Transanal minimally invasive surgery (TAMIS) for local excision of benign and malignant rectal neoplasia: a 7-year experience.

PURPOSE: Transanal minimally invasive surgery (TAMIS) is an advanced transanal platform that can be utilised to perform high-quality local excision (LE) of rectal neoplasia. This study describes clinical and midterm oncological outcomes from a single unit's 7-year experience with TAMIS. METHODS: Consecutive patients who underwent TAMIS LE at our institution between January 1st, 2016, and December 31st, 2022, were identified from a prospectively maintained database. Indication for TAMIS LE was benign lesions not amenable to endoscopic excision or histologically favourable early rectal cancers. The primary endpoints were resection quality, disease recurrence and peri-operative outcomes. The Kaplan-Meier survival analyses were used to describe disease-free survival (DFS) for patients with rectal adenocarcinoma that did not receive immediate salvage proctectomy. RESULTS: There were 168 elective TAMIS LE procedures performed for 102 benign and 66 malignant lesions. Overall, a 95.2% negative margin rate was observed, and 96.4% of lesions were submitted without fragmentation. Post-operative morbidity was recorded in 8.3% of patients, with post-operative haemorrhage, being the most common complication encountered. The mean follow-up was 17 months (SD 15). Local recurrence occurred in 1.6%, and distant organ metastasis was noted in 1.6% of patients. CONCLUSIONS: For carefully selected patients, TAMIS for local excision of early rectal neoplasia is a valid option with low morbidity that maintains the advantages of organ preservation.

Meta-analysis of SATB2 immunohistochemical expression in colorectal cancer versus primary ovarian mucinous neoplasms.

BACKGROUND: Reliably distinguishing primary ovarian mucinous neoplasms (POMNs) from metastatic colorectal cancers (CRCs) is both challenging to the histopathologist and of great clinical importance. Special AT-rich sequence binding protein-2 (SATB2) has emerged as a useful diagnostic immunohistochemical marker of colorectal cancer. This meta-analysis compares SATB2 expression in POMNs and CRC. METHODS: A systematic literature search for relevant studies was conducted. Meta-analysis of SATB2 positivity was undertaken using a random effects model. RESULTS: Seven studies including 711 CRCs and 528 POMNs were included. SATB2 positivity was seen in 81 % (95 % CI: 72-88 %) of CRCs and 4 % (95 % CI: 1-11 %) of POMNs. Variation was seen in immunohistochemical methods used for SATB2 detection and threshold for positivity. CONCLUSION: SATB2 staining remains high in CRC and low in POMNs, supporting its use in differentiating these two pathologies with vastly differing prognosis and treatment.

Multiplexed Immunofluorescence Imaging Reveals an Immune-Rich Tumor Microenvironment in Mucinous Rectal Cancer Characterized by Increased Lymphocyte Infiltration and Enhanced Programmed Cell Death Protein 1 Expression.

