SRSF3 shapes the structure of miR-17-92 cluster RNA and promotes selective processing of miR-17 and miR-20a.

MicroRNA (miRNA) biogenesis is tightly regulated to maintain distinct miRNA expression patterns. Almost half of mammalian miRNAs are generated from miRNA clusters, but this process is not well understood. We show here that Serine-arginine rich splicing factor 3 (SRSF3) controls the processing of miR-17-92 cluster miRNAs in pluripotent and cancer cells. SRSF3 binding to multiple CNNC motifs downstream of Drosha cleavage sites within miR-17-92 is required for the efficient processing of the cluster. SRSF3 depletion specifically compromises the processing of two paralog miRNAs, miR-17 and miR-20a. In addition to SRSF3 binding to the CNNC sites, the SRSF3 RS-domain is essential for miR-17-92 processing. SHAPE-MaP probing demonstrates that SRSF3 binding disrupts local and distant base pairing, resulting in global changes in miR-17-92 RNA structure. Our data suggest a model where SRSF3 binding, and potentially its RS-domain interactions, may facilitate an RNA structure that promotes miR-17-92 processing. SRSF3-mediated increase in miR-17/20a levels inhibits the cell cycle inhibitor p21, promoting self-renewal in normal and cancer cells. The SRSF3-miR-17-92-p21 pathway operates in colorectal cancer, linking SRSF3-mediated pri-miRNA processing and cancer pathogenesis.

Comparison of quality of life, symptom and functional outcomes following surgical treatment for colorectal neoplasia.

BACKGROUND: Colorectal surgical procedures can have a significant impact on quality-of-life (QoL), functional and symptom outcomes. This retrospective study conducted in a tertiary care center evaluated the influence of four colorectal surgical procedures on patient-reported outcome measures (PROMs). METHODS: 512 patients undergoing colorectal neoplasia surgery between June 2015 and December 2017 were identified via the Cabrini Monash Colorectal Neoplasia database. Primary outcomes measured were the mean changes in PROMs following surgery utilizing the International Consortium of Health Outcome Measures colorectal cancer (CRC) PROMs. RESULTS: 242 patients from 483 eligible patients responded (50% participation rate). Responders and non-responders were comparable in median age (72 vs. 70 years), gender (48% vs. 52% male), time from surgery (<1 and >1 year), overall stage at diagnosis and type of surgery. Respondents underwent either a right hemicolectomy, ultra-low anterior resection, abdominoperineal resection or a transanal endoscopic microsurgery/transanal minimally invasive surgery. Right hemicolectomy patients reported the best post-operative function and reduced symptoms, significantly better (P < 0.01) than ultra-low anterior resection patients who reported the worst outcomes in multiple areas (body image, embarrassment, flatulence, diarrhoea, stool frequency). Furthermore, patients undergoing an abdominoperineal resection reported the worst scores for body image, urinary frequency, urinary incontinence, buttock pain, faecal incontinence and male impotence. CONCLUSIONS: The differences in PROMs in CRC surgical procedures is demonstrable. The worst post-operative functional and symptom scores were reported after either an ultra-low anterior resection or an abdominoperineal resection. Implementation of PROMs will identify and aid early patient referral to allied health and support services.

Factors affecting the post-operative outcomes in patients aged over 80 following colorectal cancer surgery.

