis leaks, 24.6% were associated with and 38.1% without an abscess, 12.7% were associated with a pouch-cutaneous fistula, 15.3% were associated with a pouch-vaginal fistula, and 9.3% were diagnosed radiologically. Of the 130 patients who developed symptoms, 67% had fever, 38% had abdominoperineal pain, and 6% had perineal abscess. Twenty-nine percent of those who did not have an ileostomy had increased stool frequency. Nonoperative treatment was attempted initially in 100 patients with an 80% success rate. An operative procedure was performed in 59 patients (including those who failed nonoperative treatment), including transanal repair in 34 patients with a success rate of 66%; laparotomy with direct suture repair in 7 with a success rate of 57% and combined abdominoperineal pouch reconstruction in 18 with a success rate of 72%. Overall, 119 patients (84%) have a functioning pouch. Pouch salvage after a leak increased from 67% in 1981-1984 to 88% in 2001-2003 (P = 0.0004, chi2). CONCLUSIONS: A high rate of ileal pouch salvage can be achieved after leaks associated with the IPAA procedure if management is individualized. Improved salvage rate over time is likely a reflection of increased experience with the management of complications as well as the strategy of individualized management.

The role of chemotherapy in microsatellite unstable (MSI-H) colorectal cancer.

INTRODUCTION: High-frequency microsatellite instability (MSI-H) is an alternate pathway of colorectal carcinogenesis, which accounts for 15% of all sporadic colorectal cancers. These tumours arise from mutations in the DNA mismatch repair system and thus have different responses to chemotherapeutic agents compared to microsatellite stable (MSS) cancers. OBJECTIVE: This review aims to summarise the available literature on the responses to chemotherapy in MSI-H colorectal cancer (CRC). RESULTS AND DISCUSSION: 5 Fluorouracil (5FU) is commonly used as a chemotherapeutic agent in colon cancer and in vitro evidence shows reduced response to 5FU in MSI-H CRC. The clinical evidence is conflicting but favours a reduced response to 5FU in MSI-H CRC. Several newer agents such as COX-2 inhibitors and irinotecan are also reviewed. CONCLUSION: Available evidence suggests that MSI-H CRC have different behaviour patterns and response to chemotherapy compared with MSS CRC.

5-fluorouracil (5FU) treatment does not influence invasion and metastasis in microsatellite unstable (MSI-H) colorectal cancer.

Microsatellite instability is a recognised pathway of colorectal carcinogenesis responsible for about 15% of all sporadic colorectal cancers. Recent evidence has suggested that these tumours may not have the same response as microsatellite stable colon cancers to 5-fluorouracil (5FU)-based chemotherapy. The response to 5FU in four microsatellite unstable (MSI-H) cell lines was examined by cell viability assays and invasion assays. Flow cytometry was used to assess the effect of 5FU on MSI-H cell lines. In vivo response to 5FU was assessed by intraperitoneal injection of 5FU or control to 80 nude mice that had received intrasplenic injections of an MSI-H cell line KM12C prior to commencing treatment. There was inhibition of cell growth in MSI-H cell lines when treated with 5FU. There was no difference in invasiveness in the MSI-H cell lines when treated with 5FU. Primary tumours formed in 27 of the untreated and 25 of the 5FU treated mice (p=NS). There was a 36% reduction in splenic weight in those mice treated with 5FU (p<0.03). Metastases formed in 5 of the untreated and 9 of the treated mice (p=0.12). 5FU treatment of MSI-H tumours results in a reduction in growth but does not result in a reduction in invasion or metastasis.

Effective strategy to guide pathology test ordering in surgical patients.

BACKGROUND: Ordering of pathology testing by junior medical staff is often a haphazard process with little regard to the appropriateness of test ordering. The aim of the present study was to reduce ordering of inappropriate pathology tests in surgical patients attending the pre-admission clinic (PAC) through the introduction of a protocol-based test ordering system and to create an environment where such improvement can be sustained. METHODS: This is a prospective study with a retrospective control group. Three cohorts of patients attending the PAC were included. Group I (n = 700) attended prior to the introduction of the test protocols (April-June 2002) and acted as a control group. Group II (n = 720) attended after the protocol introduction (April-June 2003), and group III (n = 763) attended during the subsequent 3-month period from July to August 2003. The study examined the numbers of patients in each group who were ordered any of eight standard pathology tests. The average number of tests per patient, and cost of tests per patient were also ascertained. RESULTS: Following the introduction of pathology test protocols, the ordering of all but one of the eight tests was statistically significantly reduced. In particular, ordering of coagulation studies was reduced from 22.5% to 13.8% and electrolytes, urea and creatinine from 65.2% to 48.25% of patients (both P < 0.0001). Average number of tests performed per patient declined from 2.48 to 1.88, representing a savings of 10.33 dollars per patient (a decrease from 42.22 dollars to 31.89 dollars) and a projected annualized cost saving in excess of 26,000 dollars. CONCLUSIONS: Provided that certain preliminary guidelines are followed, these protocols can reduce pathology test ordering in any pre-admission Service.

