Association Between RAS/BRAF Mutations and Complete Response Following Total Neoadjuvant Therapy in Patients with Rectal Cancer: A Prospective Multicentered Study.

BACKGROUND: The impact of RAS/BRAF mutation on primary response rates after total neoadjuvant therapy (TNT) in patients with advanced rectal cancer is unclear. The aim of this study was to assess complete response rates after TNT according to RAS/BRAF mutation status. METHODS: A prospective observational study was performed in patients with rectal cancer who underwent TNT with curative intent at three South Australian hospitals between 2019 and 2023. Patients were classified according to their mutation status: mutant RAS/BRAF (mutRAS) or wild-type RAS/BRAF (wtRAS). The primary endpoint was overall complete response (oCR) rate, defined as the proportion of patients who achieved clinical complete response (cCR) and/or pathological complete response (pCR). RESULTS: Of the 150 patients eligible for inclusion, 80 patients with RAS/BRAF status available were identified. Of these, 43 (53.8%) patients were classified as mutRAS and 37 (46.3%) patients as wtRAS. Patients with mutRAS had significantly lower cCR and oCR rates after TNT than patients with wtRAS (14% vs. 37.8%, p = 0.014; 11.6% vs. 43.2%, p = 0.001, respectively). There was no significant difference in pCR rate between the groups. Of the 80 rectal cancer patients tested, 35 (43.8%) had metastatic disease (M1). There was no significant difference in complete M1 response rates between the groups (17.6% vs. 38.9%, p = 0.254). CONCLUSION: RAS/BRAF mutations negatively impact primary tumor response rates after TNT in patients with advanced rectal cancer. Large-scale national studies are needed to determine whether RAS/BRAF status could be used to select optimal oncologic therapy in rectal cancer patients.

Does Sarcopenia Predict Local Response Rates After Chemoradiotherapy for Locally Advanced Rectal Cancer?

BACKGROUND: The predictive value of sarcopenia for tumor response to neoadjuvant chemoradiotherapy is unclear. OBJECTIVE: This study aimed to investigate the association between sarcopenia and pathological tumor regression grade after neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer. DESIGN: Retrospective cohort study from a prospectively collected database. Univariate logistic regression was performed to assess the association between sarcopenia and tumor response. SETTINGS: This study was conducted at 2 tertiary care centers. PATIENTS: Participants were patients undergoing neoadjuvant chemoradiotherapy for locally advanced rectal cancer (T3/4, N0/+) between 2007 and 2018. INTERVENTION: Sarcopenia was diagnosed using sex-specific cutoffs of lean muscle mass. Using the initial staging CT, lean muscle mass was estimated using the cross-sectional area of the psoas muscle at the level of the third lumbar vertebra, normalized for patient height. MAIN OUTCOME MEASURES: The primary end point was pathological tumor regression grade, defined as good (tumor regression grade 0/1) vs poor (tumor regression grade 2/3). RESULTS: The study included 167 patients with locally advanced rectal cancer with a median age of 60 (20-91) years, with 132 in the nonsarcopenia group and 35 in the sarcopenia group. Eighty-nine percent of patients had stage 3 cancer. Nine patients (5.4%) had a complete clinical response, 1 patient did not respond to treatment and opted for nonoperative management, and the remaining 157 patients (94.0%) proceeded to surgery. Pathological data revealed no significant difference between good tumor regression grade patients in the sarcopenia group compared with the nonsarcopenia group. Univariate analysis revealed BMI ≥25 kg/m 2 to be a risk factor for good tumor regression grade ( p = 0.002). LIMITATIONS: This study was limited by its retrospective design and small sample size. CONCLUSIONS: Sarcopenia is not a predictor of poor neoadjuvant chemoradiotherapy response in patients with locally advanced rectal cancer. Increasing BMI was associated with good tumor regression grade. Future multicentered studies are warranted to validate this finding. See Video Abstract at http://links.lww.com/DCR/C78 . LA SARCOPENIA PREDICE LAS TASAS DE RESPUESTA LOCAL DESPUS DE LA QUIMIORRADIOTERAPIA PARA EL CNCER DE RECTO LOCALMENTE AVANZADO: ANTECEDENTES:El valor predictivo de la sarcopenia para la respuesta tumoral a la quimiorradioterapia neoadyuvante no está claro.OBJETIVO:Este estudio investiga la asociación entre la sarcopenia y el grado de regresión tumoral patológica después de la quimiorradioterapia neoadyuvante en pacientes con cáncer de recto localmente avanzado.DISEÑO:Estudio de cohorte retrospectivo a partir de una base de datos recolectada prospectivamente. Se realizó una regresión logística univariante para evaluar la asociación entre la sarcopenia y la respuesta tumoral.ENTORNO CLINICO:Este estudio se realizó en dos centros de atención terciaria.PACIENTES:Pacientes sometidos a quimiorradioterapia neoadyuvante por cáncer de recto localmente avanzado (T3/4, N0/+) entre 2007-2018.INTERVENCIÓNES:La sarcopenia se diagnosticó utilizando puntos de corte de masa muscular magra específicos por género. Utilizando la tomografía computarizada de estadificación inicial, se estimó la masa muscular magra utilizando el área transversal del músculo psoas a nivel de la tercera vértebra lumbar, normalizada para la altura del paciente.PRINCIPALES MEDIDAS DE VALORACIÓN:El criterio principal de valoración fue el grado de regresión tumoral patológica, definido como bueno (grado de regresión tumoral 0/1) frente a malo (grado de regresión tumoral 2/3).RESULTADOS:El estudio incluyó a 167 pacientes con cáncer de recto localmente avanzado con una mediana de edad de 60 años (20-91), 132 en el grupo sin sarcopenia y 35 en el grupo con sarcopenia. Ochenta y nueve por ciento estaban en etapa III. Seis pacientes (5,4%) tuvieron respuesta clínica completa sostenida, un paciente no respondió al tratamiento y optó por manejo conservador, los 157 restantes (94,0%) procedieron a cirugía. Los datos patológicos no revelaron diferencias significativas entre los pacientes con buen grado de regresión tumoral en el grupo de sarcopenia en comparación con el grupo sin sarcopenia. El análisis univariado reveló que un IMC ≥25 kg/m2 era un factor de riesgo para un buen grado de regresión tumoral (p = 0,002).LIMITACIONES:Este estudio estuvo limitado por su diseño retrospectivo y tamaño de muestra pequeño.CONCLUSIÓNES:La sarcopenia no es un predictor de mala respuesta a la quimiorradioterapia neoadyuvante en pacientes con cáncer de recto localmente avanzado. El aumento del IMC se asoció con un buen grado de regresión tumoral. Se justifican futuros estudios multicéntricos para validar este hallazgo. Consulte Video Resumen en http://links.lww.com/DCR/C78 . (Traducción-Dr. Ingrid Melo ).

