Use of patient-derived explants as a preclinical model for precision medicine in colorectal cancer: A scoping review.

PURPOSE: Whilst the treatment paradigm for colorectal cancer has evolved significantly over time, there is still a lack of reliable biomarkers of treatment response. Treatment decisions are based on high-risk features such as advanced TNM stage and histology. The role of the tumour microenvironment, which can influence tumour progression and treatment response, has generated considerable interest. Patient-derived explant cultures allow preservation of native tissue architecture and tumour microenvironment. The aim of the scoping review is to evaluate the utility of patient-derived explant cultures as a preclinical model in colorectal cancer. METHODS: A search was conducted using Ovid MEDLINE, EMBASE, Web of Science, and Cochrane databases from start of database records to September 1, 2022. We included all peer-reviewed human studies in English language which used patient-derived explants as a preclinical model in primary colorectal cancer. Eligible studies were grouped into the following categories: assessing model feasibility; exploring tumour microenvironment; assessing ex vivo drug responses; discovering and validating biomarkers. RESULTS: A total of 60 studies were eligible. Fourteen studies demonstrated feasibility of using patient-derived explants as a preclinical model. Ten studies explored the tumour microenvironment. Thirty-eight studies assessed ex vivo drug responses of chemotherapy agents and targeted therapies. Twenty-four studies identified potential biomarkers of treatment response. CONCLUSIONS: Given the preservation of tumour microenvironment and tumour heterogeneity, patient-derived explants has the potential to identify reliable biomarkers, treatment resistance mechanisms, and novel therapeutic agents. Further validation studies are required to characterise, refine and standardise this preclinical model before it can become a part of precision medicine in colorectal cancer.

The Impact of Neoadjuvant Chemotherapy on the Surgical Management of Colorectal Peritoneal Metastases: A Systematic Review and Meta-Analysis.

BACKGROUND: Cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) is a well-recognised treatment option for the management of colorectal peritoneal metastases (CRPM). However, incorporating the routine use of neoadjuvant chemotherapy (NAC) into this management plan is controversial. METHODS: A systematic review and meta-analysis were conducted to evaluate the impact of neoadjuvant chemotherapy on perioperative morbidity and mortality, and long-term survival of patients with CRPM undergoing CRS and HIPEC. RESULTS: Twelve studies met the inclusion criteria (n = 2,463 patients). Ten were retrospective cohort, one was prospective cohort, and one was a prospective randomised by design. Patients who received NAC followed by CRS and HIPEC experienced no difference in major perioperative morbidity and mortality compared with patients who underwent surgery first (SF). There was no difference in overall survival at 3 years, but at 5 years NAC patients had superior survival (relative risk [RR] 1.31; 95% confidence interval [CI] 1.11-1.54, P < 0.001). There were no differences in 1- and 3-year, disease-free survival (DFS) between groups. Study heterogeneity was generally high across all outcome measures. CONCLUSIONS: Patients who received neoadjuvant chemotherapy did not experience any increase in perioperative morbidity or mortality. The potential improvement in 5-year overall survival in patients receiving NAC is based on limited confidence due to several limitations in the data, but not sufficiently enough to curtail its use. The practice of NAC in this setting will remain heterogeneous and guided by retrospective evidence until prospective, randomised data are reported.

Effect of Surgical Humidification on Inflammation and Peritoneal Trauma in Colorectal Cancer Surgery: A Randomized Controlled Trial.

BACKGROUND: Pre-clinical studies indicate that dry-cold-carbon-dioxide (DC-CO2) insufflation leads to more peritoneal damage, inflammation and hypothermia compared with humidified-warm-CO2 (HW-CO2). Peritoneum and core temperature in patients undergoing colorectal cancer (CRC) surgery were compared. METHODS: Sixty-six patients were randomized into laparoscopic groups; those insufflated with DC-CO2 or HW-CO2. A separate group of nineteen patients undergoing laparotomy were randomised to conventional surgery or with the insertion of a device delivering HW-CO2. Temperatures were monitored and peritoneal biopsies and bloods were taken at the start of surgery, at 1 and 3 h. Further bloods were taken depending upon hospital length-of-stay (LOS). Peritoneal samples were subjected to scanning electron microscopy to evaluate mesothelial damage. RESULTS: Laparoscopic cases experienced a temperature drop despite Bair-HuggerTM use. HW-CO2 restored normothermia (≥ 36.5 °C) by 3 h, DC-CO2 did not. LOS was shorter for colon compared with rectal cancer cases and if insufflated with HW-CO2 compared with DC-CO2; 5.0 vs 7.2 days, colon and 11.6 vs 15.4 days rectum, respectively. Unexpectedly, one third of patients had pre-existing damage. Damage increased at 1 and 3 h to a greater extent in the DC-CO2 compared with the HW-CO2 laparoscopic cohort. C-reactive protein levels were higher in open than laparoscopic cases and lower in both matched HW-CO2 groups. CONCLUSIONS: This prospective RCT is in accord with animal studies while highlighting pre-existing damage in some patients. Peritoneal mesothelium protection, reduced inflammation and restoration of core-body temperature data suggest benefit with the use of HW-CO2 in patients undergoing CRC surgery.