PURPOSE: In 2019, in Australia, there were 500,000 people aged 85 and over. Traditionally, clinicians have adopted the view that surgery is not desirable in this cohort due to increasing perioperative risk, perceived minimal clinical benefit, and shortened life expectancy. This cohort study is aimed at investigating postoperative outcomes from elective and non-elective colorectal cancer surgery in patients aged 80 and over. METHODS: A retrospective analysis was conducted on patients from 2010 to 2020 on a prospectively maintained colorectal database. Patients aged over 80 who underwent surgical resection for colorectal cancer were reviewed. Oncological characteristics, short-term outcomes, overall survival, and relapse-free survival rates were analysed. RESULTS: A total of 832 patients were identified from the database. Females comprised 55% of patients aged 80 and above. The median age was 84 for octogenarians and 92 for nonagenarians. Most patients were ASA 2 (212) or ASA 3 (501). ASA 3 and 4 and stage III pathology were associated with higher postoperative complications. Fifty percent of over 80 s and 37% of over 90 s were surgically discharged to their own home. Overall survival at 30, 180, and 360 days and 5 years was 98.1%, 93.1%, 87.2%, and 57.2% for the over 80 s and 98.1%, 88.9%, 74.9%, and 24.4% for the over 90 s. CONCLUSION: Our results demonstrate that surgical treatment of older patients is safe with acceptable short-, medium-, and long-term survival. Nonetheless, efforts are needed to reduce the rates of complications in older patients, including utilisation of multi-disciplinary teams to assess the optimal treatment strategy and postoperative care.

Impact of Anastomotic Leak on Long-term Oncological Outcomes After Restorative Surgery for Rectal Cancer: A Retrospective Cohort Study.

BACKGROUND: Anastomotic leak after restorative surgery for rectal cancer is a major complication and may lead to worse long-term oncological and survival outcomes. OBJECTIVE: The purpose of this study was to identify risk factors associated with anastomotic leak and to assess the perioperative and long-term oncological impact of anastomotic leak in our cohort of patients with rectal cancer. DESIGN: A retrospective analysis was performed on data from the prospectively maintained Cabrini Monash colorectal neoplasia database. Patients who had undergone rectal cancer resection and subsequently received anastomosis between November 2009 and May 2020 were included in this study. Patient and tumor characteristics, technical risk factors, and short-term and perioperative as well as long-term oncological and survival outcomes were assessed. SETTINGS: The study was conducted in 3 tertiary hospitals. PATIENTS: A total of 693 patients met the inclusion criteria for this study. MAIN OUTCOME MEASURES: Univariate analyses were performed to assess the relationship between anastomotic leak and patient and technical risk factors, as well as perioperative and long-term outcomes. Univariate and multivariate proportional HR models of overall and disease-free survival were calculated. Kaplan-Meier survival analyses assessed disease-free and overall survival. RESULTS: Anastomotic leak rate was 3.75%. Males had an increased risk of anastomotic leak, as did patients with hypertension and ischemic heart disease. Patients who experience an anastomotic leak were more likely to require reoperation and hospital readmission and were more likely to experience an inpatient death. Disease-free and overall survival were also negatively impacted by anastomotic leaks. LIMITATIONS: This is a retrospective analysis of data from only 3 centers with the usual limitations. However, these effects have been minimized because of the high quality and completeness of the prospective data collection. CONCLUSIONS: Anastomotic leaks after restorative surgery negatively affect long-term oncological and survival outcomes for patients with rectal cancer. See Video Abstract at http://links.lww.com/DCR/C81 . IMPACTO DE LA FUGA ANASTOMTICA EN LOS RESULTADOS ONCOLGICOS A LARGO PLAZO TRAS CIRUGA RESTAURADORA PARA EL CNCER DE RECTO UN ESTUDIO DE COHORTE RETROSPECTIVO: ANTECEDENTES:La fuga anastomótica tras una cirugía restauradora para el cáncer de recto es una complicación mayor y puede conducir a peores resultados oncológicos y de supervivencia a largo plazo.OBJETIVO:El propósito de este estudio fue identificar los factores de riesgo asociados con la fuga anastomótica y evaluar el impacto oncológico perioperatorio y a largo plazo de la fuga anastomótica en nuestra cohorte de pacientes con cáncer de recto.DISEÑO:Se realizó un análisis retrospectivo de datos obtenidos de la base de datos Cabrini Monash sobre neoplasia colorrectal la cual es mantenida prospectivamente. Se incluyeron en este estudio pacientes que fueron sometidos a una resección del cáncer de recto y que posteriormente recibieron una anastomosis entre noviembre de 2009 y mayo de 2020. Se evaluaron las características del paciente y del tumor, los factores de riesgo relacionados a la técnica, los resultados oncológicos y de supervivencia perioperatorio, así como los resultados a corto y largo plazo.AJUSTES:El estudio se realizó en tres hospitales terciarios.PACIENTES:Un total de 693 pacientes cumplieron con los criterios de inclusión para este estudio.PRINCIPALES MEDIDAS DE RESULTADO:Se realizaron análisis univariados para evaluar la relación entre la fuga anastomótica y aquellos factores relacionados al paciente, a la técnica, así como los resultados perioperatorios y a largo plazo. Se calcularon modelos de razón de riesgo proporcional univariante y multivariante de supervivencia global y libre de enfermedad. Los análisis de supervivencia de Kaplan-Meier evaluaron la supervivencia libre de enfermedad y la supervivencia global.RESULTADOS:La tasa de fuga anastomótica fue del 3,75%. Los hombres tenían un mayor riesgo de fuga anastomótica al igual que aquellos pacientes con hipertensión y cardiopatía isquémica. Los pacientes que sufrieron una fuga anastomótica tuvieron mayores probabilidades de requerir una reintervención y reingreso hospitalario, así como también tuvieron mayores probabilidades de sufrir una muerte hospitalaria. La supervivencia libre de enfermedad y general también se vio afectada negativamente por las fugas anastomóticas.LIMITACIONES:Este es un análisis retrospectivo de datos de solo tres centros con las limitaciones habituales. Sin embargo, estos efectos han sido minimizados debido a la alta calidad y la exhaustividad de la recopilación prospectiva de datos.CONCLUSIONES:Las fugas anastomóticas después de una cirugía restauradora afectan negativamente los resultados oncológicos y de supervivencia a largo plazo para los pacientes con cáncer de recto. Consulte Video Resumen en http://links.lww.com/DCR/C81 . (Traducción-Dr. Osvaldo Gauto ).