Is preoperative sarcopenia associated with postoperative complications after pelvic exenteration surgery?

PURPOSE: Pelvic exenteration (PE) involves radical surgical resection of pelvic organs and is associated with considerable morbidity. Sarcopenia is recognised as a predictor of poor surgical outcomes. This study aimed to determine if preoperative sarcopenia is associated with postoperative complications after PE surgery. METHODS: This retrospective study included patients who underwent PE with an available preoperative CT scan between May 2008 and November 2022 at the Royal Adelaide Hospital and St. Andrews Hospital in South Australia. Total Psoas Area Index (TPAI) was estimated by measuring the cross-sectional area of the psoas muscles at the level of the third lumbar vertebra on abdominal CT, normalised for patient height. Sarcopenia was diagnosed based on gender-specific TPAI cut-off values. Logistic regression analyses were performed to identify risk factors for major postoperative complications with a Clavien-Dindo (CD) grade ≥ 3. RESULTS: In total, 128 patients who underwent PE were included, 90 of whom formed the non-sarcopenic group (NSG) and 38 the sarcopenic group (SG). Major postoperative complications (CD grade ≥ 3) occurred in 26 (20.3%) patients. There was no detectable association with sarcopenia and an increased risk of major postoperative complications. Preoperative hypoalbuminemia (P = 0.01) and a prolonged operative time (P = 0.002) were significantly associated with a major postoperative complication on multivariate analysis. CONCLUSION: Sarcopenia is not a predictor of major postoperative complications in patients undergoing PE surgery. Further efforts aimed specifically at optimising preoperative nutrition may be warranted.