BACKGROUND: Mucinous rectal cancer is associated with a higher incidence of microsatellite instability and a poorer response to neoadjuvant chemoradiotherapy compared to other subtypes of rectal adenocarcinoma. Immune checkpoint inhibitors are an emerging family of anticancer therapeutics associated with highly variable outcomes in colorectal cancer. Although the immune landscape of mucinous rectal cancer has not been fully explored, the presence of mucin is thought to act as a barrier preventing immune-cell infiltration. OBJECTIVE: The aim of this study was to determine the immune properties of mucinous rectal cancer and investigate the degree of lymphocyte infiltration in this cohort. DESIGN: This is a retrospective cohort study that involved multiplexed immunofluorescence staining of tumor microarrays. SETTINGS: Samples originated from a single university teaching hospital. PATIENTS: Our cohort included 15 cases of mucinous and 43 cases of nonmucinous rectal cancer. MAIN OUTCOME MEASURES: Immune cells were classified and quantified. Immune-cell counts were compared between mucinous and nonmucinous cohorts. Immune marker expression within tumor epithelial tissue was evaluated to determine the degree of lymphocyte infiltration. RESULTS: Cytotoxic ( p = 0.022) and regulatory T cells ( p = 0.010) were found to be overrepresented in the mucinous cohort compared to the nonmucinous group. Programmed cell death protein 1 expression was also found to be significantly greater in the mucinous group ( p = 0.001). CD3 ( p = 0.001) and CD8 ( p = 0.054) expressions within the tumor epithelium were also higher in the mucinous group, suggesting adequate immune infiltration despite the presence of mucin. In our analysis, microsatellite instability status was not a predictor of immune marker expression. LIMITATIONS: The relatively small size of the cohort. CONCLUSIONS: Mucinous rectal cancer is associated with an immune-rich tumor microenvironment, which was not associated with microsatellite instability status. See Video Abstract at http://links.lww.com/DCR/C65 . IMGENES DE INMUNOFLUORESCENCIA MULTIPLEXADAS REVELAN UN MICROAMBIENTE TUMORAL RICO EN INMUNIDAD EN EL CNCER RECTAL MUCINOSO CARACTERIZADO POR UNA MAYOR INFILTRACIN DE LINFOCITOS Y UNA EXPRESIN MEJORADA DE PD: ANTECEDENTES:El cáncer rectal mucinoso se asocia con una mayor incidencia de inestabilidad de microsatélites y una peor respuesta a la quimiorradioterapia neoadyuvante en comparación con otros subtipos de adenocarcinoma rectal. Los inhibidores de puntos de control inmunitarios son una familia emergente de tratamientos contra el cáncer asociados con resultados muy variables en el cáncer colorrectal. Aunque el panorama inmunitario del cáncer rectal mucinoso no se ha explorado completamente, se cree que la presencia de mucina actúa como una barrera que previene la infiltración de células inmunitarias.OBJETIVO:El objetivo de este estudio fue determinar las propiedades inmunes del cáncer de recto mucinoso e investigar el grado de infiltración de linfocitos en esta cohorte.DISEÑO:Este es un estudio de cohorte retrospectivo que involucró la tinción de inmunofluorescencia multiplexada de micromatrices tumorales.AJUSTES:Las muestras se originaron en un solo hospital docente universitario.PACIENTES:Nuestra cohorte incluyó 15 casos de cáncer de recto mucinoso y 43 casos de cáncer de recto no mucinosoPRINCIPALES MEDIDAS DE RESULTADO:Las células inmunitarias se clasificaron y cuantificaron. Se compararon los recuentos de células inmunitarias entre cohortes mucinosas y no mucinosas. Se evaluó la expresión del marcador inmunitario dentro del tejido epitelial tumoral para determinar el grado de infiltración de linfocitos.RESULTADOS:Se encontró que las células T citotóxicas ( p = 0,022) y reguladoras ( p = 0,010) estaban sobrerrepresentadas en la cohorte mucinosa en comparación con el grupo no mucinoso. También se encontró que la expresión de PD-1 era significativamente mayor en el grupo mucinoso ( p = 0,001). La expresión de CD3 ( p = 0,001) y CD8 ( p = 0,054) dentro del epitelio tumoral también fue mayor en el grupo mucinoso, lo que sugiere una infiltración inmunitaria adecuada a pesar de la presencia de mucina. En nuestro análisis, no se encontró que el estado de inestabilidad de los microsatélites sea un predictor de la expresión del marcador inmunitario.LIMITACIONES:El tamaño relativamente pequeño de la cohorte.CONCLUSIONES:El cáncer rectal mucinoso se asocia con un microambiente tumoral rico en inmunidad, que no se asoció con el estado de inestabilidad de microsatélites. Consulte el Video del Resumen en http://links.lww.com/DCR/C65 . (Traducción- Dr. Yesenia Rojas-Khalil ).

A prospective evaluation of the effect of transanal minimally invasive surgery (TAMIS) on low anterior resection syndrome.

PURPOSE: Transanal minimally invasive surgery (TAMIS) is a surgical alternative to transanal endoscopic microsurgery (TEM), transanal excision and proctectomy in the management of benign rectal polyps and early rectal cancers. Low anterior resection syndrome (LARS) describes the constellation of symptoms which result from and are common after distal colorectal resection. Symptoms include incontinence, frequency, urgency and evacuatory dysfunction. The aim of the current study was to prospectively evaluate pre- and post-operative LARS in patients who undergo TAMIS. METHODS: We conducted a prospective analysis of a consecutive series of patients who underwent TAMIS at our institution between January 2021 and February 2022. A LARS questionnaire was undertaken preoperatively, at 1 month and at 6 months post-operatively. RESULTS: Twenty patients were recruited to this pilot study. The mean age was 63 ± 12 years, 11 of the patients were male, mean pre-operative BMI was 29 ± 6 kg/m2, and 30% (n = 6) of patients underwent TAMIS for an invasive rectal cancer, with all patients receiving an R0 resection. Mean distance from the anal verge was 5.7 ± 3.2 cm, and mean lesion diameter was 46 ± 20.5 mm. A statistically significant interval reduction was observed between preoperative (20.3 ± 12.9) and 6-month post-operative (12.6 ± 9.7) LARS scores (p = 0.02) and also between 1-month (18.2 ± 10.6) and 6-month post-operative scores (p = 0.01). CONCLUSIONS: We noted a high prevalence of LARS across our cohort preoperatively, and this had improved significantly at 6-month review post-TAMIS. This study reaffirms the safety and efficacy of TAMIS for the treatment of early rectal neoplasia.