Patient-Related Functional Outcomes After Robotic-Assisted Rectal Surgery Compared With a Laparoscopic Approach: A Systematic Review and Meta-analysis.

BACKGROUND: Robotic surgery has gained significant momentum in rectal cancer surgery. Most studies focus on short-term and oncological outcomes, showing similar outcomes to laparoscopic surgery. Increasing survivorship mandates greater emphasis on quality of life and long-term function. OBJECTIVE: This study aimed to compare quality of life and urinary, sexual, and lower GI functions between robotic and laparoscopic rectal surgeries. DATA SOURCES: A systematic search of Medline, PubMed, Embase, Clinical Trials Register, and Cochrane Library-identified articles comparing robotic with laparoscopic rectal resections was performed. MAIN OUTCOME MEASURES: The outcome measures were quality of life and urinary, sexual, and GI functions between robotic and laparoscopic rectal resection patient groups. Where comparable data were available, results were pooled for analysis. RESULTS: The initial search revealed 1777 papers; 101 were reviewed in full, and 14 studies were included for review. Eleven assessed male sexual function; 7 favored robotic surgery, and the remaining studies showed no significant difference. Pooled analysis of 5 studies reporting rates of male sexual dysfunction at 12 months showed significantly lower rates after robotic surgery (OR, 0.51; p = 0.043). Twelve studies compared urinary function. Six favored robotic surgery, but in 2 studies, a difference was seen at 6 months but not sustained at 12 months. Pooled analysis of 4 studies demonstrated significantly better urinary function scores at 12 months after robotic surgery (OR, 0.26; p = 0.016). Quality of life and GI function were equivalent, but very little data exist for these parameters. LIMITATIONS: A small number of studies compare outcomes between these groups; only 2 are randomized. Different scoring systems limit comparisons and pooling of data. CONCLUSIONS: The limited available data suggest that robotic rectal cancer resection improves male sexual and urinary functions when compared with laparoscopy, but there is no difference in quality of life or GI function. Future studies should report all facets of functional outcomes using standardized scoring systems.

Exercise and colorectal cancer survival: an updated systematic review and meta-analysis.

PURPOSE: The benefit of exercise to colorectal cancer patients has been advocated. However, comparative data to quantify the survival benefit is lacking. The aim of this review was to assess the effect of exercise on colorectal cancer survival. METHODS: An up-to-date systematic review was performed on the available literature between 2000 and 2021 on PubMed, EMBASE, Medline, and Cochrane Library databases. All studies reporting on the impact of exercise and colorectal cancer outcomes in patients treated for non-metastatic colorectal cancer were analysed. The main outcome measures were the overall survival (OS), cancer specific survival (CSS) and disease free survival (DFS). RESULTS: A total of 13 prospective observational studies were included, accounting for 19,135 patients. Compared to negligible physical activity, overall survival (OS) was significantly increased for both moderate and highest activity group (HR 0.82, 95% CI: 0.74-0.90, p < 0.001 and HR 0.64, 0.56-0.72, p < 0.001 respectively). This was also reflected in cancer specific survival (CSS) analysis, but not disease-free survival (DFS) analysis. CONCLUSION: Exercise was associated with an increased in overall survival after a colorectal cancer resection. This would support the promotion of exercise interventions amongst colorectal cancer patients.

Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer: A Systematic Review and Metaanalysis of Oncological and Operative Outcomes.

