The generation and validation of a dual cardiac HAND1-Tomato NKX2-5-GFP human embryonic stem cell line UMANe002-A-3.

The transcription factor HAND1 is a critical regulator of cardiac development which is expressed in sub-populations of cardiac progenitors and cardiomyocytes. The transcription factor NKX2-5, in contrast, is expressed more widely in cardiac cells. Here we report the generation of a dual reporter hESC line where the expression of these genes can be simultaneously measured, enabling lineage analysis as well as studies of HAND1 and NKX2-5 gene regulation and protein function. This tool will have wide utility particularly for research on developmental biology and disease modelling.

The generation and validation of two NKX2-5 fluorescent reporter human embryonic stem cell lines: UMANe002-A-1 and UMANe002-A-2.

The transcription factor NKX2-5 is a highly conserved master regulator of heart development which is widely expressed in cardiac progenitors and cardiomyocytes. Fluorescent reporters of NKX2-5 that minimally perturb normal protein expression can enable the identification, quantification and isolation of NKX2-5-expressing cells in a normal physiological state. Here we report the generation of two new hESC lines with eGFP inserted upstream (5') or downstream (3') of NKX2-5, linked by a cleavable T2A peptide. These complementary reporters produce a robust fluorescent signal in cardiac cells and have wide utility particularly for research on developmental biology and disease modelling.

Consensus-led recommendations defining practical principles of achieving optimal surgical outcomes in robotic colorectal surgery in the Asia-Pacific region.

Recent innovations within the field of robotic surgery have particular relevance to colorectal surgery. Although a robotic approach has been associated with satisfactory outcomes, there remains a wide variation in levels of adoption. In particular, this study focuses on patient positioning, docking, and table placement, with the intent of understanding the strength of opinion of colorectal surgeons in the Asia-Pacific region to the practical application of these developments to achieve optimal surgical outcomes. Using a modified Delphi methodology, a steering group of colorectal surgeons with experience in robotic surgery from across the Asia-Pacific region identified 35 consensus statements. An online 4-point Likert scale questionnaire was distributed to surgeons in the Asia-Pacific region using convenience sampling. Respondents were excluded from further analysis if they did not perform colorectal surgery or had no experience in robotic surgery. A total of 140 responses (71.8% response rate) were received between August and October 2021. 22 statements attained a very high degree of agreement (≥ 90%). High agreement (< 90% and ≥ 75%) was achieved in another 12, and one failed to meet the consensus threshold (< 75%). A set of five recommendations were developed based on these results. The high levels of agreement demonstrate recognition amongst colorectal surgeons within the Asia-Pacific region of the potential advantage of recent improvements in robotic surgery technology to further improve surgical outcomes. The recommendations may inform a set of practical principles to help standardise the use of colorectal robotic surgery, which may also be relevant to other surgical fields.

Mouse organoids as an in vitro tool to study the in vivo intestinal response to cytotoxicants.

Cross-species comparison of drug responses at the organoid level could help to determine the human relevance of findings from animal studies. To this end, we first need to evaluate the in vitro to in vivo translatability of preclinical organoids. Here, we used 5-fluorouracil (5-FU) as an exemplar drug to test whether the in vivo gut response to this cytotoxicant was preserved in murine intestinal organoids. Mice treated with 5-FU at 20 or 50 mg/kg IV (low and high dose, respectively) displayed diarrhea at clinically relevant exposures. 5-FU also induced intestinal lesions, increased epithelial apoptosis, and decreased proliferation in a dose-dependent manner. To enable comparison between the in vitro and in vivo response, top nominal in vitro drug concentrations that caused significant cytotoxicity were chosen (dose range 1-1000 µM). The inferred intracellular concentration in organoids at 1000 µM was within the tissue exposure range related to intestinal toxicity in vivo. 5-FU at ≥ 100 µM decreased ATP levels and increased Caspase-3 activity in intestinal organoids. In keeping with the in vivo findings, 5-FU increased the percentage of Caspase-3-positive cells and reduced Ki67 staining. At the transcriptome level, there was an overlap in the activity of pathways related to 5-FU's mode of action, lipid and cholesterol metabolism and integrin signaling across in vivo gut and organoids. The predicted activity state of upstream regulators was generally well preserved between setups. Collectively, our results suggest that despite their inherent limitations, organoids represent an adequate tool to explore the intestinal response to cytotoxicants.