Outruling cholangiocarcinoma in patients with primary sclerosing cholangitis wait-listed for liver transplantation: A report on the Irish national experience.

BACKGROUND: The presence of diffuse biliary stricturing in Primary Sclerosing Cholangitis (PSC) makes the diagnosis of early Cholangiocarcinoma (CCA) in this context difficult. A finding of incidental CCA on liver explant is associated with poor oncological outcomes, despite this; there remains no international consensus on how best to outrule CCA in this group ahead of transplantation. The objectives of this study were to report the Irish incidence of incidental CCA in individuals with PSC undergoing liver transplantation, and to critically evaluate the accuracy of diagnostic modalities in outruling CCA in our wait-listed PSC cohort. METHODS: We conducted a retrospective analysis of our prospectively maintained database, which included all PSC patients wait-listed for liver transplant in Ireland. RESULTS: 4.41% of patients (n = 3) were found to have an incidental finding of CCA on liver explant. Despite only being performed in 35.06% of wait-listed PSC patients (n = 27), Endoscopic Retrograde Cholangiopancreatogram (ERCP) with brush cytology was found to be the most effective tool in correctly outruling CCA in this context; associated with a specificity of 96.15%. CONCLUSION: Our findings support a future role for routine surveillance of PSC patients awaiting liver transplantation; however further research is required in order to identify which investigative modalities are of optimal diagnostic utility in this specific context.

Serine-Arginine Protein Kinase 1 (SRPK1): a systematic review of its multimodal role in oncogenesis.

Alternative splicing is implicated in each of the hallmarks of cancer, and is mechanised by various splicing factors. Serine-Arginine Protein Kinase 1 (SRPK1) is an enzyme which moderates the activity of splicing factors rich in serine/arginine domains. Here we review SRPK1's relationship with various cancers by performing a systematic review of all relevant published data. Elevated SRPK1 expression correlates with advanced disease stage and poor survival in many epithelial derived cancers. Numerous pre-clinical studies investigating a host of different tumour types; have found increased SRPK1 expression to be associated with proliferation, invasion, migration and apoptosis in vitro as well as tumour growth, tumourigenicity and metastasis in vivo. Aberrant SRPK1 expression is implicated in various signalling pathways associated with oncogenesis, a number of which, such as the PI3K/AKT, NF-КB and TGF-Beta pathway, are implicated in multiple different cancers. SRPK1-targeting micro RNAs have been identified in a number of studies and shown to have an important role in regulating SRPK1 activity. SRPK1 expression is also closely related to the response of various tumours to platinum-based chemotherapeutic agents. Future clinical applications will likely focus on the role of SRPK1 as a biomarker of treatment resistance and the potential role of its inhibition.

Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab.

BACKGROUND: Bococizumab, a humanized monoclonal antibody targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), reduces levels of low-density lipoprotein (LDL) cholesterol. However, the variability and durability of this effect are uncertain. METHODS: We conducted six parallel, multinational lipid-lowering trials enrolling 4300 patients with hyperlipidemia who were randomly assigned to receive 150 mg of bococizumab or placebo subcutaneously every 2 weeks and who were followed for up to 12 months; 96% were receiving statin therapy at the time of enrollment. The patients were assessed for lipid changes over time, stratified according to the presence or absence of antidrug antibodies detected during the treatment period. RESULTS: At 12 weeks, patients who received bococizumab had a reduction of 54.2% in the LDL cholesterol level from baseline, as compared with an increase of 1.0% among those who received placebo (absolute between-group difference, -55.2 percentage points). Significant between-group differences were also observed in total cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) (P<0.001 for all comparisons). However, high-titer antidrug antibodies developed in a substantial proportion of the patients who received bococizumab, which markedly diminished the magnitude and durability of the reduction in LDL cholesterol levels. In addition, among patients with no antidrug antibodies, there was wide variability in the reduction in LDL cholesterol levels at both 12 weeks and 52 weeks. Major cardiovascular events occurred in 57 patients (2.5%) who received bococizumab and in 55 (2.7%) who received placebo (hazard ratio, 0.96; 95% confidence interval, 0.66 to 1.39; P=0.83). The most common adverse event among patients who received bococizumab was injection-site reaction (12.7 per 100 person-years). CONCLUSIONS: In six multinational trials evaluating bococizumab, antidrug antibodies developed in a large proportion of the patients and significantly attenuated the lowering of LDL cholesterol levels. Wide variation in the relative reduction in cholesterol levels was also observed among patients in whom antidrug antibodies did not develop. (Funded by Pfizer; SPIRE ClinicalTrials.gov numbers, NCT01968954 , NCT01968967 , NCT01968980 , NCT02100514 , NCT02135029 , and NCT02458287 .).