BACKGROUND: Total neoadjuvant therapy in rectal cancer refers to the administration of chemoradiotherapy plus chemotherapy before surgery. Recent studies have shown improved pathological complete response and disease-free survival with this approach. However, survival benefits remain unproven. Our objective is to present a metaanalysis of oncological outcomes of total neoadjuvant therapy in locally advanced rectal cancer. PATIENTS AND METHODS: A comprehensive search was performed on PubMed, Medline, and Google Scholars. Studies comparing total neoadjuvant therapy with standard neoadjuvant chemoradiotherapy were included. Data extracted from the individual studies were pooled and a metaanalysis performed. The outcomes of interest are the rate of complete pathological response, nodal response, resection margin, anal preservation, anastomotic leak, local recurrence, distant recurrence, disease-free survival, and overall survival. RESULTS: There were 15 comparative studies with 2437 patients in the neoadjuvant chemoradiotherapy group and 2284 in the total neoadjuvant therapy group. The pooled complete pathological response was 22.3% in the total neoadjuvant therapy group, compared with 14.2% in the standard neoadjuvant chemoradiotherapy group (p < 0.001). Even though there was no difference in local recurrence rate, there was a significantly lower rate of distant recurrence (OR 0.81, p = 0.02), and better 3-year disease-free survival (70.6% vs. 65.3%, respectively, p < 0.001) and overall survival (84.9% vs. 82.3%, respectively, p = 0.006), favoring the total neoadjuvant therapy group. Due to significant heterogeneity in the study protocols, there remains uncertainty on the ideal chemotherapy/radiotherapy sequence. CONCLUSIONS: This study provides supporting evidence on the favorable immediate and intermediate oncological outcomes with the use of total neoadjuvant therapy for locally advanced rectal cancer.

Robotic versus laparoscopic ileal pouch-anal anastomosis (IPAA): a systematic review and meta-analysis.

BACKGROUND: Restorative proctocolectomy with ileal-pouch anal anastomosis (IPAA) is a curative and cancer preventative procedure in patients with ulcerative colitis (UC) and familial adenomatous polyposis (FAP). It can be technically difficult laparoscopically, and hence the robotic platform has been suggested as a way to enable minimally invasive surgery in more patients. This systematic review examines robotic proctectomy or proctocolectomy with IPAA. A limited meta-analysis was performed on data comparing the robotic approach to laparoscopy. METHODS: We searched MEDLINE, EMBASE and the Cochrane database for case series of robotic IPAA procedures and studies comparing the robotic to laparoscopic or open procedures. Data examined includes operating time, conversion to open, length of stay, complications, blood loss, return of bowel function, reoperation rate and functional outcomes. RESULTS: Five non-randomised studies compared robotic to laparoscopic techniques; one compared robotic to open surgery and three case series are included. Operating time was significantly longer in robotic cases. Estimated blood loss was significantly less in three of four studies which reported this; hospital stay was significantly less in two. There were nonsignificant reductions in complications and readmission rates. Pooled analysis of four papers with adequate data showed a nonstatistically significant trend to less complications in robotic procedures. Three studies assessed functional and quality of life outcomes, with little difference between the platforms. CONCLUSIONS: Available data suggests that the robotic platform is safe to use for IPAA procedures. There is minimal evidence for clinical advantages, but with little data to base decisions and significant potential for improvements in technique and cost-effectiveness, further use of the platform for this operation is warranted. It is vital that this occurs within an evaluation framework.

Neoadjuvant chemotherapy in locally advanced colon cancer: a systematic review and meta-analysis.

