Search

Background: Lymph node yield (LNY) of 12 or more in resection of colorectal cancer is recommended in current international guidelines. Although a low LNY (less than 12) is associated with poorer outcome in some studies, its prognostic value is unclear in patients with early‐stage colorectal or rectal cancer with a complete pathological response following neoadjuvant therapy. Lymph node ratio (LNR), which reflects the proportion of positive to total nodes obtained, may be more accurate in predicting outcome in stage III colorectal cancer. This study aimed to identify factors correlating with LNY and evaluate the prognostic role of LNY and LNR in colorectal cancer. Methods: An observational study was performed on patients with colorectal cancer treated at three hospitals in Melbourne, Australia, from January 2010 to March 2016. Association of LNY and LNR with clinical variables was analysed using linear regression. Disease‐free (DFS) and overall (OS) survival were investigated with Cox regression and Kaplan–Meier survival analyses. Results: Some 1585 resections were analysed. Median follow‐up was 27·1 (range 0·1–71) months. Median LNY was 16 (range 0–86), and was lower for rectal cancers, decreased with increasing age, and increased with increasing stage. High LNY (12 or more) was associated with better DFS in colorectal cancer. Subgroup analysis indicated that low LNY was associated with poorer DFS and OS in stage III colonic cancer, but had no effect on DFS and OS in rectal cancer (stages I–III). Higher LNR was predictive of poorer DFS and OS. Conclusion: Low LNY (less than 12) was predictive of poor DFS in stage III colonic cancer, but was not a factor for stage I or II colonic disease or any rectal cancer. LNR was a predictive factor in DFS and OS in stage III colonic cancer, but influenced DFS only in rectal cancer. The prognostic role of lymph node yield (LNY) and lymph node ratio (LNR) in stage I–III colorectal cancer revealed low LNY was predictive of poor disease‐free survival in later stage cancers and LNR was a predictive factor in disease‐free and overall survival particularly in stage III colorectal cancer. Supports wider use of measuring lymph node ratios [ABSTRACT FROM AUTHOR]

Interactions between cancer cells and the surrounding medium are not fully understood. In this study, we demonstrate that ascites induces selective changes in the expression of integrins and urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) in ovarian cancer cells. We hypothesise that this change of integrin and uPA/uPAR expression triggers signalling pathways responsible for modulating phenotype-dependent functional changes in ovarian cancer cells. Human ovarian surface epithelial (HOSE) cell lines and epithelial ovarian cancer cell lines were treated with ascites for 48 h. Ascites induced upregulation of alpha6 integrin, without any change in the expression of alphav, beta1 and beta4 integrin subunits. Out of the four ovarian cancer cell lines studied, ascites induced enhancement in the expression of uPA/uPAR in the more invasive OVCA 433 and HEY cell lines without any change in the noninvasive OVHS1 and moderately invasive PEO.36 cell lines. On the other hand, no change in the expression of alpha6 integrin or uPAR, in response to ascites, was observed in HOSE cells. In response to ascites, enhancement in proliferation and in adhesion was observed in all four ovarian cancer cell lines studied. In contrast, no significant increase in proliferation or adhesion by ascites was observed in HOSE cells. Ascites-induced expression of uPA/uPAR correlated with the increased invasiveness of HEY and OVCA 433 cell lines but was not seen in OVHS1, PEO.36 and HOSE cell lines. Upregulation of alpha6 integrin and uPA/uPAR correlated with the activation of Ras and downstream Erk pathways. Ascites-induced activation of Ras and downstream Erk can be inhibited by using inhibitory antibodies against alpha6 and beta1 integrin and uPAR, consistent with the inhibition of proliferation, adhesion and invasive functions of ovarian cancer cell lines. Based on these findings, we conclude that ascites can induce selective upregulation of integrin and uPA/uPAR in ovarian cancer cells and these changes may modulate the functions of ovarian carcinomas. [ABSTRACT FROM AUTHOR]