Asthmatic children from lower-income families are less likely to own an individualised asthma action plan.

AIM: This study aimed to explore the relationship between indicators of socio-economic status (SES) and prescription of a paediatric individualised asthma action plan (IAAP), as well as compliance with that plan. METHODS: Between May and September 2017, parents/carers of children aged 2-16 years who presented with acute respiratory symptoms and a prior diagnosis of asthma to the emergency department at one regional and one metropolitan hospital in NSW, Australia, were invited to participate in a questionnaire-based study. RESULTS: A total of 175 eligible participants were identified, of which 113 completed the questionnaire. Eighty-seven children had been prescribed an IAAP (77%). Forty-nine parents/carers reported non-compliance with that plan (56.3%). Children from low- to middle-income families were significantly less likely to have a plan (P = 0.001). Being an only child was associated with greater IAAP compliance (P = 0.007) and better asthma control (P = 0.035). No significant relationship between other indicators of SES and rates of plan ownership or compliance was demonstrated. CONCLUSION: Although relatively high in our study sample, IAAP ownership rates remain well below published guidelines. Given the income-based disparity in plan ownership, physicians must routinely prescribe plans to all asthmatics. Strategies to ensure IAAP ownership and promote their use, especially in the public health sector, would be valuable. Repeating a similar study with a larger sample size will allow more robust conclusions to be drawn regarding the impact of parental SES on compliance.

The effect of implementing a transanal minimally invasive surgical programme for the local excision of early rectal neoplasia on outcomes in a tertiary referral rectal cancer centre.

Transanal minimally invasive surgery (TAMIS) is a surgical alternative to proctectomy in the management of complex rectal polyps and early rectal cancers. In 2016, our institution introduced a TAMIS programme. The purpose of this study was to evaluate changes in practice and outcomes in our institution in the 3 years before and after the implementation of TAMIS. We conducted a retrospective analysis of a prospective database of patients who underwent proctectomy or TAMIS for the management of complex rectal polyps or early rectal cancers at our institution between 2013 and 2018. 96 patients were included in this study (41 proctectomy vs 55 TAMIS). A significant reduction was noted in the number of proctectomies performed in the 3 years after the implementation of TAMIS as compared to the 3 years before (13 vs 28) ( P  < 0.001); 43% of patients ( n  = 12) who underwent proctectomy in the period prior to implementation of TAMIS were American Society of Anaesthesiologists grade III, as compared to only 15% ( n  = 2) of patients during the period following TAMIS implementation ( P  = 0.02). TAMIS was associated with a significant reduction in length of inpatient stay ( P  < 0.001). Oncological outcomes were comparable between groups (log rank P  = 0.83). Our findings support TAMIS as a safe and effective alternative to radical resection. The availability of TAMIS has resulted in a significant reduction in the number of comorbid patients undergoing proctectomy at our institution. Consequently, we have observed a significant reduction in postoperative complications over this time period.

Spatial transcriptomic analysis reveals local effects of intratumoral fusobacterial infection on DNA damage and immune signaling in rectal cancer.