BACKGROUND: There is increasing evidence to support the use of neoadjuvant chemotherapy (NAC) in locally advanced colon cancer (LACC). However, its safety, efficacy and side effect profile is yet to be completely elucidated. This review aims to assess NAC regimens, duration, compare completion rates, intra-operative and post-operative complication profiles and oncological outcomes, in order to provide guidance for clinical practice and further research. METHODS: PubMed, EMBASE and MEDLINE were searched for a systematic review of the literature from 2000 to 2020. Eight eligible studies were included, with a total of 1213 patients, 752 (62%) of whom received NAC. Of the eight studies analysed, two were randomised controlled trials comparing neoadjuvant chemotherapy followed by oncological resection to upfront surgery and adjuvant chemotherapy, three were prospective single-arm phase II trials analysing neoadjuvant chemotherapy followed by surgery only, one was a retrospective study comparing neoadjuvant chemotherapy followed by surgery versus surgery first followed by adjuvant chemotherapy and the remaining two were single-arm retrospective studies of neoadjuvant chemotherapy followed by surgery. RESULTS: All cases of LACC were determined and staged by computed tomography; majority of the studies defined LACC as T3 with extramural depth of 5 mm or more, T4 and/or nodal positivity. NAC administered was either folinic acid, fluorouracil and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (XELOX) with the exception of one study which utilised 5-fluorouracil and mitomycin. Most studies had NAC completion rates of above 83% with two notable exceptions being Zhou et al. and The Colorectal Cancer Chemotherapy Study Group of Japan who both recorded a completion rate of 52%. Time to surgery from completion of NAC ranged on average from 16 to 31 days. The anastomotic leak rate in the NAC group ranged from 0 to 4.5%, with no cases of postoperative mortality. The R0 resection rate in the NAC group was 96.1%. Meta-analysis of both RCTs included in this study showed that neoadjuvant chemotherapy increased the likelihood of a negative resection margin T3/4 advanced colon cancer (pooled relative risk of 0.47 with a 95% confidence interval) with no increase in adverse consequence of anastomotic leak, wound infection or return to theatre. CONCLUSIONS: Our systematic review and meta-analysis show that NAC is safe with an acceptable side effect profile in the management of LACC. The current data supports an oncological benefit for tumour downstaging and increased in R0 resection rate.

Robotic versus laparoscopic ventral mesh rectopexy: a systematic review and meta-analysis.

INTRODUCTION: Ventral mesh rectopexy is frequently performed as a means of improving the quality of life for sufferers of rectal prolapse. The minimally invasive approach is highly desirable but can be technically difficult to achieve in the narrow confines of the pelvis. The robotic platform is becoming a more common means of overcoming these difficulties, but evidence of an objective benefit over standard laparoscopy is scarce. This study seeks to review and analyse the data comparing outcomes after robotic and laparoscopic ventral mesh rectopexy. METHOD: We searched MEDLINE, EMBASE and the Cochrane database for papers comparing robotic to laparoscopic ventral mesh rectopexy. Comparable data was pooled for meta-analysis. RESULTS: Six studies compared outcomes between robotic and laparoscopic ventral mesh rectopexy. Sample sizes were relatively small, and only two of the studies were randomised. Pooled analysis was possible for data on operating time, complication rates, conversion rates and length of stay in hospital. This showed a non-significant trend towards longer operating times and a statistically significant reduction in length of stay after robotic procedures. There was no significant difference in complication and conversion rates. CONCLUSION: The frequent finding of longer operating time for robotic surgery was not confirmed in this study. Shorter length of stay in hospital was seen, with other post-operative outcomes showing no significant difference. More data is needed with cost-benefit analyses to show whether the robotic platform is justified.

Does rectal tube/transanal stent placement after an anterior resection for rectal cancer reduce anastomotic leak? A systematic review and meta-analysis.

BACKGROUND: There is increasing evidence that either a transanal stent (TAS) or rectal tube (RT) can decrease the risk of anastomotic leakage (AL) after anterior resection for rectal cancer, in which a diverting stoma may not be required. OBJECTIVES: The aim of this review was to investigate the efficacy and safety of RT/TAS in preventing AL after anterior resections. DATA SOURCES: An up-to-date systematic review was performed on the available literature between 2000 and 2020 on PubMed, EMBASE, Medline and Cochrane Library databases. STUDY SELECTION: All studies reporting on anterior resections in adults, comparing transanal tube/stent versus non-tube/stent, were analysed. MAIN OUTCOME MEASURE: The primary outcome was rates of AL, whereas secondary outcomes compared associated unplanned re-operation for AL and hospital length of stay (LOS). RESULTS: Two randomized controlled trials and 13 observational studies were included, with 1714 patients receiving RT/TAS and 1741 patients without. There were 119 (7%) patients with AL in the RT/TAS group compared to 216 (12.3%) patients in the non-RT/TAS group (OR: 0.48, 95% CI: 0.38-0.62, p < 0.001). There were 47 (2.9%) patients with AL complications requiring surgery in the RT/TAS group compared to 132 (8%) patients in the non-RT/TAS group (OR: 0.29, 95% CI: 0.20-0.42, p < 0.001) and no significant difference identified with the standardized mean difference (SMD) favouring the RT/TAS group for hospital LOS (SMD: -0.23, 95% CI: -0.51 to 0.06, p = 0.115). CONCLUSION: The use of RT/TAS post restorative anterior resection for rectal cancer should be considered, given the benefits shown from this meta-analysis.