Robotic Surgery for the Ileal Pouch.

BACKGROUND: A robotic approach to total colectomy/proctectomy and ileal pouch reconstruction would seem to be a sensible use of the platform's enhanced reach, visualization, and dexterity. OBJECTIVE: The study aimed to discuss current published data for robotic ileal pouch surgery. STUDY SELECTION: The study selection included a paucity of published data to date, representing early learning curves and case series with small numbers. CONCLUSIONS: Current robotic platforms may offer advantages, particularly in the low pelvis beyond what is found with a laparoscopic approach.

Comparison of metal bioaccumulation in crop types and consumable parts between two growth periods.

A high proportion of populations in most developing countries live below the poverty line and those near refuse grounds resort to dumpsite farming to grow food. Consequently, high levels of waste-derived contaminants are found in crops consumed by these people. This study investigates the extent to which crops cultivated on the Mbale dumpsite (Uganda) were contaminated by 11 metals and 2 non-metals: iron (Fe), aluminum (Al), zinc (Zn), manganese (Mn), copper (Cu), mercury (Hg), lead (Pb), nickel (Ni), cobalt (Co), cadmium (Cd), selenium (Se), chromium (Cr), and arsenic (As). We investigated how element bioaccumulation in crops was influenced by the growth period (short- and long-term crop maturity). The short-term crops were Zea mays and Amaranthus cruentus, whereas the long-term crops were Manihot esculenta, Colocasia esculenta, Musa acuminata, Carica papaya, Coffea arabica, and Saccharum officinarum. Results showed that nine metals were present at concentrations above World Health Organization/Food and Agriculture Organization (WHO/FAO) food safety recommendations and hence may pose health risks to consumers. In this study, leaves contained higher metal concentrations than other analyzed consumable parts. Pb and Co were found at higher concentrations in leaves of short-term crops than in long-term crops. Among short-term crops, only Z. mays seeds contained permissible metal concentrations by WHO/FAO standards. The growth period was also found to influence metal bioaccumulation in crop types. Pb, Co, Fe, Al, and Cu concentrations were significantly higher in the short-term crops than in long-term crops, while Mn, Ni, and Cr concentrations were higher in long-term crops than in short-term crops. Overall, public awareness about the health risks associated with consuming short-term leafy crops grown on dumpsites should be improved to reduce toxic metal exposure. While implementing such a campaign, the food supply of individuals whose survival depends on such crops should not be jeopardized. Therefore, farmers need alternative farming areas outside dumpsites. Integr Environ Assess Manag 2022;18:1056-1071. © 2021 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Predicting cow milk quality traits from routinely available milk spectra using statistical machine learning methods.

Numerous statistical machine learning methods suitable for application to highly correlated features, as those that exist for spectral data, could potentially improve prediction performance over the commonly used partial least squares approach. Milk samples from 622 individual cows with known detailed protein composition and technological trait data accompanied by mid-infrared spectra were available to assess the predictive ability of different regression and classification algorithms. The regression-based approaches were partial least squares regression (PLSR), ridge regression (RR), least absolute shrinkage and selection operator (LASSO), elastic net, principal component regression, projection pursuit regression, spike and slab regression, random forests, boosting decision trees, neural networks (NN), and a post-hoc approach of model averaging (MA). Several classification methods (i.e., partial least squares discriminant analysis (PLSDA), random forests, boosting decision trees, and support vector machines (SVM)) were also used after stratifying the traits of interest into categories. In the regression analyses, MA was the best prediction method for 6 of the 14 traits investigated [curd firmness at 60 min, αS1-casein (CN), αS2-CN, κ-CN, α-lactalbumin, and ß-lactoglobulin B], whereas NN and RR were the best algorithms for 3 traits each (rennet coagulation time, curd-firming time, and heat stability, and curd firmness at 30 min, ß-CN, and ß-lactoglobulin A, respectively), PLSR was best for pH, and LASSO was best for CN micelle size. When traits were divided into 2 classes, SVM had the greatest accuracy for the majority of the traits investigated. Although the well-established PLSR-based method performed competitively, the application of statistical machine learning methods for regression analyses reduced the root mean square error compared with PLSR from between 0.18% (κ-CN) to 3.67% (heat stability). The use of modern statistical machine learning methods for trait prediction from mid-infrared spectroscopy may improve the prediction accuracy for some traits.