Mucinous colorectal cancer (CRC) is a common histological subtype of colorectal adenocarcinoma, associated with a poor response to chemoradiotherapy. The commensal facultative anaerobes fusobacteria, have been associated with poor prognosis specifically in mesenchymal CRC. Interestingly, fusobacterial infection is especially prevalent in mucinous CRC. The objective of this study was therefore to increase our understanding of beneficial and detrimental effects of fusobacterial infection, by contrasting host cell signaling and immune responses in areas of high vs. low infection, using mucinous rectal cancer as a clinically relevant example. We employed spatial transcriptomic profiling of 106 regions of interest from 8 mucinous rectal cancer samples to study gene expression in the epithelial and immune segments across regions of high versus low fusobacterial infection. Fusobacteria high regions were associated with increased oxidative stress, DNA damage, and P53 signaling. Meanwhile regions of low fusobacterial prevalence were characterized by elevated JAK-STAT, Il-17, Il-1, chemokine and TNF signaling. Immune masks within fusobacterial high regions were characterized by elevated proportions of cytotoxic (CD8+) T cells (p = 0.037), natural killer (NK) cells (p < 0.001), B-cells (p < 0.001), and gamma delta T cells (p = 0.003). Meanwhile, fusobacteria low regions were associated with significantly greater M2 macrophage (p < 0.001), fibroblast (p < 0.001), pericyte (p = 0.002), and endothelial (p < 0.001) counts.

Increased Fusobacterium tumoural abundance affects immunogenicity in mucinous colorectal cancer and may be associated with improved clinical outcome.

There is currently an urgent need to identify factors predictive of immunogenicity in colorectal cancer (CRC). Mucinous CRC is a distinct histological subtype of CRC, associated with a poor response to chemotherapy. Recent evidence suggests the commensal facultative anaerobe Fusobacterium may be especially prevalent in mucinous CRC. The objectives of this study were to assess the association of Fusobacterium abundance with immune cell composition and prognosis in mucinous CRC. Our study included two independent colorectal cancer patient cohorts, The Cancer Genome Atlas (TCGA) cohort, and a cohort of rectal cancers from the Beaumont RCSI Cancer Centre (BRCC). Multiplexed immunofluorescence staining of a tumour microarray (TMA) from the BRCC cohort was undertaken using Cell DIVE technology. Our cohorts included 87 cases (13.3%) of mucinous and 565 cases (86.7%) of non-mucinous CRC. Mucinous CRC in the TCGA dataset was associated with an increased proportion of CD8 + lymphocytes (p = 0.018), regulatory T-cells (p = 0.001) and M2 macrophages (p = 0.001). In the BRCC cohort, mucinous RC was associated with enhanced CD8 + lymphocyte (p = 0.022), regulatory T-cell (p = 0.047), and B-cell (p = 0.025) counts. High Fusobacterium abundance was associated with an increased proportion of CD4 + lymphocytes (p = 0.031) and M1 macrophages (p = 0.006), whilst M2 macrophages (p = 0.043) were under-represented in this cohort. Patients with increased Fusobacterium relative abundance in our mucinous CRC TCGA cohort tended to have better clinical outcomes (DSS: likelihood ratio p = 0.04, logrank p = 0.052). Fusobacterium abundance may be associated with improved outcomes in mucinous CRC, possibly due to a modulatory effect on the host immune response. KEY MESSAGES: • Increased Fusobacterium relative abundance was not found to be associated with microsatellite instability in mucinous CRC. • Increased Fusobacterium relative abundance was associated with an M2/M1 macrophage switch, which is especially significant in mucinous CRC, where M2 macrophages are overexpressed. • Increased Fusobacterium relative abundance was associated with a significant improvement in disease specific survival in mucinous CRC. • Our findings were validated at a protein level within our own in house mucinous and non-mucinous rectal cancer cohorts.

Relationship between atorvastatin dose and the harm caused by torcetrapib.

Development of the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib, was halted after the ILLUMINATE trial revealed an increase in both all-cause mortality (ACM) and major cardiovascular events (MCVEs) associated with its use. We now report that the harm caused by torcetrapib was confined to those in the 10 mg atorvastatin subgroup for both ACM [hazard ratio (HR) = 2.68, 95% CI (1.58, 4.54), P < 0.0001] and MCVEs [HR = 1.41, 95% CI (1.14, 1.74), P = 0.002], with no evidence of harm when torcetrapib was coadministered with higher doses of atorvastatin. In the atorvastatin 10 mg subgroup, age, prior heart failure and stroke were significantly associated with ACM, independent of torcetrapib treatment, whereas low apoA-I, smoking, hypertension, heart failure, myocardial infarction, and stroke were independently associated with MCVEs. After adjusting for these factors, the HR associated with torcetrapib treatment in the 10 mg atorvastatin subgroup remained elevated for both ACM [HR = 2.67, 95% CI (1.57, 4.54), P < 0.001] and MCVE [HR = 1.36, 95% CI (1.10, 1.69), P = 0.005]. Thus, the harm caused by torcetrapib was confined to individuals taking atorvastatin 10 mg. The harm could not be explained by torcetrapib-induced changes in lipid levels, blood pressure, or electrolytes. It is conceivable that higher doses of atorvastatin protected against the harm caused by torcetrapib.