Artificial intelligence for pre-operative lymph node staging in colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: Artificial intelligence (AI) is increasingly being used in medical imaging analysis. We aimed to evaluate the diagnostic accuracy of AI models used for detection of lymph node metastasis on pre-operative staging imaging for colorectal cancer. METHODS: A systematic review was conducted according to PRISMA guidelines using a literature search of PubMed (MEDLINE), EMBASE, IEEE Xplore and the Cochrane Library for studies published from January 2010 to October 2020. Studies reporting on the accuracy of radiomics models and/or deep learning for the detection of lymph node metastasis in colorectal cancer by CT/MRI were included. Conference abstracts and studies reporting accuracy of image segmentation rather than nodal classification were excluded. The quality of the studies was assessed using a modified questionnaire of the QUADAS-2 criteria. Characteristics and diagnostic measures from each study were extracted. Pooling of area under the receiver operating characteristic curve (AUROC) was calculated in a meta-analysis. RESULTS: Seventeen eligible studies were identified for inclusion in the systematic review, of which 12 used radiomics models and five used deep learning models. High risk of bias was found in two studies and there was significant heterogeneity among radiomics papers (73.0%). In rectal cancer, there was a per-patient AUROC of 0.808 (0.739-0.876) and 0.917 (0.882-0.952) for radiomics and deep learning models, respectively. Both models performed better than the radiologists who had an AUROC of 0.688 (0.603 to 0.772). Similarly in colorectal cancer, radiomics models with a per-patient AUROC of 0.727 (0.633-0.821) outperformed the radiologist who had an AUROC of 0.676 (0.627-0.725). CONCLUSION: AI models have the potential to predict lymph node metastasis more accurately in rectal and colorectal cancer, however, radiomics studies are heterogeneous and deep learning studies are scarce. TRIAL REGISTRATION: PROSPERO CRD42020218004 .

Altered colonic motility is associated with low anterior resection syndrome.

AIM: Patients frequently suffer from low anterior resection syndrome (LARS) after distal colorectal resection. The pathophysiology of LARS has not been clearly elucidated. We hypothesized that rectosigmoid resection could impair motility patterns in the distal colon, such as the rectosigmoid brake, which contribute to control of stool form and frequency. METHOD: High-resolution colonic manometry was performed in patients who had previously undergone distal colorectal resection (mean 6.8 years after resection) and non-operative controls before and after a standardized meal. Symptoms were assessed using the LARS score. Propagating contractions were compared between patients with and without LARS, and controls. RESULTS: Data were analysed from 23 patients (11 no-LARS; 12 LARS) and nine controls. All groups demonstrated a significant meal response. LARS patients had fewer post-prandial antegrade propagating contractions than controls (P = 0.028), and fewer retrograde propagating contractions both pre- (P = 0.005) and post-prandially (P = 0.004). Post-prandially, the LARS group had a significantly lower percentage of propagating contractions that met the criteria for the cyclic motor pattern compared to the control group (26% vs. 58%; P = 0.009). There were significant differences in antegrade and retrograde amplitude (P = 0.049; P = 0.018) and distance of propagation (P = 0.003; P = 0.002) post-prandially between LARS patients and controls. CONCLUSION: Rectosigmoid resection alters the meal response following anterior resection, including impairment of the rectosigmoid brake cyclic motor pattern. These findings help to quantify the impaired functional motility after rectosigmoid resection and offer new insights into the mechanisms of LARS.

Prolonged Postoperative Ileus Significantly Increases the Cost of Inpatient Stay for Patients Undergoing Elective Colorectal Surgery: Results of a Multivariate Analysis of Prospective Data at a Single Institution.

BACKGROUND: Prolonged postoperative ileus is a common major complication after abdominal surgery. Retrospective data suggest that ileus doubles the cost of inpatient stay. However, current economic impact data are based on retrospective studies that rely on clinical coding to diagnose ileus. OBJECTIVE: The aim of this study was to determine the economic burden of ileus for patients undergoing elective colorectal surgery. DESIGN: Economic data were audited from a prospective database of patients who underwent surgery at Auckland City Hospital between September 2012 and June 2014. SETTINGS: Auckland City Hospital is a large tertiary referral center, using an enhanced recovery after surgery protocol. PATIENTS: Patients were prospectively diagnosed with prolonged postoperative ileus using a standardized definition. MAIN OUTCOME MEASURES: The cost of inpatient stay was analyzed with regard to patient demographics and operative and postoperative factors. A multivariate analysis was performed to determine the cost of ileus when accounting for other significant covariates. RESULTS: Economic data were attained from 325 patients, and 88 patients (27%) developed ileus. The median inpatient cost (New Zealand dollars) for patients with prolonged ileus, including complication rates and length of stay, was $27,981 (interquartile range= $20,198 to $42,174) compared with $16,317 (interquartile range = $10,620 to $23,722) for other patients, a 71% increase in cost (p < 0.005). Ileus increased all associated healthcare costs, including medical/nursing care, radiology, medication, laboratory costs, and allied health (p < 0.05). Multivariate analysis showed that ileus remained a significant financial burden (p < 0.005) when considering rates of major complications and length of stay. LIMITATIONS: This is a single-institution study, which may impact the generalizability of our results. CONCLUSIONS: Prolonged ileus causes a substantial financial burden on the healthcare system, in addition to greater complication rates and length of stay in these patients. This is the first study to assess the financial impact of prolonged ileus, diagnosed prospectively using a standardized definition. See Video Abstract at http://links.lww.com/DCR/A825.