Interactions between cancer cells and the surrounding medium are not fully understood. In this study, we demonstrate that ascites induces selective changes in the expression of integrins and urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) in ovarian cancer cells. We hypothesise that this change of integrin and uPA/uPAR expression triggers signalling pathways responsible for modulating phenotype-dependent functional changes in ovarian cancer cells. Human ovarian surface epithelial (HOSE) cell lines and epithelial ovarian cancer cell lines were treated with ascites for 48?h. Ascites induced upregulation ofa6 integrin, without any change in the expression ofav,ß1 andß4 integrin subunits. Out of the four ovarian cancer cell lines studied, ascites induced enhancement in the expression of uPA/uPAR in the more invasive OVCA 433 and HEY cell lines without any change in the noninvasive OVHS1 and moderately invasive PEO.36 cell lines. On the other hand, no change in the expression ofa6 integrin or uPAR, in response to ascites, was observed in HOSE cells. In response to ascites, enhancement in proliferation and in adhesion was observed in all four ovarian cancer cell lines studied. In contrast, no significant increase in proliferation or adhesion by ascites was observed in HOSE cells. Ascites-induced expression of uPA/uPAR correlated with the increased invasiveness of HEY and OVCA 433 cell lines but was not seen in OVHS1, PEO.36 and HOSE cell lines. Upregulation ofa6 integrin and uPA/uPAR correlated with the activation of Ras and downstream Erk pathways. Ascites-induced activation of Ras and downstream Erk can be inhibited by using inhibitory antibodies againsta6 andß1 integrin and uPAR, consistent with the inhibition of proliferation, adhesion and invasive functions of ovarian cancer cell lines. Based on these findings, we conclude that ascites can induce selective upregulation of integrin and uPA/uPAR in ovarian cancer cells and these changes may modulate the functions of ovarian carcinomas.British Journal of Cancer (2005) 92, 1475-1485. doi:10.1038/sj.bjc.6602495 www.bjcancer.com Published online 29 March 2005 [ABSTRACT FROM AUTHOR]

The peroxisome proliferator-activated receptors (PPARs) belong to a subclass of nuclear hormone receptor that executes important cellular transcriptional functions. Previous studies have demonstrated the expression of PPAR?in several tumours including colon, breast, bladder, prostate, lung and stomach. This study demonstrates the relative expression of PPAR?in normal ovaries and different pathological grades of ovarian tumours of serous, mucinous, endometrioid, clear cell and mixed subtypes. A total of 56 ovarian specimens including 10 normal, eight benign, 10 borderline, seven grade 1, nine grade 2 and 12 grade 3 were analysed using immunohistochemistry. Immunoreactive PPAR?was not expressed in normal ovaries. Out of eight benign and 10 borderline tumours, only one tumour in each group showed weak cytoplasmic PPAR?expression. In contrast, 26 out of 28 carcinomas studied were positive for PPAR?expression with staining confined to cytoplasmic and nuclear regions. An altered staining pattern of PPAR?was observed in high-grade ovarian tumours with PPAR?being mostly localized in the nuclei with little cytoplasmic immunoreactivity. On the other hand, predominant cytoplasmic staining was observed in lower-grade tumours. Significantly increased PPAR?immunoreactivity was observed in malignant ovarian tumours (grade 1, 2 and 3) compared to benign and borderline tumours (?2=48.80, P<0.001). Western blot analyses showed significant elevation in the expression of immunoreactive PPAR?in grade 3 ovarian tumours compared with that of normal ovaries and benign ovarian tumours (P<0.01). These findings suggest an involvement of PPAR?in the onset and development of ovarian carcinoma and provide an insight into the regulation of this molecule in the progression of the disease.British Journal of Cancer (2005) 92, 113-119. doi:10.1038/sj.bjc.6602244 www.bjcancer.com Published online 7 December 2004 [ABSTRACT FROM AUTHOR]