The Effect of Corticosteroids on Prostate Cancer Outcome Following Treatment with Enzalutamide: A Multivariate Analysis of the Phase III AFFIRM Trial.

PURPOSE: The clinical impact of concurrent corticosteroid use (CCU) on enzalutamide-treated patients with metastatic castration-resistant prostate cancer (mCRPC) is unknown. We investigated the association of CCU with overall survival (OS), radiographic progression-free survival (rPFS), and time to prostate-specific antigen progression (TTPP) in post-chemotherapy, enzalutamide-treated patients with mCRPC. PATIENTS AND METHODS: Post hoc analysis of AFFIRM (NCT00974311) with patients (n = 1,199) randomized 2:1 to enzalutamide 160 mg/day or placebo. Treatment group, CCU, and known prognostic factors were evaluated for impact on OS, rPFS, and TTPP using a multivariate Cox proportional hazards model. CCU was defined as "baseline" (use started at baseline) or "on-study" (baseline plus use that was started during the trial). RESULTS: Enzalutamide significantly improved OS, rPFS, and TTPP independent of baseline CCU but was associated with inferior clinical outcomes when compared with no baseline CCU, including a shorter OS [10.8 months vs. not reached (NR); HR for use vs. no use, 2.13; 95% confidence interval (CI), 1.79-2.54], rPFS (5.2 months vs. 8.0 months; HR, 1.49; 95% CI, 1.29-1.72], and TTPP (4.6 months vs. 5.7 months; HR, 1.50; 95% CI, 1.25-1.81). These findings held in a multivariate analysis adjusting for baseline prognostic factors wherein baseline CCU was independently associated with decreased OS (HR, 1.71; 95% CI, 1.43-2.04; P < 0.0001) and rPFS (HR, 1.28; 95% CI, 1.11-1.48; P = 0.0007). CONCLUSIONS: Patients with mCRPC benefited from enzalutamide treatment independent of CCU, but CCU was associated with worse baseline prognostic factors and outcomes.

Enzalutamide versus bicalutamide in patients with nonmetastatic castration-resistant prostate cancer: a prespecified subgroup analysis of the STRIVE trial.

BACKGROUND: In the phase 2, randomized, double-blind STRIVE trial, enzalutamide significantly reduced the risk of prostate cancer progression or death versus bicalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) and nonmetastatic CRPC (nmCRPC). The objective of this protocol-specified subgroup analysis of STRIVE was to investigate the benefit of enzalutamide versus bicalutamide specifically in patients with nmCRPC. METHODS: Patients (N = 139) were stratified by disease stage and randomized to enzalutamide 160 mg/day plus androgen deprivation therapy (ADT; n = 70) or bicalutamide 50 mg/day plus ADT (n = 69). RESULTS: Baseline characteristics of patients with nmCRPC were comparable between groups. At a median of 17 months follow-up, enzalutamide reduced the risk of progression or death by 76% versus bicalutamide in patients with nmCRPC (hazard ratio [HR], 0.24; 95% CI 0.14-0.42). Enzalutamide reduced risk of prostate-specific antigen progression by 82% versus bicalutamide in patients with nmCRPC (HR, 0.18; 95% CI 0.10-0.34). The most frequently reported adverse events by patients receiving enzalutamide were fatigue (36.2%), hot flush (20.3%), decreased appetite (17.4%), dizziness (17.4%), and nausea (17.4%). CONCLUSIONS: This STRIVE subgroup analysis of patients with nmCRPC illustrates the benefit of enzalutamide in reducing the risk of progression or death versus bicalutamide in patients with nmCRPC. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01664923.

Statin and metformin use and outcomes in patients with castration-resistant prostate cancer treated with enzalutamide: A meta-analysis of AFFIRM, PREVAIL and PROSPER.