Preferential Antibody and Drug Conjugate Targeting of the ADAM10 Metalloprotease in Tumours.

ADAM10 is a transmembrane metalloprotease that sheds a variety of cell surface proteins, including receptors and ligands that regulate a range of developmental processes which re-emerge during tumour development. While ADAM10 is ubiquitously expressed, its activity is normally tightly regulated, but becomes deregulated in tumours. We previously reported the generation of a monoclonal antibody, 8C7, which preferentially recognises an active form of ADAM10 in human and mouse tumours. We now report our investigation of the mechanism of this specificity, and the preferential targeting of 8C7 to human tumour cell xenografts in mice. We also report the development of novel 8C7 antibody-drug conjugates that preferentially kill cells displaying the 8C7 epitope, and that can inhibit tumour growth in mice. This study provides the first demonstration that antibody-drug conjugates targeting an active conformer of ADAM10, a widely expressed transmembrane metalloprotease, enable tumour-selective targeting and inhibition.

Surgical Techniques for Abdominoperineal Resection for Rectal Cancer: One Size Does Not Fit All.

Abdominoperineal resection (APR) of rectal cancer is associated with poorer oncological outcomes than anterior resection. This may be due to higher rates of intra-operative perforation (IOP) and circumferential resection margin (CRM) involvement causing higher recurrence rates and surgical complications. To address these concerns, several centers advocated a change in technique from a standard APR to a more radical extra-levator abdominoperineal excision (ELAPE). Initial reports showed that ELAPE reduced IOP rates and CRM involvement but increased wound complications and longer surgical duration. However, many of these studies had unacceptable rates of IOP and CRM before retraining in ELAPE. This may indicate that it was a sub-optimal surgical technique, which improved upon training, that had influenced the high CRM and IOP rates rather than the technique itself. Subsequent studies demonstrated that the CRM involvement rate for ELAPE was not always lower than for standard APR and, in some cases, significantly higher. The morbidity of ELAPE can be high, with studies reporting higher adverse events than APR, especially in terms of wound complications from the larger perineal incision required in ELAPE. Whether ELAPE improves short- or long-term oncological outcomes for patients has not been clearly demonstrated. The authors propose that all centers performing rectal cancer surgery audit surgical outcomes of patients undergoing APR or ELAPE and examine CRM involvement, IOP rates, and local recurrence rates, preferably through a national body. If rates of adverse technical or oncological outcomes exceed acceptable levels, then retraining in the appropriate surgical techniques may be indicated.