Comparing functional outcomes between transanal total mesorectal excision (TaTME) and laparoscopic total mesorectal excision (LaTME) for rectal cancer: a systematic review and meta-analysis.

BACKGROUND: There is concern that transanal total mesorectal excision (TaTME) may result in poorer functional outcomes as compared to laparoscopic TME (LaTME). These concerns arise from the fact that TaTME entails both a low anastomosis and prolonged dilatation of the anal sphincter from the transanal platform. OBJECTIVES: This paper aimed to assess the comparative functional outcomes following TaTME and LaTME, with a focus on anorectal and genitourinary outcomes. DATA SOURCES: A meta-analysis and systematic review was performed on available literature between 2000 and 2020 from the PubMed, EMBASE, Medline, and Cochrane Library databases. STUDY SELECTION: All comparative studies assessing the functional outcomes following taTME versus LaTME in adults were included. MAIN OUTCOME MEASURE: Functional anorectal and genitourinary outcomes were evaluated using validated scoring systems. RESULTS: A total of seven studies were included, consisting of one randomised controlled trial and six non-randomised studies. There were 242 (52.0%) and 233 (48.0%) patients in the TaTME and LaTME groups respectively. Anorectal functional outcomes were similar in both groups with regard to LARS scores (30.6 in the TaTME group and 28.3 in the LaTME group), Jorge-Wexner incontinence scores, and EORTC QLQ C30/29 scores. Genitourinary function was similar in both groups with IPSS scores of 5.5 to 8.0 in the TaTME group, and 3.5 to 10.1 in the LaTME group. (p = 0.835). CONCLUSION: This review corroborates findings from previous studies in showing that the transanal approach is not associated with increased anal sphincter damage. Further prospective clinical trials are needed in this field of research.

The learning curve in robotic colorectal surgery compared with laparoscopic colorectal surgery: a systematic review.

AIM: The learning curve has implications for efficient surgical training. Robotic surgery is perceived to have a shorter learning curve than laparoscopy; however, detailed analysis is lacking. The aim of this work was to analyse studies comparing robotic and laparoscopic colorectal learning curves. Simulation studies comparing novices' learning curves were analysed in order to surmise applicability to colorectal surgery. METHOD: A systematic search of Medline, PubMed, Embase and the Cochrane Library identified colorectal papers (from 1 January 2000 to 3 March 2021) comparing robotic and laparoscopic learning curves where surgeons lacked laparoscopic colorectal experience. Simulation studies comparing learning curves were also included. The learning curve was defined as the period of ongoing improvement in speed and/or accuracy. RESULTS: From 576 abstracts reviewed, three operative and 16 simulation studies were included. The robotic learning curve for right colectomy was significantly faster in one study (16 vs. 25 cases) and equal for anterior resection in two studies (44 vs. 41 cases and 55 vs. 55). One study showed fewer complications for robotic patients (14.6% vs. 0%, p = 0.013). Ten simulation studies reported faster times and eight recorded error rates favouring robotic surgery. Seven studies measured the learning curve. Four favoured laparoscopic surgery, but operating times were faster using the robotic platform. CONCLUSION: Operating times for robotic surgery may be faster than laparoscopy when surgeons are inexperienced with both platforms. This may be related to a superior baseline performance rather than a shorter learning curve. Whether a shorter learning curve on the laparoscopic platform will persist for long enough to enable skills to overtake robotic ability needs further investigation.

Is neoadjuvant therapy an alternative strategy to immediate surgery in locally perforated colon cancer?