BACKGROUND: Statins and metformin are commonly prescribed for patients, including those with prostate cancer. Preclinical and epidemiologic studies of each agent have suggested anti-cancer properties. METHODS: Patient data from three randomised, double-blind, placebo-controlled, phase III studies evaluating enzalutamide (AFFIRM, PREVAIL and PROSPER) in patients with castration-resistant prostate cancer were included in this analysis. This post hoc, retrospective study examined the association of statin and metformin on radiographic progression-free survival (rPFS), metastasis-free survival (MFS), toxicity and overall survival (OS). After adjusting for available clinical prognostic variables, multivariate analyses were performed on pooled data from AFFIRM and PREVAIL, all three trials pooled, and each trial individually, to assess differential efficacy in these end-points associated with the baseline use of these medications. RESULTS: In the multivariate analysis of the individual trials, OS and rPFS/MFS were not significantly influenced by statin or metformin use in AFFIRM or PROSPER. However, in PREVAIL, OS was significantly influenced by statin (hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.59-0.89) and rPFS was significantly influenced by metformin (HR, 0.48; 95% CI 0.34-0.70). In pooled analyses, improved OS was significantly associated with statin use but not metformin use for AFFIRM+PREVAIL trials (HR 0.83; 95% CI 0.72-0.96) and AFFIRM+PREVAIL+PROSPER (HR 0.75; 95% CI 0.66-0.85). CONCLUSIONS: The association between statin or metformin use and rPFS, MFS and OS was inconsistent across three trials. Analyses of all three trials pooled and AFFIRM+PREVAIL pooled revealed that statin but not metformin use was significantly associated with a reduced risk of death in enzalutamide-treated patients. Additional prospective, controlled studies are warranted. CLINICAL TRIAL REGISTRATION: AFFIRM (NCT00974311), PREVAIL (NCT01212991) and PROSPER (NCT02003924).

Peripheral nerve defect repair with epineural tubes supported with bone marrow stromal cells: a preliminary report.

INTRODUCTION: This study was performed to assess the effects of nerve gap repair with isogenic epineural tubes filled with isogenic bone marrow stromal cells (BMSC) as an alternative to autograft repair. METHODS: A total of 24 epineural tubes were transplanted as a conduit to bridge 20 mm nerve gap defects in 2 experimental groups. In group 1, the tube was filled with saline, whereas in group 2 with isogenic BMSC prestained with PKH-dye. In all, 12 autograft sciatic nerve repairs served as a control. Sensory and motor recovery was evaluated by gastrocnemius muscle index; pinprick, toe-spread tests; and somatosensory-evoked potentials at 6 and 12 weeks postrepair. Histomorphometry and immunostaining were also performed. RESULTS: Evidence of successful nerve regeneration was present in all animals at 6 and 12 weeks. There were no significant differences between experimental groups in functional recovery--toe-spread and pinprick tests; however, epineural conduit groups trended toward better toe-spread scores compared with autograft repair at 6 weeks. All animals had full sensory recovery as evaluated by pinprick at 12 weeks. Saline group had significantly higher gastrocnemius muscle index compared with other groups at 6 weeks; however, no differences were noted at 12 weeks. Histomorphometrical assessment did not reveal superiority of any group at 6 weeks postrepair. However, at 12 weeks, the BMSC group had significantly increased myelin thickness compared with other groups and larger diameter nerve fibers than autograft. In group 2, PKH-positive cells and expression of nerve growth factor, Laminin B2, glial fibrillary acidic protein, and vascular endothelial growth factor were confirmed. nerve growth factor- and glial fibrillary acidic protein-positive BMSC were also found inside the tube. CONCLUSION: The epineural tube is a viable, naturally occurring biologic conduit for nerve repair. Cotransplantation of BMSC-enhanced nerve regeneration by means of increased myelinization and expression of neurotrophic factors. Overall, obtained results with epineural tube/BMSC construct were comparable to autograft repair.

Routine Endoscopy After Acute Sigmoid Diverticulitis: Would a Sigmoidoscopy be Sufficient?

BACKGROUND:  Current guidelines suggest that patients should undergo colonoscopy after CT confirmed acute diverticulitis to outrule colorectal cancer (CRC). The aim of this study was to determine if flexible sigmoidoscopy (FS) could be a viable alternative to full colonoscopy following acute sigmoid diverticulitis. METHODS:  A retrospective study of 271 patients was performed who were diagnosed with acute sigmoid diverticulitis by CT and subsequently underwent full colonoscopy. Medical records, CT reports, endoscopy reports, and histopathological reports were reviewed. RESULTS:  Sigmoid diverticulosis was confirmed on colonoscopy in all patients. No colorectal malignancies were detected. Adenomatous polyps were found in 16 (5.9%) patients, of which three had polyps detected beyond the sigmoid colon. The overall proportion of abnormalities found beyond the sigmoid colon was 1.1% (n=3). CONCLUSION:  The detection of CRC cancer in patients undergoing full colonoscopy following an episode of acute sigmoid diverticulitis is rare. Despite this, current guidelines still advocate for endoscopy due to the potentially serious consequences of a missed malignancy. However, given that the area of concern in these cases is the sigmoid colon, FS may be a feasible means of outruling malignancy in the absence of red flag features that would necessitate a full colonoscopy. Our results support this approach, with no CRC detected and a polyp detection rate equivalent to that of the general population. This offers numerous advantages to a full colonoscopy for the patient and health service by being a quicker, cheaper, safer procedure without the need for full bowel preparation or IV sedation.