Uncomplicated Acute Diverticulitis: Identifying Risk Factors for Severe Outcomes.

BACKGROUND: The management of uncomplicated (Modified Hinchey Classification Ia) acute diverticulitis (AD) has become increasingly conservative, with a focus on symptomatic relief and supportive management. Clear criteria for patient selection are required to implement this safely. This retrospective study aimed to identify risk factors for severe clinical course in patients with uncomplicated AD. MATERIALS AND METHODS: Patients admitted to General Surgery at two New Zealand tertiary centres over a period of 18 months were included. Univariate and multivariate analyses were carried out in order to identify factors associated with a more severe clinical course. This was defined by three endpoints: need for procedural intervention, admission >7 days and 30-day readmission; these were analysed separately and as a combined outcome. RESULTS: Uncomplicated AD was identified in 319 patients. Fifteen patients (5%) required procedural intervention; this was associated with SIRS (OR 3.92). Twenty-two (6.9%) patients were admitted for >7 days; this was associated with patient-reported pain score >8/10 (OR 5.67). Thirty-one patients (9.8%) required readmission within 30 days; this was associated with pain score >8/10 (OR 6.08) and first episode of AD (OR 2.47). Overall, 49 patients had a severe clinical course, and associated factors were regular steroid/immunomodulator use (OR 4.34), pain score >8/10 (OR 5.9) and higher temperature (OR 1.51) and CRP ≥200 (OR 4.1). CONCLUSION: SIRS, high pain score and CRP, first episode and regular steroid/immunomodulator use were identified as predictors of worse outcome in uncomplicated AD. These findings have the potential to inform prospective treatment decisions in this patient group.

Loss of Interstitial Cells of Cajal and Patterns of Gastric Dysrhythmia in Patients With Chronic Unexplained Nausea and Vomiting.

BACKGROUND & AIMS: Chronic unexplained nausea and vomiting (CUNV) is a debilitating disease of unknown cause. Symptoms of CUNV substantially overlap with those of gastroparesis, therefore the diseases may share pathophysiologic features. We investigated this hypothesis by quantifying densities of interstitial cells of Cajal (ICCs) and mapping slow-wave abnormalities in patients with CUNV vs controls. METHODS: Clinical data and gastric biopsy specimens were collected from 9 consecutive patients with at least 6 months of continuous symptoms of CUNV but normal gastric emptying who were treated at the University of Mississippi Medical Center, and from 9 controls (individuals free of gastrointestinal disease or diabetes). ICCs were counted and ultrastructural analyses were performed on tissue samples. Slow-wave propagation profiles were defined by high-resolution electrical mapping (256 electrodes; 36 cm(2)). Results from patients with CUNV were compared with those of controls as well as patients with gastroparesis who were studied previously by identical methods. RESULTS: Patients with CUNV had fewer ICCs than controls (mean, 3.5 vs 5.6 bodies/field, respectively; P < .05), with mild ultrastructural abnormalities in the remaining ICCs. Slow-wave dysrhythmias were identified in all 9 subjects with CUNV vs only 1 of 9 controls. Dysrhythmias included abnormalities of initiation (stable ectopic pacemakers, unstable focal activities) and conduction (retrograde propagation, wavefront collisions, conduction blocks, and re-entry), operating across bradygastric, normal (range, 2.4-3.7 cycles/min), and tachygastric frequencies; dysrhythmias showed velocity anisotropy (mean, 3.3 mm/s longitudinal vs 7.6 mm/s circumferential; P < .01). ICCs were less depleted in patients with CUNV than in those with gastroparesis (mean, 3.5 vs 2.3 bodies/field, respectively; P < .05), but slow-wave dysrhythmias were similar between groups. CONCLUSIONS: This study defined cellular and bioelectrical abnormalities in patients with CUNV, including the identification of slow-wave re-entry. Pathophysiologic features of CUNV were observed to be similar to those of gastroparesis, indicating that they could be spectra of the same disorder. These findings offer new insights into the pathogenesis of CUNV and may help to inform future treatments.

Effect of Diversion Ileostomy on the Occurrence and Consequences of Chemotherapy-Induced Diarrhea.