Cancer invasion is regulated by cell surface proteinases and adhesion molecules. Interaction between specific cell surface molecules such as urokinase plasminogen activator receptor (uPAR) and integrins is crucial for tumour invasion and metastasis. In this study, we examined whether uPAR and beta1 integrin form a functional complex to mediate signalling required for tumour invasion. We assessed the expression of uPAR/beta1 integrin complex, Erk signalling pathway, adhesion, uPA and matrix metalloproteinase (MMP) expression, migration/invasion and matrix degradation in a colon cancer cell line in which uPAR expression was modified. Antisense inhibition of the cell surface expression of uPAR by 50% in human colon carcinoma HCT116 cells (A/S) suppressed Erk-MAP kinase activity by two-fold. Urokinase plasminogen activator receptor antisense treatment of HCT116 cells was associated with a 1.3-fold inhibition of adhesion, approximately four-fold suppression of HMW-uPA secretion and inhibition of pro-MMP-9 secretion. At a functional level, uPAR antisense resulted in a four-fold decline in migration/invasion and abatement of plasmin-mediated matrix degradation. In empty vector-transfected cells (mock), uPA strongly elevated basal Erk activation. In contrast, in A/S cells, uPA induction of Erk activation was not observed. Urokinase plasminogen activator receptor associated with beta1 integrin in mock-transfected cells. Disruption of uPAR-beta1 integrin complex in mock-transfected cells with a specific peptide (P25) inhibited uPA-mediated Erk-MAP kinase pathway and inhibited migration/invasion and plasmin-dependent matrix degradation through suppression of pro-MMP-9/MMP-2 expression. This novel paradigm of uPAR-integrin signalling may afford opportunities for alternative therapeutic strategies for the treatment of cancer. [ABSTRACT FROM AUTHOR]

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., (© 2023 Royal Australasian College of Surgeons.)

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 )., (Copyright © The ASCRS 2022.)

Backgrounds: Magnetic resonance imaging is the primary method for local staging in rectal cancer patients. Administration of intravenous (IV) hyoscine butylbromide is thought to improve accuracy, but there are contraindications and potential adverse effects. The aim was to assess the efficacy of IV hyoscine butylbromide on the accuracy of MRI rectal cancer staging of T2 and T3 rectal cancers., Methods: A retrospective cohort study was carried out on patients prospectively recorded on the Cabrini Monash colorectal neoplasia database. A total of 74 patients (53 males, 21 females) MRI pelvis and rectums with antispasmodics were performed at multiple centres in the pre-operative setting between 2010 and 2016. Each patient underwent total mesorectal excision of rectal cancer. The excision specimens were assessed and given a pathological TNM stage, which was considered the reference standard., Results: There was no statistically significant impact on the overall accuracy of MRI rectal cancer staging between patient groups who received IV hyoscine butylbromide and groups who did not receive IV hyoscine butylbromide. The accuracy of T2 and T3 staged rectal cancers was more likely to be correct (compared with T1 cancers) with the administration of IV hyoscine butylbromide. Still, there was no improvement in the accuracy of N-staging., Conclusion: Given the potential side effects and adverse outcomes of IV anti-spasmodic agents, department protocols may need to be re-assessed regarding the prescription of these medications for MRI rectal cancer staging., (© 2023 Royal Australasian College of Surgeons.)

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., (© 2023. The Author(s).)

Background: Cytoreductive nephrectomy (CN) for the treatment of metastatic renal cell carcinoma (mRCC) was called into question following the publication of the CARMENA trial. While previous retrospective studies have supported CN alongside targeted therapies, there is minimal research establishing its role in conjunction with immune checkpoint inhibitor (ICI) therapy., Objective: To evaluate the association between CN and oncological outcomes in patients with mRCC treated with immunotherapy., Materials and Methods: A multicenter retrospective cohort study of patients diagnosed with mRCC between 2000 and 2020 who were treated at the Seattle Cancer Care Alliance and The Ohio State University and who were treated with ICI systemic therapy (ST) at any point in their disease course. Overall survival (OS) was estimated using Kaplan Meier analyses. Multivariable Cox proportional hazards models evaluated associations with mortality., Results: The study cohort consisted of 367 patients (CN+ST n = 232, ST alone n = 135). Among patients undergoing CN, 30 were deferred. Median survivor follow-up was 28.4 months. ICI therapy was first-line in 28.1%, second-line in 17.4%, and third or subsequent line (3L+) in 54.5% of patients. Overall, patients who underwent CN+ST had longer median OS (56.3 months IQR 50.2-79.8) compared to the ST alone group (19.1 months IQR 12.8-23.8). Multivariable analyses demonstrated a 67% reduction in risk of all-cause mortality in patients who received CN+ST vs. ST alone (P < 0.0001). Similar results were noted when first-line ICI therapy recipients were examined as a subgroup. Upfront and deferred CN did not demonstrate significant differences in OS., Conclusions: CN was independently associated with longer OS in patients with mRCC treated with ICI in any line of therapy. Our data support consideration of CN in well selected patients with mRCC undergoing treatment with ICI., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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.