Modeling colorectal cancer: A bio-resource of 50 patient-derived organoid lines.

BACKGROUND AND AIM: Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. To improve outcomes for these patients, we need to develop new treatment strategies. Personalized cancer medicine, where patients are treated based on the characteristics of their own tumor, has gained significant interest for its promise to improve outcomes and reduce unnecessary side effects. The purpose of this study was to examine the potential utility of patient-derived colorectal cancer organoids (PDCOs) in a personalized cancer medicine setting. METHODS: Patient-derived colorectal cancer organoids were derived from tissue obtained from treatment-naïve patients undergoing surgical resection for the treatment of CRC. We examined the recapitulation of key histopathological, molecular, and phenotypic characteristics of the primary tumor. RESULTS: We created a bio-resource of PDCOs from primary and metastatic CRCs. Key histopathological features were retained in PDCOs when compared with the primary tumor. Additionally, a cohort of 12 PDCOs, and their corresponding primary tumors and normal sample, were characterized through whole exome sequencing and somatic variant calling. These PDCOs exhibited a high level of concordance in key driver mutations when compared with the primary tumor. CONCLUSIONS: Patient-derived colorectal cancer organoids recapitulate characteristics of the tissue from which they are derived and are a powerful tool for cancer research. Further research will determine their utility for predicting patient outcomes in a personalized cancer medicine setting.

Rectum versus colon: should malignant polyps be treated differently?

BACKGROUND: The management of malignant colorectal polyps removed at endoscopy remains controversial with patients either undergoing surgical resection or regular endoscopic surveillance. Lymph node (LN) metastases occur in 6-16% of patients with malignant polyps. This study assessed the rate of LN metastases in patients undergoing surgical resection for malignant polyps removed endoscopically to determine if there is a difference in the rate of LN metastases between colonic and rectal polyps. METHODS: A retrospective review of a prospectively maintained database was performed from 2010 to 2018. All patients who underwent surgical resection following endoscopic removal of a malignant colorectal polyp were reviewed. Clinical data including patient demographics and tumour characteristics were examined. RESULTS: A total of 177 patients underwent surgical resection in the study period. The median age at diagnosis was 65 years (range 22-88 years) with females comprising 52% of the patient cohort (n = 92/177). Polyps were located in the colon in 60.5% of cases with the remainder located in the rectum. The median number of LN harvested was 14 (range 0-44) with malignant LN (including a mesenteric tumour deposit) identified in 8.5% of resection specimens (n = 15/177). Malignant LNs were retrieved in 5.5% of right-sided tumours, 5.6% of left-sided tumours and 12.9% of rectal tumours (P = 0.090). CONCLUSION: A small proportion of patients with malignant polyps removed endoscopically will have LN metastases. The results of this study suggest that the tumour location might be a useful predictive marker; however, a further study with increased patient numbers is required to properly establish this finding.

Mesenchymal Niche-Derived Neuregulin-1 Drives Intestinal Stem Cell Proliferation and Regeneration of Damaged Epithelium.

Epidermal growth factor (EGF) maintains intestinal stem cell (ISC) proliferation and is a key component of organoid growth media yet is dispensable for intestinal homeostasis, suggesting roles for multiple EGF family ligands in ISC function. Here, we identified neuregulin 1 (NRG1) as a key EGF family ligand that drives tissue repair following injury. NRG1, but not EGF, is upregulated upon damage and is expressed in mesenchymal stromal cells, macrophages, and Paneth cells. NRG1 deletion reduces proliferation in intestinal crypts and compromises regeneration capacity. NRG1 robustly stimulates proliferation in crypts and induces budding in organoids, in part through elevated and sustained activation of mitogen-activated protein kinase (MAPK) and AKT. Consistently, NRG1 treatment induces a proliferative gene signature and promotes organoid formation from progenitor cells and enhances regeneration following injury. These data suggest mesenchymal-derived NRG1 is a potent mediator of tissue regeneration and may inform the development of therapies for enhancing intestinal repair after injury.