Laparoscopic totally extraperitoneal hernia repair performed by surgical trainees: overcoming the learning curve.

BACKGROUND: Surgical trainees struggle to obtain experience in laparoscopic inguinal hernia repair (LIHR) due to a perceived steep learning curve. The purpose of this study was to compare outcomes in totally extraperitoneal (TEP) repair performed by surgical consultants and trainees under supervision as part of a standardised training regimen to assess the safety of residency training in this technique. METHODS: A retrospective review of patients managed by TEP repair by either a consultant or a supervised trainee was performed. Demographic, perioperative and postoperative data were collected and compared. All trainees underwent a standardised approach to teaching TEP repair. RESULTS: Trainees performed 133 procedures and consultants performed 121 procedures. Estimated blood loss was minimal in both cohorts. A significant difference was noted in mean operating time between consultants and trainees (33 vs. 50 min). However, it was also observed that the trainee mean operating time reduced significantly with experience (from 61 to 42 min). No statistically significant difference was demonstrated in postoperative complications, recurrence rate or length of stay. All trainees achieved the ability to complete a laparoscopic TEP repair under unscrubbed consultant supervision during a 1-year placement. CONCLUSION: With senior supervision and in the presence of a structured training regimen, trainees can safely and effectively perform LIHR, progressing to performing the procedure under unscrubbed consultant supervision. This is valuable information that can serve to inform the structure and direction of surgical training programmes as the ability to offer LIHR is increasingly becoming an expectation of consultant surgeons.

Isolated perforated jejunal diverticulitis: a case report.

Jejunal diverticulosis is a rare phenomenon often identified either incidentally on imaging or intra-operatively. Complications of jejunal diverticulosis are associated with high rates of mortality. For this reason, it remains important that this pathology is considered amongst differentials for an acute abdomen. A 78-year old gentleman presented with a short history of generalized lower abdominal pain. Computer tomography scan revealed a large inflammatory abscess relating to a perforated jejunal diverticulum. The patient was taken to theatre where he underwent small bowel resection with primary anastomosis. Early cross sectional imaging is vital to allow early diagnosis and prompt management of this pathology. Small bowel resection with primary anastomosis was associated with an excellent clinical outcome.

Axitinib plus pembrolizumab in patients with advanced renal-cell carcinoma: Long-term efficacy and safety from a phase Ib trial.

BACKGROUND: Axitinib plus pembrolizumab showed superior overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) versus sunitinib in a randomised phase III trial in patients with advanced renal-cell carcinoma (RCC). We report long-term efficacy and safety of the axitinib/pembrolizumab from the phase I trial (NCT02133742), after 46-55 months from study initiation (data cut-off date, 23rd July 2019). METHODS: Fifty-two treatment-naïve patients with advanced RCC were treated with oral axitinib 5 mg twice daily and intravenous pembrolizumab 2 mg/kg every 3 weeks. PFS, duration of response (DoR) and OS were summarised using the Kaplan-Meier method. RESULTS: At a median follow-up of 42.7 months (95% confidence interval [CI]: 41.1-44.1), median OS was not reached; 38 (73.1%) patients were alive. The probability of being alive at 4 years was 66.8% (95% CI: 49.1-79.5). Median PFS in the overall population was 23.5 months (95% CI: 15.4-30.4). ORR was 73.1%; five patients had complete response. Median DoR was 22.1 months (95% CI: 15.1-34.5). Grade III/IV adverse events (AEs) were reported in 38 (73.1%) patients and 20 (38.5%) discontinued treatment because of AEs: 17 (32.7%) discontinued axitinib, 13 (25.0%) discontinued pembrolizumab, and 10 (19.2%) discontinued both drugs. Common AEs included diarrhoea (84.6%), fatigue (80.8%), hypertension (53.8%), cough (48.1%) and dysphonia (48.1%). There were no new AE terms reported and no treatment-related deaths. CONCLUSIONS: In patients with advanced RCC with ~4 years of follow-up, combination axitinib/pembrolizumab continued to demonstrate clinical benefit, with no new safety signals.