Patient and pharmacist perspectives on pharmacist-prescribed contraception: A systematic review.

OBJECTIVE: Increasingly, states authorize pharmacists to prescribe hormonal contraception to patients without a prescription from another healthcare provider. The purpose of this review is to investigate pharmacist and patient perspectives on pharmacist-prescribed contraception in the United States. STUDY DESIGN: We searched Medline, Embase, PsycInfo, CINAHL, Scopus, and the Cochrane Library from inception through July 10, 2019. We included qualitative and mixed-methods studies, quantitative surveys, observational studies, and randomized trials in the United States. Risk of bias was assessed using tools for quantitative and qualitative studies. RESULTS: Fifteen studies met inclusion criteria, including studies on pharmacists and student pharmacists (n = 9), patients (n = 5), and both (n = 1). Study samples ranged from local to national. Studies had moderate to high risk of bias, primarily due to low response rates and lack of validated instruments. Most pharmacists (57-96%) across four studies were interested in participating in pharmacist-prescribed contraception services. Among patients, 63-97% across three studies supported pharmacist-prescribed contraception, and 38-68% across four studies intended to participate in these services. At least half of pharmacists across four studies felt comfortable prescribing contraception, though pharmacists identified additional training needs. Pharmacists and patients identified several reasons for interest in pharmacist-prescribed contraception services, including increasing patient access, reducing unintended pregnancies, and offering professional development for pharmacists. They also identified barriers, including payment, time and resource constraints, liability, and patient health concerns. CONCLUSIONS: Most pharmacists and patients across 15 studies were interested in expanded access to contraception through pharmacist-prescribed contraception. Findings on facilitators and barriers may inform implementation efforts. IMPLICATIONS: Pharmacist-prescribed contraception is a strategy to expand patient access to contraception. Reducing barriers to implementation could improve participation among pharmacists and patients.

Abdominoperineal excision in Australasia: clinical outcomes, predictive factors and recent trends of nonrestorative rectal cancer surgery.

AIM: The decision to perform an abdominoperineal excision (APR) rather than restorative bowel resection relies on a number of clinical factors. There remains great variability in APR rates internationally. The aim of this study was to demonstrate trends of APR surgery in low rectal cancer (< 6 cm from the anal verge) in Australasia and identify predictors of nonrestoration. METHOD: This study reviewed a prospectively maintained colorectal registry - the Binational Colorectal Cancer Audit (BCCA) - from general/colorectal surgical units across Australia and New Zealand. Data were analysed to determine factors predictive of nonrestorative resection. Patients were analysed based on the presence (control) or absence (comparison) of a primary anastomosis. RESULTS: Of 3628 patients with rectal cancer, 2096 were diagnosed with low rectal cancer between 2007 and 2017. The incidence of APR remained constant over the study period, with 58% of all resections of low rectal cancer being APR. The majority of resections were performed by consultants in urban hospitals (86% vs 14%). Tumours ≤ 3 cm from the anal verge, T4, M1 disease and neoadjuvant therapy were the greatest predictors of APR (P < 0.001). A significantly increased rate of restorative surgery was observed in public hospital settings (59% vs 41%, P < 0.05). The rate of positive circumferential resection margin (CRM) was 7.95%, with significantly increased rates in patients undergoing APR (12.2% vs 6.2%, P < 0.001). CRM positivity was increased in open approaches, T4, N2 and M1 staged disease and in an emergency/urgent setting (P < 0.001 and P < 0.045, respectively). Significantly increased wound and pulmonary complications were observed in the APR cohort (P < 0.01). CONCLUSION: The rates of APR in Australia and New Zealand remain high but are comparable to international figures, with one-third of rectal cancers being treated by APR. The main determinants of APR are tumour height, T stage and neoadjuvant therapy requirement. CRM positivity was higher in APR patients.