BACKGROUND: Perforations are a rare but serious complication of colorectal cancer. The current standard of treatment is emergent surgery followed by adjuvant chemotherapy. The concern with this approach is not only the uncertainty of achieving a R0 resection but also potential injury to adjacent vessels, nerves and ureters due to inflamed tissue planes. A subset of this patient population with a contained perforation who are clinically stable may have superior oncological outcomes with local sepsis control, neoadjuvant therapy followed by radical resection. The aim of this study is to report on the pre-operative safety profile for neoadjuvant therapy in the setting of an abscess from colon cancer perforation and the short-term oncological surgical quality outcomes. METHODS: In this retrospective observational study, all consecutive perforated colon cancer receiving neoadjuvant therapy from Jan 2010 to Dec 2019 were included. RESULTS: There were 21 patients that met the inclusion criteria. The most common symptom at presentation was abdominal pain (71.4%) and most common site of perforation was sigmoid colon (61.9%). Local sepsis control was achieved with a combination of radiological or surgical drainage, diverting ostomy and/or intravenous antibiotics. Thirteen patients had long-course chemoradiation and eight patients had neoadjuvant chemotherapy. Of these, 13 (61.9%) had tumour regression, with one patient having a pathological complete response. All patients achieved a R0 resection. CONCLUSIONS: In a small subset of patients with colon cancer perforation, this study has demonstrated the potential safe usage of neoadjuvant therapy first before radical surgery to achieve a clear resection margin.

Appendiceal pseudomyxoma peritonei: predictors of recurrence and iterative surgery.

AIM: Appendiceal pseudomyxoma peritonei (PMP) is a rare entity, with recurrence rates up to 26% despite optimal cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Evidence specific to PMP originating from non-infiltrative appendiceal mucinous neoplasms (low grade - LAMN and high grade - HAMN) is lacking. The aim of this study was to identify patterns of recurrence and predictive factors for patients appropriate for iterative surgery. METHOD: A bi-institutional retrospective analysis was performed on patients undergoing complete cytoreduction and HIPEC for PMP derived from perforated LAMN or HAMN. Multivariate logistic regression was performed to identify independent predictors for re-do CRS. Five-year overall survival (OS) was stratified according to surgical intervention, and 5-year disease-free survival (DFS) was stratified according to histological PMP grade. Cox regression analysis was performed to identify independent predictors for OS and DFS. RESULTS: Sixty of 239 (25.1%) patients developed peritoneal recurrence between 2007 and 2020. The median time to recurrence was 20.7 months. The risk of disease recurrence was highest with high-grade PMP (P <0.001) and increasing PCI (P <0.001). Patients with high-grade histology from their index procedure and aged over 60 years were less likely to be offered iterative surgery on multivariate analysis. Patients who underwent iterative CRS and HIPEC had a 5-year survival of 100%. CONCLUSION: Iterative CRS and HIPEC is feasible in selected patients with recurrent PMP, displaying good oncological outcomes. Age, index histology and level of abdominal quadrant involvement are predictive of proceeding to re-do surgery.

Predictive factors for distant recurrence of colorectal cancer in patients after curative resection for stage I-III colorectal cancer in Australia.

PURPOSE: Distant recurrence is a devastating occurrence after colorectal cancer resection. This study aimed to identify the risk factors for distant recurrence following surgery. METHODS: All consecutive colorectal cancer resections with curative intent were included from a prospectively maintained colorectal cancer database. The primary outcome was to identify predictive factors for distant recurrence of colorectal cancer. RESULTS: A total of 670 eligible cases were identified with 88 (13.1%) developing distant recurrence during the follow-up period. The median time to distant recurrence was 1.2 years with the most common sites of distant recurrence being the lung (44.3%) and liver (44.3%). Predictive factors for distant recurrence in colon cancer included a high tumor, nodal, and overall stage of the primary cancer (p < 0.001 for all). Surgical complications (p = 0.007), including anastomotic leak (p = 0.023), were associated with a higher risk of developing distant recurrence in rectal cancer patients. Independent variables associated with distant recurrence included tumor stage (OR 1.61, p = 0.011), nodal stage (OR 2.18, p < 0.001), and both KRAS (OR 11.04, p < 0.001) and MLH/PMS2 (OR 0.20, p = 0.035) genetic mutations. Among patients with distant recurrence, treatment with surgery conferred the best survival, with patients < 50 years of age having the best overall 5-year survival. CONCLUSION: Predictive factors for distant recurrence include advanced tumor and nodal stages, and the presence of KRAS and MLH/PSM2 mutations. Clinicians should be cognizant of these risk factors, and instate close surveillance plans for patients exhibiting these features.

Pelvic Exenteration for Anal and Urogenital Squamous Cell Carcinoma: Experience and Outcomes from an Exenteration Unit Over 12 Years.