Background: This study aimed to investigate whether an extracorporeal side-to-side (SS) or end-to-side (ES) stapled anastomosis impacts short-term and long-term outcomes after an oncological laparoscopic right hemicolectomy., Methods: A retrospective cohort study of prospectively collected data from two Victorian tertiary referral hospitals was performed. Patients who underwent oncological resection for colorectal cancer between February 2010 and September 2020 were selected from the colorectal neoplasia database. Patients were divided into two groups depending on the type of stapled anastomosis: Group 1 (functional end-to-end/side-to-side (SS)); and Group 2 (end-to-side (ES)). Primary outcomes were anastomotic leak, postoperative ileus, mortality and morbidity, length of stay post-surgery, readmission to hospital, and 30-day mortality., Results: This large case series of 1040 patients (SS = 625, ES = 415) demonstrated that the type of stapling technique impacted operative duration and postoperative ileus rates. Patients in the SS group had a faster operation of 108 min rather than 130 min in the ES group (p < 0.001). The SS group were more likely to experience a post-operative ileus (p < 0.001) with no impact on length of stay (SS, 7 days versus ES, 7 days; p = 0.14). There were no differences between the two groups with respect to lymph node yield, lymph node ratio, anastomotic leaks, return to theatre, 30-day mortality and 5-year overall survival., Discussion: The type of extracorporeal stapled anastomosis following an oncological laparoscopic right hemicolectomy has minimal impact on morbidity and survival outcomes; however, a side-to-side stapled anastomosis is more likely to be a faster operation with a higher postoperative ileus rate., (© 2022 The Authors. ANZ Journal of Surgery published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Surgeons.)

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., (© 2022 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Being a parent plays an important role in people's life trajectory and identity. Though the general cultural perception is that having children is a source of subjective well-being, there is evidence that, at least in some societies, the subjective well-being of those who are parents is worse, in some aspects, than that of those who are not. This gap has been the object of interest and controversy. The aim of this study was to compare Chilean adults with and without children in a broad set of well-being indicators, controlling for other sociodemographic variables. A public national probabilistic database was used. The results show that, in terms of positive and negative affect, those who are not parents achieve greater well-being than those who have children. Other results also pointed in that direction. The implications of the social context and gender, which are aspects that pose a burden for the exercise of parenthood in Chile, are discussed.

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., (© 2020 Royal Australasian College of Surgeons.)