The relative contributions of carboxylesterase and beta-glucuronidase in the formation of SN-38 in human colorectal tumours.

Irinotecan (CPT-11) is a prodrug that is used to treat metastatic colorectal cancer. It is activated to the topoisomerase poison SN-38 by carboxylesterases. SN-38 is subsequently metabolised to its inactive glucuronide, SN-38G, which can however be reactivated to SN-38 by beta-glucuronidase. The purpose of this study was to examine the role of carboxylesterases and beta-glucuronidase in the in vitro production of SN-38 in human colorectal tumours. The production of SN-38 from CPT-11 and SN-38G was measured by HPLC in human colorectal tumour homogenates. Carboxylesterase and beta-glucuronidase activities were found to be lower in tumour tissues compared to matched normal colon mucosa samples. In colorectal tumour, beta-glucuronidase and carboxylesterase-mediated SN-38 production rates were comparable at clinically relevant concentrations of SN-38G and CPT-11, respectively. Therefore, tumour beta-glucuronidase may play a significant role in the exposure of tumours to SN-38 in vivo, particularly during prolonged infusions of CPT-11.

There is no increase in frequency of somatic mutations in metastases compared with primary colorectal carcinomas with microsatellite instability.

This study investigates the molecular features of metastasis in sporadic colon carcinomas with high-level microsatellite instability (MSI-H). DNA from 51 regions from 10 MSI-H metastatic carcinomas and 26 corresponding metastases was analyzed for mutations in TGFBRII, IGFIIR, BAX, MSH3, MSH6, and TCF4, which are associated with MSI-H carcinomas. In addition, 10 metastatic and 10 non-metastatic MSI-H carcinomas and 10 metastatic microsatellite-stable (MSS) carcinomas were examined for expression of vascular endothelial growth factor (VEGF) and mutant TP53. The frequency of microsatellite instability and somatic mutations was not significantly increased in the metastases compared with the that of primary carcinomas. Although significantly fewer MSI-H carcinomas expressed VEGF (P < 0.01) and mutant TP53 (P < 0.005) than MSS carcinomas, there was no difference in VEGF and mutant TP53 expression in metastatic and non-metastatic MSI-H carcinomas. In conclusion, metastasis does not appear to be associated with an increase in somatic mutation rate in any of the genes examined in MSI-H colon carcinomas. Furthermore, VEGF and TP53 expression did not appear to be involved in metastasis in MSI-H colon carcinomas.

Incidence of microsatellite instability in synchronous tumors of the ovary and endometrium.

PURPOSE: Families with hereditary nonpolyposis colorectal cancer (HNPCC) have an increased lifetime risk of endometrial (40%) and ovarian (10%) carcinomas. Endometrial and ovarian carcinomas from members of these families frequently display a mutator phenotype as manifest by high levels of microsatellite instability (MSI-H). Microsatellite instability (MSI) occurs in 17-32% of sporadic endometrial carcinomas and 3-17% of sporadic ovarian carcinomas. We hypothesized that there might be a higher rate of MSI in tumors from women with synchronous primary carcinomas of the ovary and endometrium. EXPERIMENTAL DESIGN: We identified 52 cases of synchronous tumors of the ovary and endometrium from the databases of four gynecological oncology units. Archival material and clinical data were available on 45 of these patients. We examined DNA extracted from ovarian and endometrial tumor tissue for MSI using DNA extracted from normal tissue of that patient as a germ-line DNA control. MSI was assessed using a panel of five standard microsatellite markers: D2S123, D5S346, D17S250, BAT25, and BAT26. MSI-H was defined by more than two markers being positive. Low-level MSI (MSI-L) was defined as one or two markers positive and microsatellite stable (MSS) was defined as no markers positive. RESULTS: The 45 patients had a median age at diagnosis of 53 years. Of a total of 134 samples analyzed, only three samples (3.3%) were MSI-H. No patient had high levels of MSI in both ovarian and endometrial tumors. One ovarian carcinoma had five of five markers positive with the corresponding endometrial carcinoma being MSI-L. Two endometrial carcinomas were MSI-H, and the corresponding ovarian carcinomas were MSI-L and MSS, respectively. Seven ovarian tumors and seven endometrial tumors were MSI-L. The majority of patients had early-stage ovarian carcinoma [International Federation of Gynecology and Obstetrics (FIGO) stage I, 44.4%; stage II, 26.7%; and stage III, 26.6%]. Eighty-two % of the endometrial primaries were FIGO stage I. Progression-free survival was significantly better for patients with synchronous primaries than those presenting with ovarian carcinoma alone [adjusted hazards ratio, 1.94; P = 0.023; 95% confidence interval, 1.096-3.44]. CONCLUSION: Synchronous primary carcinomas of the ovary and endometrium are unlikely to be part of the HNPCC syndrome unless the family history is in keeping with the modified Amsterdam criteria.