Predictive factors of complete pathological response in patients with locally advanced rectal cancer.

PURPOSE: Patients with locally advanced rectal cancer who achieve pathologic complete response (pCR) following neoadjuvant therapy have better long-term outcomes and could be spared from the perioperative and long-term morbidity of rectal resection. The aim of this study was to identify factors that predict the ability to achieve pCR at completion of conventional neoadjuvant therapy, therefore determining their suitability for non-surgical management. METHODS: A retrospective analysis was performed on data obtained from a prospectively maintained colorectal neoplasia database. Patients treated for biopsy-proven primary rectal adenocarcinoma between January 1, 2010, and February 28, 2018, who received neoadjuvant radiotherapy or chemoradiotherapy and had undergone surgical resection, were included in this study. Five-year oncologic outcome data was also obtained for 144 patients. Clinicopathological tumour characteristics and treatment regimens were analysed for correlation to clinical outcome. RESULTS: Three hundred fifty-four patients met inclusion criteria for this study. We identified significant differences between patients achieving a pCR and those that did not for tumour type (adenocarcinoma vs. mucinous/signet ring; p = 0.008), pre-treatment serum CEA level (

Clostridioides difficile infection damages colonic stem cells via TcdB, impairing epithelial repair and recovery from disease.

Gastrointestinal infections often induce epithelial damage that must be repaired for optimal gut function. While intestinal stem cells are critical for this regeneration process [R. C. van der Wath, B. S. Gardiner, A. W. Burgess, D. W. Smith, PLoS One 8, e73204 (2013); S. Kozar et al., Cell Stem Cell 13, 626-633 (2013)], how they are impacted by enteric infections remains poorly defined. Here, we investigate infection-mediated damage to the colonic stem cell compartment and how this affects epithelial repair and recovery from infection. Using the pathogen Clostridioides difficile, we show that infection disrupts murine intestinal cellular organization and integrity deep into the epithelium, to expose the otherwise protected stem cell compartment, in a TcdB-mediated process. Exposure and susceptibility of colonic stem cells to intoxication compromises their function during infection, which diminishes their ability to repair the injured epithelium, shown by altered stem cell signaling and a reduction in the growth of colonic organoids from stem cells isolated from infected mice. We also show, using both mouse and human colonic organoids, that TcdB from epidemic ribotype 027 strains does not require Frizzled 1/2/7 binding to elicit this dysfunctional stem cell state. This stem cell dysfunction induces a significant delay in recovery and repair of the intestinal epithelium of up to 2 wk post the infection peak. Our results uncover a mechanism by which an enteric pathogen subverts repair processes by targeting stem cells during infection and preventing epithelial regeneration, which prolongs epithelial barrier impairment and creates an environment in which disease recurrence is likely.

Patient-Derived Colorectal Cancer Organoids Upregulate Revival Stem Cell Marker Genes following Chemotherapeutic Treatment.

Colorectal cancer stem cells have been proposed to drive disease progression, tumour recurrence and chemoresistance. However, studies ablating leucine rich repeat containing G protein-coupled receptor 5 (LGR5)-positive stem cells have shown that they are rapidly replenished in primary tumours. Following injury in normal tissue, LGR5+ stem cells are replaced by a newly defined, transient population of revival stem cells. We investigated whether markers of the revival stem cell population are present in colorectal tumours and how this signature relates to chemoresistance. We examined the expression of different stem cell markers in a cohort of patient-derived colorectal cancer organoids and correlated expression with sensitivity to 5-fluorouracil (5-FU) treatment. Our findings revealed that there was inter-tumour variability in the expression of stem cell markers. Clusterin (CLU), a marker of the revival stem cell population, was significantly enriched following 5-FU treatment and expression correlated with the level of drug resistance. Patient outcome data revealed that CLU expression is associated with both lower patient survival and an increase in disease recurrence. This suggests that CLU is a marker of drug resistance and may identify cells that drive colorectal cancer progression.