BACKGROUND: The benefits of adjuvant chemotherapy in the treatment of colorectal cancer are well established. Chemotherapy-induced diarrhea is a common adverse effect of these regimens. The occurrence of chemotherapy-induced diarrhea not only directly affects patient health but may also compromise treatment efficacy because of consequent dosing alterations or discontinuation. OBJECTIVE: This study aimed to investigate the effect of diverting loop ileostomy during chemotherapy on the occurrence and consequences of chemotherapy-induced diarrhea. DESIGN: This was a retrospective evaluation of a prospective surgical database. SETTINGS: This was a single-institution retrospective study. PATIENTS: All patients receiving curative adjuvant chemotherapy after anterior resection for colorectal cancer at Auckland Hospital from 2002 to 2013 were retrospectively evaluated. MAIN OUTCOME MEASURES: Patient-, perioperative-, and chemotherapy-related variables were collected. Chemotherapy-induced diarrhea occurrence was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events. Logistic regression analysis was performed to identify independent predictors for chemotherapy-induced diarrhea occurrence, treatment modifications, and hospital admission. RESULTS: A total of 109 identified patients received 691 chemotherapy cycles; 84% of patients with a diverting ileostomy experienced chemotherapy-induced diarrhea compared with 47% in those who were not defunctioned (p < 0.01). On logistic regression analysis, the presence of a diverting ileostomy during chemotherapy was an independent predictor of chemotherapy-induced diarrhea grade 3 or higher (OR, 13.6 (95% CI: 1.2-150.9); p = 0.02), the need for a dosing reduction (OR, 4.0 (95% CI: 1.3-12.4); p = 0.02), and the need for any modification in the chemotherapy regimen (OR, 3.4 (95% CI: 1.2-9.6); p = 0.02). LIMITATIONS: This study is limited by its retrospective design, potentially limiting the accuracy of chemotherapy-induced diarrhea grade reporting. CONCLUSIONS: The presence of an ileostomy during adjuvant chemotherapy is a predictor of severe chemotherapy-induced diarrhea and the need for modifications in the chemotherapy regimen. This may have important consequences for long-term survival. Prospective investigation is needed to further assess the impact of diverting ileostomy on the delivery of chemotherapy and oncologic outcomes.

Gastrografin in Prolonged Postoperative Ileus: A Double-blinded Randomized Controlled Trial.

OBJECTIVE: To investigate the therapeutic value of Gastrografin in shortening duration of prolonged postoperative ileus (PPOI) after elective colorectal surgery. BACKGROUND: Gut wall edema is central to the pathogenesis of PPOI. Hyperosmotic, orally administered, water-soluble contrast media such as Gastrografin are theoretically capable of mitigating this edema. METHODS: A double-blinded, placebo-controlled, randomized trial was conducted. Participants were allocated to receive 100 mL of Gastrografin (Exposure Group) or flavored distilled water (Control Group) administered enterally. Other aspects of management were standardized. Resolution of PPOI was assessed 12-hourly. RESULTS: Eighty patients were randomized equally, with 5 in the Exposure Group and 4 in the Control Group excluded from analysis. Participants were evenly matched at baseline. Mean duration of PPOI did not differ between Exposure and Control Groups (83.7 vs 101.3 hours; P = 0.191). When considering individual markers of PPOI resolution, Gastrografin did not affect time to resolution of nausea and vomiting (64.5 vs 74.3 hours; P = 0.404) or consumption of oral diet (75.8 vs 90.0 hours; P = 0.297). However, it accelerated time to flatus or stool (18.9 vs 32.7 hours; P = 0.047) and time to resolution of abdominal distension (52.8 vs 77.7 hours; P = 0.013). There were no significant differences between groups in nasogastric output; analgesia, antiemetic, or fluid requirement; complications; or length of stay. CONCLUSIONS: Gastrografin is not clinically useful in shortening an episode of PPOI characterized by upper and lower gastrointestinal symptoms. It may however be of therapeutic benefit in the subset of PPOI patients who display lower gastrointestinal symptoms exclusively after surgery.

Cost analysis of early versus delayed loop ileostomy closure: a case-matched study.