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 (

Background: Globally, colorectal cancer (CRC) is the third and second leading cancer in men and women respectively with 600,000 deaths per year. Traditionally, clinicians have relied solely on nodal disease involvement, and measurements such as lymph node ratio (LNR; the ratio of metastatic/positive lymph nodes to total number of lymph nodes examined), when determining patient prognosis in CRC. The log odds of positive lymph nodes (LODDS) is a logistic transformation formula that uses pathologic lymph node data to stratify survival differences among patients within a single stage of disease. This formula allows clinicians to identify whether patients with clinically aggressive tumours fall into higher-risk groups regardless of nodal positivity and can potentially guide adjuvant treatment modalities. The aim of this study was to investigate whether LODDS in colon cancer provides better prognostication compared to LNR., Methods: A retrospective study of patients on the prospectively maintained Cabrini Monash University Department of Surgery colorectal neoplasia database, incorporating data from hospitals in Melbourne Australia, identified patients entered between January 2010 and March 2016. Association of LODDS and LNR with clinical variables were analysed. Disease-free (DFS) and overall (OS) survival were investigated with Cox regression and Kaplan-Meier survival analyses., Results: There were 862 treatment episodes identified in the database (402 male, 47%). The median patient age was 73 (range 22-100 years). There were 799 colonic cancers and 63 rectosigmoid cancers. The lymph node yield (LNY) was suboptimal (< 12) in 168 patients (19.5%) (p = 0.05). The 5-year OS for the different LNR groups were 86, 91 and 61% (p < 0.001) for LNR 0 (655 episodes), LNR 1 (128 episodes) and LNR 2 (78 episodes), respectively. For LODDS, they were 85, 91 and 61% (p < 0.001) in LODDS 0 (569 episodes), LODDS 1 (217 episodes) and LODDS 2 (75 episodes) groups (p < 0.001). Overall survival rates were comparable between the LNR and LODDS group and for LNY < 12 and stage III patients when each were sub-grouped by LODDS and LNR., Conclusion: This study has shown for that the prognostic impact of LODDS is comparable to LNR for colon cancer patients. Accordingly, LNR is recommended for prognostication given its ease of calculation.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors declare no conflict of interest.

Background: The primary aim of this study was to investigate whether a preoperative elevation in serum CEA is an independent prognostic factor for both 5-year overall and disease-free survival within an Australian patient cohort., Materials and Methods: A retrospective study of a prospectively maintained colorectal neoplasia database for patients between January 2010 and June 2016 was performed. Patients were categorized into two groups according to the preoperative serum CEA level: low (<2.5), high CEA (≥2.5), and elevated (≥5 ng/ml); and further stratified by disease stage. Inclusion criteria were patients having had a resection for either a colonic or upper third rectal adenocarcinoma and with a preoperative CEA value. Data on patient demographics, mortality, and morbidity and survival were compiled. Five-year estimates of overall (OS) and disease-free survival (DFS) were assessed., Results: 623 patients met the inclusion criteria. The median patient age was 73 (range 22-97) and 55% female (n = 340). There were 572 colonic cancers and 51 rectal cancers. The median follow-up time was 25 months (range 1-71). Eight patients (1%) had a local recurrence and 62 patients (10%) had evidence of metastatic disease after the initial curative resection. The 5-year OS and DFS rates for patients with CEA level <2.5 ng/ml were 85% and 86% respectively, which were higher than those with CEA level ≥2.5 ng/ml (73% and 79% respectively). Independent predictors of recurrence were a CEA ≥5 ng/ml (HR 1.8; 95% CI 1.09-3.00; p = 0.002) and stage II (HR 5.33; 95% CI 1.59-17.90; p = 0.007) and stage III (HR 10.91; 95% CI 3.34-35.60; p=<0.001). A CEA ≥5 ng/ml was associated with a higher risk of death (HR 1.79; 95% CI 1.00-3.19; p = 0.046)., Conclusion: Preoperative CEA levels were associated with age, BMI, ASA and tumour stage. Overall, CEA remains a reliable predictor of recurrence and survival after curative surgery in patients with colorectal cancer., (Copyright © 2019. Published by Elsevier Ltd.)