Molecular signature of interleukin-22 in colon carcinoma cells and organoid models.

Interleukin (IL)-22 activates STAT (signal transducer and activator of transcription) 3 and antiapoptotic and proproliferative pathways; but beyond this, the molecular mechanisms by which IL-22 promotes carcinogenesis are poorly understood. Characterizing the molecular signature of IL-22 in human DLD-1 colon carcinoma cells, we observed increased expression of 26 genes, including NNMT (nicotinamide N-methyltransferase, ≤10-fold) and CEA (carcinoembryonic antigen, ≤7-fold), both known to promote intestinal carcinogenesis. ERP27 (endoplasmic reticulum protein-27, function unknown, ≤5-fold) and the proinflammatory ICAM1 (intercellular adhesion molecule-1, ≤4-fold) were also increased. The effect on CEA was partly STAT3-mediated, as STAT3-silencing reduced IL-22-induced CEA by ≤56%. Silencing of CEA or NNMT inhibited IL-22-induced proliferation/migration of DLD-1, Caco-2, and SW480 colon carcinoma cells. To validate these results in primary tissues, we assessed IL-22-induced gene expression in organoids from human healthy colon and colon cancer patients, and from normal mouse small intestine and colon. Gene regulation by IL-22 was similar in DLD-1 cells and human and mouse healthy organoids. CEA was an exception with no induction by IL-22 in organoids, indicating the 3-dimensional organization of the tissue may produce signals absent in 2D cell culture. Importantly, augmentation of NNMT was 5-14-fold greater in human cancerous compared to normal organoids, supporting a role for NNMT in IL-22-mediated colon carcinogenesis. Thus, NNMT and CEA emerge as mediators of the tumor-promoting effects of IL-22 in the intestine. These data advance our understanding of the multifaceted role of IL-22 in the gut and suggest the IL-22 pathway may represent a therapeutic target in colon cancer.

Written instructions to patients to confirm pathology results: is this effective in the transmission of results?

BACKGROUND: Bowel cancer is the second most common internal malignancy in Australia. Bowel cancer is suited to community screening methods such as faecal occult blood testing and colonoscopy. Typical reporting of histopathology results after colonoscopy takes 3-5 days. Patients were given written instructions to call the clinician within 3-5 days to discuss the histopathology results. The objective of the study was to perform an audit whether patients call the clinician to discuss their histopathology results after undergoing a colonoscopy, gastroscopy or both. METHODS: A retrospective study was performed of patients attending for gastroscopy or colonoscopy at a single colorectal clinic at Cabrini Hospital, Melbourne, between 1 January and 31 December 2014. Age, pre-scope category and compliance with written instructions to callback were analysed. RESULTS: A total of 176 patients met the selection criteria, of whom 32.9% did not callback to discuss their histopathology results. Age and pre-scope category were independent predictors for patients to callback after endoscopy. The mean age of the patients who called back was higher (P < 0.01). Compared with patients who had a previous polyp or resection, patients in the pre-scope category of faecal occult blood testing/screening were more likely to callback (odds ratio: 4.37; 95% confidence interval: 1.17-16.31). CONCLUSION: Patients undergoing a colonoscopy for the purposes of screening and older patients were more likely to callback. Patients aged 62 years and younger were less likely to callback and should be targeted. Enhancements to the way information is presented to patients (e.g. video) should be considered for future studies.

New Monoclonal Antibodies to Defined Cell Surface Proteins on Human Pluripotent Stem Cells.