BACKGROUND/AIMS: The optimal timing for the closure of loop ileostomies remains controversial. The aim of the current study was to investigate whether early ileostomy closure (EC) (<2 weeks post-formation) results in significant healthcare savings as against late closure (LC). METHODS: Patients with available cost data that underwent EC between January 2008 and December 2012 were compared against matched patients undergoing LC during the same period. Direct hospital costs for the two groups were compared. RESULTS: There were 42 EC patients and 61 LC patients. EC patients had significantly less ileostomy-related complications (p < 0.001) and hospital readmissions (p < 0.001). Operative time (p < 0.001) and operative cost (p = 0.002) were also both significantly less in the EC group. Community nursing costs favoured the LC group (p = 0.047). The EC group had an increased post-closure wound infection rate (p = 0.02). The mean total direct cost per patient was NZD 13,724 (SD NZD 3,736) for EC and NZD 16,728 (SD NZD 8,028) for LC. Representing an average costs saving of NZD 3,004 per patient favouring EC (p = 0.012). CONCLUSION: Although EC increases the post-closure wound infection rate, EC reduces ileostomy complications, hospital readmissions and operative costs resulting in significant healthcare savings. In order to improve patient outcomes and make EC even more cost effective, efforts should be taken to reduce wound infections.

Impact of ischaemic preconditioning on experimental steatotic livers following hepatic ischaemia-reperfusion injury: a systematic review.

BACKGROUND: Steatotic livers are vulnerable to the deleterious effects of ischaemia-reperfusion injury (IRI) that occur after hepatic surgery. Ischaemic preconditioning (IPC) has been shown to abrogate the effects of IRI in patients undergoing hepatic surgery. Experimental studies have suggested that IPC may be beneficial in steatotic livers subjected to IRI. OBJECTIVE: The aim of this systematic review was to evaluate the effects of IPC on steatotic livers following hepatic IRI in experimental models. METHODS: An electronic search of the OVID Medline and EMBASE databases was performed to identify studies that reported clinically relevant outcomes in animal models of hepatic steatosis subjected to IPC and IRI. RESULTS: A total of 1093 articles were identified, of which 18 met the inclusion criteria. There was considerable heterogeneity in the type of animal model, and duration and type of IRI. Increased macrovesicular steatosis (> 30%) was associated with a poor outcome following IRI. Ischaemic preconditioning was found to be beneficial in > 30% steatotic livers and provided for decreased histological damage, improved liver function findings and increased survival. CONCLUSIONS: Experimental evidence supports the use of IPC in steatotic livers undergoing IRI. These findings may be applicable to patients undergoing liver surgery. However, clinical studies are required to validate the efficacy of IPC in this setting.

Clinical tumour size and nodal status predict pathologic complete response following neoadjuvant chemoradiotherapy for rectal cancer.

PURPOSE: Pathologic complete response (pCR) to neoadjuvant treatment for rectal cancer has been associated with improved local control, reduced distant disease and a survival advantage when compared with non-complete responders. Approximately 10-25 % of patients undergoing neoadjuvant chemoradiotherapy for rectal cancer achieve pCR; however, predictors for its occurrence are inadequately defined. This study aimed to identify clinical and tumour factors that predict pCR in patients receiving neoadjuvant chemoradiotherapy for rectal cancer. METHODS: Consecutive rectal cancer patients diagnosed and treated in the Auckland region between 1 January 2002 and 1 February 2013 were retrospectively identified. Cases were stratified by the occurrence of pCR or non-pCR. Predictive capacity of several patient, tumour and treatment-related variables were then assessed by univariate and regression analyses. RESULTS: Two hundred ninety-seven patients received neoadjuvant chemoradiotherapy, of whom 34 (11.4 %) achieved pCR. There were no significant differences in age, gender, ethnicity, BMI, pretreatment clinical T or N stage, tumour distance from the anal verge, tumour differentiation, chemoradiotherapy regimen and time interval to surgery between the pCR and non-pCR groups. Univariate analysis identified pretreatment serum CEA levels, a reduction in pre- to post-treatment serum CEA and smaller tumours as significant correlates of pCR. Logistic regression analysis found smaller tumour size and pretreatment clinical N stage as independent clinical predictors for achieving pCR. CONCLUSIONS: Smaller tumour size and pretreatment clinical N stage were independent clinical predictors for achieving pCR. Prospective analysis is recommended for more rigorous risk factor assessment.

Postoperative ileus: mechanisms and future directions for research.