BACKGROUND: Pelvic exenteration has increasingly been shown to improve disease-free and overall survival for patients with locally advanced pelvic malignancies. Squamous cell carcinoma (SCC) is the second most common pelvic malignancy requiring exenteration. OBJECTIVE: The aim of this study was to report the clinical and oncological outcomes from patients treated with pelvic exenteration for anal and urogenital SCC from a single, high-volume unit. METHODS: A review of a prospectively maintained database from 1991 to 2018 at a high-volume specialised institution was performed. Primary endpoints included R0 resection rates, local recurrence and overall survival (OS) rates. RESULTS: From January 1999 to July 2018, 361 patients underwent pelvic exenteration of which 31 patients were identified with SCC (15 anal SCC, 16 urogenital SCC). The majority of patients were females (n = 24, 77.4%). Median age was 59 (range 35-81). Twenty-seven patients underwent resection with curative intent with an R0 resection rate of 81.5%. Four patients underwent a palliative procedure [R1 = 3 (8%), R2 = 1 (3.3%)]. Mean hospital length of stay was 32 days (range 8-122 days). Disease-free survival was significantly increased in anal SCC with no significant difference in OS compared to urogenital SCC (p = 0.03, p = 0.447 respectively). Advanced pathological T stage was associated with decreased OS (p = 0.023). In the curative intent group the disease-free survival and OS rate was 59.3% and 70% at 24 months, respectively. CONCLUSION: Complete R0 resection is achievable in a high proportion of patients. Urogenital SCC is associated with significantly worse disease-free survival, and advanced T-stage was a significant prognostic factor for OS.

Complications After Extended Radical Resections for Locally Advanced and Recurrent Pelvic Malignancies: A 25-Year Experience.

BACKGROUND: The oncological role of pelvic exenteration for locally advanced and recurrent pelvic malignancies arising from the anorectum, gynaecological, or urological systems is now well-established. Despite this, the surgical community has been slow to accept pelvic exenteration, undoubtedly due to concerns about high morbidity and mortality rates. This study assessed the general major complications and predictors of morbidity following extended radical resections for locally advanced and recurrent pelvic malignancies. METHODS: Data were collected from prospective databases at two high-volume institutions specialising in beyond TME surgery for locally advanced and recurrent pelvic malignancies between 1990 and 2015. The primary outcome measures were major complications (Clavien-Dindo 3 or above) and predictors for morbidity. RESULTS: A total of 646 consecutive patients required extended surgery for local advanced pelvic malignancies. The median age was 63 (range 19-89) years, and the majority were female (371; 57.4%). One or more major complications were observed in 106 patients (16.4%). The most common major complications were intra-abdominal collection (43.7%; n = 59/135) and wound infection (14.1%; n = 19/135). The overall inpatient mortality rate was 0.46% (n = 3/646). Independent predictors for major morbidity following surgery for locally advanced or recurrent pelvic malignancies were squamous cell carcinoma of anus, sacrectomy, and blood transfusion requirement. CONCLUSIONS: This series adds increasing evidence that good outcomes can be achieved for extended radical resections in locally advanced and recurrent pelvic malignancies. A coordinated approach in specialist centres for beyond TME surgery demonstrates that this is a safe and feasible procedure, offering low major complication rates.

Predictors of overall survival following extended radical resections for locally advanced and recurrent pelvic malignancies.

PURPOSE: In an era of personalised medicine, there is an overwhelming effort for predicting patients who will benefit from extended radical resections for locally advanced pelvic malignancy. However, there is paucity of data on the effect of comorbidities and postoperative complications on long-term overall survival (OS). The aim of this study was to define predictors of 1-year and 5-year OS. METHODS: Data were collected from prospective databases at two high-volume institutions specialising in beyond TME surgery for locally advanced and recurrent pelvic malignancies between 1990 and 2015. The primary outcome measures were 1-year and 5-year OS. RESULTS: A total of 646 consecutive extended radical resections were performed between 1990 and 2015. The majority were female patients (371, 57.4%) and the median age was 63 years (range 19-89 years). One-year OS, primary rectal adenocarcinoma had the best survival while recurrent colon cancer had the worse survival (p = 0.047). The 5-year OS between primary and recurrent cancers were 64.7% and 53%, respectively (p = 0.004). Poor independent prognostic markers for 5-year OS were increasing ASA score, cardiovascular disease, recurrent cancers, ovarian cancers, pulmonary embolus and acute respiratory distress syndrome. A positive survival benefit was demonstrated with preoperative radiotherapy (HR 0.55; 95% CI 0.4-0.75, p < 0.001). CONCLUSION: Patient comorbidities and specific complications can influence long-term survival following extended radical resections. This study highlights important predictors, enabling clinicians to better inform patients of the potential short- and long-term outcomes in the management of locally advanced and recurrent pelvic malignancy.