The study and application of human pluripotent stem cells (hPSCs) will be enhanced by the availability of well-characterized monoclonal antibodies (mAbs) detecting cell-surface epitopes. Here, we report generation of seven new mAbs that detect cell surface proteins present on live and fixed human ES cells (hESCs) and human iPS cells (hiPSCs), confirming our previous prediction that these proteins were present on the cell surface of hPSCs. The mAbs all show a high correlation with POU5F1 (OCT4) expression and other hPSC surface markers (TRA-160 and SSEA-4) in hPSC cultures and detect rare OCT4 positive cells in differentiated cell cultures. These mAbs are immunoreactive to cell surface protein epitopes on both primed and naive state hPSCs, providing useful research tools to investigate the cellular mechanisms underlying human pluripotency and states of cellular reprogramming. In addition, we report that subsets of the seven new mAbs are also immunoreactive to human bone marrow-derived mesenchymal stem cells (MSCs), normal human breast subsets and both normal and tumorigenic colorectal cell populations. The mAbs reported here should accelerate the investigation of the nature of pluripotency, and enable development of robust cell separation and tracing technologies to enrich or deplete for hPSCs and other human stem and somatic cell types. Stem Cells 2017;35:626-640.

The Effect of Diabetes on the Perioperative Outcomes of Colorectal Cancer Surgery Patients.

There are approximately 1.3 million patients in Australia with diabetes. Conflicting reports exist in the literature as to the effect of diabetes on the outcomes of colorectal cancer patients. We hypothesized that patients with diabetes would have poorer perioperative outcomes, and that diabetes was an independent risk factor for both 30-day mortality and perioperative morbidity. The aim of this study was to assess the impact of diabetes on perioperative colorectal cancer surgery outcomes, as compared to a diabetes-free reference population, and to examine factors affecting perioperative risk. We conducted an analysis of a prospectively collected, clinician-led colorectal cancer database of patients from 2010-2015. Patients with diabetes were compared to patients without diabetes on a range of perioperative outcomes. Pearson χ-squared tests, Wilcoxon rank sum tests and t-tests were employed for univariate analyses. Confounding factors were controlled for by separate logistic and linear regression analyses. The Huber-White Sandwich Estimator was used to calculate robust standard errors. A total of 1725 patients were analysed over 1745 treatment episodes in the study period with 267 patients (268 episodes) with diabetes studied. Diabetes contributed to medical, surgical complications, and increased length of inpatient stay in univariate analyses. Multivariable analysis adjusted for variables independently associated with each outcome revealed that diabetes was an independent contributor to an increased risk of surgical complications, with no significant effect on medical complications, return to the operating room, 30-day mortality, or readmission within 30 days. In this study, where overall baseline morbidity and mortality levels are low, the effect of diabetes alone on perioperative surgical outcomes appears to be overstated with control of associated perioperative risk factors such as cardiac, renal and respiratory factors being more important.

Colorectal Cancer Surgery in the Very Elderly: Nonagenarians.

BACKGROUND: Surgery in the very elderly is a topic that has not been well studied, despite the steady rise in this population. With the rise in this population, there is now discussion on the safety of surgery in this cohort for colorectal cancer. OBJECTIVE: The purpose of this study was to investigate elective and nonelective colorectal cancer surgery outcomes in patients aged ≥90 years at both private and public hospitals in Melbourne, Victoria, Australia. DESIGN: This was a retrospective analysis of patients aged ≥90 years who were included in the prospectively maintained Cabrini Monash University Department of Surgery colorectal neoplasia database for patients entered between January 2010 and February 2015. Comorbidity, ASA score, acuity of surgery, treatment, mortality, morbidity, and survival were analyzed. SETTINGS: This study was conducted in a tertiary referral hospital. PATIENTS: A total of 48 patients were identified from the database. The majority of these patients were women (58.0%), ASA score III to IV (91.7%), and treated in an elective setting (79.2%). The median age was 91.8 years. MAIN OUTCOME MEASURES: We measured 30-day mortality, 180-day mortality, and perioperative morbidity. RESULTS: Thirty-day mortality rate was 2.1%. The 180-day mortality rate was 10.4%. A total of 29.2% of patients had a perioperative complication. Median follow-up was 21 months (range, 13-54 months). In 180-day mortality, minimally invasive surgery was associated with a lower mortality rate vs open surgery (p = 0.043). Perioperative complications were associated with nonelective surgery (p = 0.045), open surgery procedures (p = 0.014), and higher stages of disease (p = 0.014). A total of 81.3% of patients were able to return home after surgery. LIMITATIONS: This was a retrospective study with the usual limitations; however, these have been minimized with the use of a high-quality, prospective data collection database. The median follow-up was 21 months. CONCLUSIONS: Colorectal surgery was generally safe for nonagenarians in this study. This study demonstrates that excellent outcomes can be achieved in a selected group. Additional prospective studies with larger numbers and 5-year follow-up are recommended.