Nonalcoholic fatty liver disease (NAFLD) is a well-recognized health problem, with an estimated worldwide prevalence of 25%. 1 It is associated with metabolic syndrome (MetSx) and complications such as cirrhosis and hepatocellular carcinoma. However, the main cause of death in patients with NAFLD is derived from cardiovascular disease, and outcome seems to be determined by the degree of hepatic fibrosis. 2 The prevalence of NAFLD and associated cardiovascular risk factors in asymptomatic patients in Mexico are poorly documented, despite having one of the highest rates of obesity and metabolic syndrome worldwide. 3 ., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background/objectives: Adjuvant chemotherapy for Stage II colon cancer offers a small (2-3%) overall survival benefit and is not universally recommended. Mismatch repair deficiency (dMMR) confers an improved prognosis identifying patients unlikely to benefit from adjuvant chemotherapy. The aim of this study was to investigate the use of dMMR immunohistochemistry in two major cancer treatment centres., Methods: Prospective data were collected on all patients with resected Stage II colon cancer between 2010 and 2015 across two large Australian hospitals. Data collected included patient demographics, tumour histology, dMMR immunohistochemistry, chemotherapy use, and outcomes., Results: All 355 patients (56.1% female, median age 81) with resected Stage 2 Colon cancer entered on to the surgical database were included in this analysis. MMR testing was performed on 167 patient samples (47%), most occurred post-2013 (73.1% vs. 26.9% patients). dMMR rates were 34.1%. 25 (7.3%) received adjuvant chemotherapy, with no patient >80 years receiving treatment. Presence of ≥2 high-risk feature increased the likelihood of adjuvant chemotherapy. Only 3.6% dMMR patients received chemotherapy; both were young with high-risk features. 27/288 (7.6%) patients (with follow up) relapsed, with 7 disease-free post-resection of metastatic disease, 9 are alive with metastatic disease, and 11 deceased., Conclusions: Unlike clinical trial populations, Stage 2 colon cancer patients are often elderly, have high rates of dMMR tumours, are rarely offered chemotherapy, yet still have excellent outcomes. dMMR immunohistochemistry is being increasingly used to identify Stage 2 patients who do not require chemotherapy., (Copyright © 2018 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

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., (© 2016 The Authors Stem Cells published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

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., Competing Interests: The authors have declared that no competing interests exist.

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.

The Behavior Rating Inventory of Executive Functions evaluates executive functioning through the observation of students' performance in real contexts. Most psychometric studies of the scale have only tested the first-order structure, despite the hierarchical configuration of its theoretical model. A bifactor model was conducted on a normative sample of 5- to 18-year-old Chileans (M age = 11.3 years, SD = 3.7) to test a hierarchical structure of three first-order factors and an independent second-order factor. Bifactor analyses showed best fit for the proposed hierarchical structure. Findings supported a method to evaluate executive functioning models that provides a general global factor score that may complement existing indices and thus help clinicians to make better inferences., (© The Author(s) 2016.)

Background: Many studies have shown significantly improved outcomes (reduced local recurrence and improved overall survival) for patients achieving a complete pathological response from neoadjuvant chemoradiotherapy., Objective: This study aimed to document the complete pathological response rate and outcomes in patients receiving preoperative long-course chemoradiotherapy stratified for the extent of T3 mesorectal invasion measured on preoperative imaging., Design: This is a retrospective study of prospectively collected data, of patients with rectal cancer in the Cabrini Monash University Department of Surgery colorectal neoplasia database, incorporating data from Cabrini Hospital and The Alfred Hospital, identifying patients entered between January 2010 and June 2014., Patients and Settings: One hundred eighteen patients with T3 rectal cancer met the selection criteria for the study; 26 achieved complete pathological response (22%)., Main Outcome Measures: Outcomes in terms of complete pathological response and oncological outcomes such as disease-free and overall survival were analyzed., Results: Patients with complete pathological response had significantly less preoperative invasion than those with no complete pathological response (p < 0.001). Depth of invasion was the only variable associated with complete pathological response (p < 0.002), and the likelihood of complete pathological response decreased by 35% for every millimeter of invasion. Complete pathological response was associated with increased disease-free survival (p = 0.018) and a lower risk of cancer progression (p = 0.046). Depth of invasion was associated with an increased risk of death after surgery; HR increased by 1.07 (95% CI, 1.00-1.15) for each 1-mm increase in invasion., Limitations: This was a retrospective study with the usual limitations, although these were minimized through the use of a clinician-driven prospective database., Conclusions: The smaller the degree of T3 invasion, the higher the chance of achieving complete pathological response (up to 35%), which is associated with improved disease-free and overall survival. A higher complete pathological response rate is observed in early T3 disease in comparison with more extensive T3 invasion.

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.