Postoperative ileus (POI) is an abnormal pattern of gastrointestinal motility characterized by nausea, vomiting, abdominal distension and/or delayed passage of flatus or stool, which may occur following surgery. Postoperative ileus slows recovery, increases the risk of developing postoperative complications and confers a significant financial load on healthcare institutions. The aim of the present review is to provide a succinct overview of the clinical features and pathophysiological mechanisms of POI, with final comment on selected directions for future research.Terminology used when describing POI is inconsistent, with little differentiation made between the obligatory period of gut dysfunction seen after surgery ('normal POI') and the more clinically and pathologically significant entity of a 'prolonged POI'. Both normal and prolonged POI represent a fundamentally similar pathophysiological phenomenon. The aetiology of POI is postulated to be multifactorial, with principal mediators being inflammatory cell activation, autonomic dysfunction (both primarily and as part of the surgical stress response), agonism at gut opioid receptors, modulation of gastrointestinal hormone activity and electrolyte derangements. A final common pathway for these effectors is impaired contractility and motility and gut wall oedema. There are many potential directions for future research. In particular, there remains scope to accurately characterize the gastrointestinal dysfunction that underscores an ileus, development of an accurate risk stratification tool will facilitate early implementation of preventive measures and clinical appraisal of novel therapeutic strategies that target individual pathways in the pathogenesis of ileus warrant further investigation.

Exploring the role of sporadic BRAF and KRAS mutations during colorectal cancer pathogenesis: A spotlight on the contribution of the endosome-lysosome system.

The highly heterogenous nature of colorectal cancer can significantly hinder its early and accurate diagnosis, eventually contributing to high mortality rates. The adenoma-carcinoma sequence and serrated polyp-carcinoma sequence are the two most common sequences in sporadic colorectal cancer. Genetic alterations in adenomatous polyposis coli (APC), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and tumour protein 53 (TP53) genes are critical in adenoma-carcinoma sequence, whereas v-Raf murine sarcoma viral oncogene homolog B (BRAF) and MutL Homolog1 (MLH1) are driving oncogenes in the serrated polyp-carcinoma sequence. Sporadic mutations in these genes contribute differently to colorectal cancer pathogenesis by introducing distinct alterations in several signalling pathways that rely on the endosome-lysosome system. Unsurprisingly, the endosome-lysosome system plays a pivotal role in the hallmarks of cancer and contributes to specialised colon function. Thus, the endosome-lysosome system might be distinctively influenced by different mutations and these alterations may contribute to the heterogenous nature of sporadic colorectal cancer. This review highlights potential connections between major sporadic colorectal cancer mutations and the diverse pathogenic mechanisms driven by the endosome-lysosome system in colorectal carcinogenesis.

Non-steroidal anti-inflammatory drugs for lower urinary tract symptoms in benign prostatic hyperplasia: systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To assess the effects of non-steroidal anti-inflammatory drugs (NSAIDs) in men with benign prostatic hyperplasia (BPH) using systematic review and meta-analysis of clinical trials. SUBJECTS: Men treated with NSAIDs in comparison with placebo or other BPH medications. METHODS: All aspects of the Preferred Reporting for Systematic Reviews and Meta-Analyses (PRISMA) statement were followed. Trials were eligible for inclusion provided they (i) randomized men with BPH to receive NSAIDs in comparison with placebo or other BPH medications, and (ii) included clinical outcomes such as urological symptom scales, symptoms or urodynamic measurements. Data analysis was performed using REVIEW MANAGER Version 5.0 software. Study weight was calculated by the inverse variances of the study effect estimates. RESULTS: In all, 183 men from three randomized, placebo-controlled trials (lasting 4-24 weeks) were assessed. NSAIDs improved urinary symptom scores and flow measures. The weighted mean difference for the International Prostate Symptom Score (IPSS) was -2.89 IPSS points (95% CI -3.84 to -1.95, P < 0.001, n = 3 studies). The weighted mean difference for peak urine flow was 0.89 mL/s (95% CI 0.21-1.58, P = 0.01, n = 3 studies) and for reported adverse effects was 1.51 (95% CI 0.66-3.43, P = 0.32, n = 3 studies,). All patients assigned to NSAIDs continued the treatment. There were no serious adverse effects and there were no withdrawals or losses to follow-up. CONCLUSION: The evidence suggests that NSAIDs improve urinary symptoms and flow measures. Their long-term effectiveness, safety and ability to prevent BPH complications are not known.

Risk factors for the development of prolonged post-operative ileus following elective colorectal surgery.