ERBB3 Positively Correlates with Intestinal Stem Cell Markers but Marks a Distinct Non Proliferative Cell Population in Colorectal Cancer.

Several studies have suggested ERBB3/HER3 may be a useful prognostic marker for colorectal cancer. Tumours with an intestinal stem cell signature have also been shown to be more aggressive. Here, we investigate whether ERBB3 is associated with intestinal stem cell markers in colorectal cancer and if cancer stem cells within tumours are marked by expression of ERBB3. Expression of ERBB3 and intestinal stem cell markers (LGR5, EPHB2, CD44s and CD44v6) was assessed by qRT-PCR in primary colorectal tumours (stages 0 to IV) and matched normal tissues from 53 patients. The localisation of ERBB3, EPHB2 and KI-67 within tumours was investigated using co-immunofluorescence. Expression of ERBB3 and intestinal stem cell markers were significantly elevated in adenomas and colorectal tumours compared to normal tissue. Positive correlations were found between ERBB3 and intestinal stem cell markers. However, co-immunofluorescence analysis showed that ERBB3 and EPHB2 marked specific cell populations that were mutually exclusive within tumours with distinct proliferative potentials, the majority of ERBB3+ve cells being non-proliferative. This pattern resembles cellular organisation within normal colonic epithelium where EPHB2 labelled proliferative cells reside at the crypt base and ERBB3+ve cells mark differentiated cells at the top of crypts. Our results show that ERBB3 and intestinal stem cell markers correlate in colorectal cancers. ERBB3 localises to differentiated cell populations within tumours that are non-proliferative and distinct from cancer stem cells. These data support the concept that tumours contain discrete stem, proliferative and differentiation compartments similar to that present in normal crypts.

Long-term outcomes of the australasian randomized clinical trial comparing laparoscopic and conventional open surgical treatments for colon cancer: the Australasian Laparoscopic Colon Cancer Study trial.

OBJECTIVE: : We report a multicentered randomized controlled trial across Australia and New Zealand comparing laparoscopic-assisted colon resection (LCR) with open colon resection (OCR) for colon cancer. BACKGROUND: : Colon cancer is a significant worldwide health issue. This trial investigated whether the short-term benefits associated with LCR for colon cancer could be achieved safely, without survival disadvantages, in our region. METHODS: : A total of 601 patients with potentially curable colon cancer were randomized to receive LCR or OCR. Primary endpoints were 5-year overall survival, recurrence-free survival, and freedom from recurrence rates, compared using an intention-to-treat analysis. RESULTS: : On April 5, 2010, 587 eligible patients were followed for a median of 5.2 years (range, 1 week-11.4 years) with 5-year confirmed follow-up data for survival and recurrence on 567 (96.6%). Significant differences between the 2 trial groups were as follows: LCR patients were older at randomization, and their pathology specimens showed smaller distal resection margins; OCR patients had some worse pathology parameters, but there were no differences in disease stages. There were no significant differences between the LCR and OCR groups in 5-year follow-up of overall survival (77.7% vs 76.0%, P = 0.64), recurrence-free survival (72.7% vs 71.2%, P = 0.70), or freedom from recurrence (86.2% vs 85.6%, P = 0.85). CONCLUSIONS: : In spite of some differences in short-term surrogate oncological markers, LCR was not inferior to OCR in direct measures of survival and disease recurrence. These findings emphasize the importance of long-term data in formulating evidence-based practice guidelines.