Complications and 5-year survival after radical resections which include urological organs for locally advanced and recurrent pelvic malignancies: analysis of 646 consecutive cases.

BACKGROUND: Extensive multi-visceral resection, including components of the urinary tract, is often required to achieve clear resection margins, which is now well established as a key predictor of long-term survival for locally advanced pelvic tumours. The aims of this study were to analyse major morbidity and factors predicting complications and long-term outcomes following a urological procedure within extended radical resections. METHODS: Data were collected from prospective databases at two high-volume institutions specialising in extended radical resections for locally advanced and recurrent pelvic malignancies between 1990 and 2015. The primary endpoints were general major complications (Clavien-Dindo ≥ 3) and factors influencing complications and overall survival after urological resection. RESULTS: A total of 646 consecutive patients requiring an extended radical resection for locally advanced or recurrent pelvic malignancies were identified. The median age was 63 years (range 19-89 years) and the majority were female (371; 57.4%). A urological resection was performed as part of the resection in 226 patients (35.0%). The overall 30-day major complication rate was significantly higher in the urological intervention group (23%; n = 52) compared to the non-urological group (12.9%; n = 54 patients; p = 0.001). Intestinal anastomotic leak (p = 0.001) and intra-abdominal collections (p = 0.001) were more common in the urological cohort. Ileal conduit formation was an independent predictor of major morbidity (OR 1.95; 95% CI 1.24-3.07; p = 0.004). Independent prognostic markers for poor 5-year survival following urological procedures were recurrent tumour, cardiovascular disease, previous thromboembolic event and postoperative pulmonary embolism. CONCLUSIONS: Extended radical resections which include a urological resection are associated with significantly more major morbidity than those without urological resection. Ileal conduit formation is independently associated with the development of major morbidity. Five-year overall survival is no different for patients who had or did not have urological resection as part of extended radical surgery for locally advanced or recurrent pelvic malignancy.

Prognostic Impact of Tumor-Infiltrating Lymphocytes in Primary and Metastatic Colorectal Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: There is increasing literature emerging on the significance of tumor-infiltrating lymphocytes in colorectal cancer. However, there have been inconsistent findings, secondary to small patient numbers and varied methods for identifying these lymphocytes. OBJECTIVE: The aim of this study was to determine the prognostic and predictive power of tumor-infiltrating lymphocytes in colon, rectal (in neoadjuvant setting), and metastatic colorectal cancer. DATA SOURCES: A comprehensive search of PubMed and Embase was undertaken from January 2006 to December 2016. STUDY SELECTION: The inclusion criteria included a description of the tumor-infiltrating lymphocyte subset(s) assessed with reporting of associated short- and long-term outcomes. MAIN OUTCOME MEASURES: The main outcome measures, were disease-free and overall survival. RESULTS: A total of 25 studies were included, 15 for primary colorectal cancer (4719 patients), 7 for locally advanced rectal cancer (727 patients), and 3 studies for metastatic colorectal cancer (418 patients). High CD3, CD8, FoxP3, and CD45RO densities were associated with improved overall survival for primary colorectal cancer, with pooled estimated HRs of 0.88, 0.81, 0.70, and 0.63 (all p < 0.001) respectively. Furthermore, in locally advanced rectal cancer, the levels of CD8 cells were a significant predictor of good tumor regression grade after chemoradiotherapy. LIMITATIONS: The retrospective nature of included studies and the significant interstudy heterogeneity were limitations. CONCLUSIONS: There is increasing evidence that tumor-infiltrating lymphocytes play an important role in predicting prognosis in colorectal cancer and tumor regression after neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Clinical researchers are now in a unique position to build on this work to identify robust predictive markers to stratify patients not only to currently available therapies but also to immunotherapy, which has demonstrated success in improving patient outcomes.