PURPOSE: Prolonged post-operative ileus (PPOI) increases post-operative morbidity and prolongs hospital stay. An improved understanding of the elements which contribute to the genesis of PPOI is needed in the first instance to facilitate accurate risk stratification and institute effective preventive measures. The aim of this retrospective cohort study was to therefore determine the perioperative risk factors associated with development of PPOI. METHODS: All elective intra-abdominal operations undertaken by the Colorectal Unit at Auckland District Health Board from 1 January to 31 December 2011 were accessed. Data were extracted for an assortment of patient characteristics and perioperative variables. Cases were stratified by the occurrence of clinician-diagnosed PPOI. Univariate and regression analyses were performed to identify correlates and independent risk factors, respectively. RESULTS: Two hundred and fifty-five patients were identified of whom 50 (19.6%) developed PPOI. The median duration for PPOI was 4 days with 98% resolving spontaneously with conservative measures. Univariate analysis identified increasing age; procedure type; increasing opiate consumption; elevated preoperative creatinine; post-operative haemoglobin drop, highest white cell count and lowest sodium; and increasing complication grade as significant correlates. Logistic regression found increasing age (OR 1.032, 95% CI 1.004-1.061; p = 0.026) and increasing drop in pre- to post-operative haemoglobin (OR 1.043, 95% CI 1.002-1.085; p = 0.037) as the only independent predictors for developing PPOI. An important limitation of this study was its retrospective nature. CONCLUSIONS: Increasing age and increasing drop in haemoglobin are independent predictors for developing PPOI. Prospective assessment is required to facilitate more accurate risk factor analysis.

Clinical and biochemical predictors of tumor response after neoadjuvant therapy in rectal cancer.

BACKGROUND: Patients who have a good clinical and/or pathologic response to neoadjuvant chemoradiotherapy (nCRT) for rectal cancer have better long-term outcomes and can potentially be spared morbid surgery. This study aimed to identify pretreatment clinical and biochemical predictors of response to neoadjuvant treatment for rectal cancer. METHODS: Patients undergoing neoadjuvant therapy for rectal cancer between 2007 and 2022 were retrospectively included. Those patients who achieved a complete clinical response were offered a nonoperative management strategy and the remaining patients underwent surgical resection. The primary endpoint was tumor regression grade (TRG) based on radiological imaging (mrTRG) or pathology (pTRG). Patient response was classified as good (mrTRG 1-2 or pTRG 0-1) versus poor (mrTRG 3-4 or pTRG 2-3). Logistic regression was performed to determine predictors of TRG. RESULTS: A total of 984 patients with rectal cancer were identified of which 274 met the inclusion criteria. Of 274 patients, 228 (83%) underwent surgical resection. A good TRG response was observed in 119 (41%) patients, and a complete response was achieved in 53 (17%) patients. On univariable and multivariable logistic regression, clinical T2 stage and body mass index of ≥25 kg/m2 were significant predictors of a good TRG. Clinical T2 stage and a personalised total neoadjuvant therapy regimen were significant predictors of complete response. CONCLUSION: Clinical T2 stage and a BMI≥25 kg/m2 were predictors of good response to neoadjuvant therapy for rectal cancer. Future prospective studies are required to confirm these findings and evaluate their potential use in better targeting of nCRT.

Personalized total neoadjuvant therapy versus chemotherapy during the 'wait period' versus standard chemoradiotherapy for locally advanced rectal cancer.

BACKGROUND: This study aimed to compare current treatment response rates with personalized Total Neoadjuvant Therapy (pTNT), against extended chemotherapy in the 'wait period' (xCRT) and standard chemoradiotherapy (sCRT) with adjuvant chemotherapy for rectal cancer. METHODS: This was a multicentre retrospective cohort analysis. Consecutive patients with rectal cancer treated with pTNT over a 3.9-year period were compared to a historical cohort of patients treated with xCRT or sCRT as part of the published WAIT Trial. pTNT patients received 8 cycles mFOLFOX6 or 6 cycles CAPOX in the neoadjuvant setting (no adjuvant treatment). Patients in the WAIT Trial received either 3 cycles 5-FU/LV during the 10-week wait period after chemoradiotherapy or standard chemoradiotherapy, followed by adjuvant chemotherapy. The primary endpoint was overall complete response (oCR) rate defined as the proportion of patients who achieved either complete clinical response (cCR) or pathological complete response (pCR). RESULTS: Of 284 patients diagnosed with rectal cancer during the 3.9-year period, 107 received pTNT. Forty of these were matched with 49 patients from the WAIT Trial (25 received xCRT and 24 received sCRT). There was a significant difference in oCR between the groups (pTNT n = 21, xCRT n = 6, sCRT n = 7, P = 0.043). Of the patients that underwent surgery, pCR occurred in 13 patients with no significant difference between groups (P = 0.415). There were no significant differences in 2-year disease-free survival or overall survival. CONCLUSION: Compared with sCRT and xCRT, pTNT results in a significantly higher complete response rate which may facilitate organ preservation.