Robotic multivisceral pelvic resection: experience from an exenteration unit.

BACKGROUND: Pelvic exenteration remains a viable and effective treatment option for the management of locally advanced or recurrent pelvic malignancy. The aim of this study was to present an early experience of robotic multivisceral resection of pelvic malignancy, and to compare this experience with similar series through a systematic review of the literature. METHODS: A retrospective study was performed on patients who had robotic-assisted multi-visceral resection for pelvic malignancy at a single Colorectal Surgical unit based between two tertiary academic hospitals. Primary outcomes observed included operation type, operation time, perioperative complications, and hospital length of stay. Secondary outcomes included R0 resection status, lymph node harvest, and rate of recurrence at clinical follow-up. RESULTS: Eight cases of robotic multivisceral resection were performed for primary locally advanced pelvic malignancy involving a rectal resection as part of their operative management. The median age of patients undergoing resection was 56 years (range 29-83 years). The male:female ratio was 6:2. The mean total operating time was 8.3 h (range 6-10 h). Perioperative blood transfusion requirements were minimal. Mean hospital length of stay was 15 days (range 7-26 days). No patients experienced any serious postoperative morbidity or mortality. All patients had clear margins on histological assessment and no patients have recurrence at 12-month follow-up. CONCLUSIONS: Robotic multivisceral resection for malignant disease of the pelvis is a safe and feasible minimally invasive approach in highly selected cases.

Simulation-based acquisition of non-technical skills to improve patient safety.

Traditional surgical training has focused on the acquisition of technical skills and knowledge with minimal focus on teaching nontechnical skills. Patient safety depends on both technical and nontechnical skills, with a higher rate of non-technical skills failure leading to patient harm. Many surgical training and regulatory bodies have incorporated nontechnical skills in the required competencies of a surgeon, but few have introduced formal training in nontechnical skills. Emerging research shows simulation-based education to be a powerful tool to teach nontechnical skills to individual surgeons and surgeons in training, and to interprofessional surgical teams with subsequent improvement of patient safety outcomes.

Successful patient-oriented surgical outcomes in robotic vs laparoscopic right hemicolectomy for cancer - a systematic review.

AIM: Minimally invasive surgical approaches for cancer of the right colon have been well described with significant patient and equivalent oncological benefits. Robotic surgery has advanced in its ability to provide multi-quadrant abdominal access, leading the surgical community to widen its application outside of the pelvis to other abdominal compartments. Globally it is being realized that a patient's surgical episode of care is becoming the epicentre of cancer treatment. In order to establish the role of robotic surgery in a patient's episode of care, 'successful patient-oriented surgical' parameters in right hemicolectomy for malignancy were measured. The objective was to examine the rates of successful patient-oriented surgical outcomes in robotic right hemicolectomy (RRH) compared to laparoscopic right hemicolectomy (LRH) for cancer. METHODS: A systematic search of MEDLINE (Ovid: 1946-present), PubMed (NCBI), Embase (Ovid: 1966-present) and Cochrane Library was conducted using PRISMA for parameters of successful patient-oriented surgical outcomes in RRH and LRH for malignancy alone. The parameters measured included postoperative ileus, anastomotic complication, surgical wound infection, length of stay (LOS), incisional hernia rate, conversion to open, margin status, lymph node harvest and overall morbidity and mortality. RESULTS: There were 15 studies which included 831 RRH patients and 3241 LRH patients, with a median age of 62-74 years. No study analysed the concept of successful patient-oriented surgical outcomes. There was no significant difference in the incidence of postoperative ileus, with less time to first flatus in RRH (2.0-2.7 days, compared with 2.5-4.0 days, P < 0.05). Anastomotic leak rate in one study reported a significant increase in LRH compared to RRH (P < 0.05, 0% vs 8.3%). Significantly decreased LOS following RRH was outlined in six studies. One study reported a significantly higher rate of incisional hernias following LRH with extracorporeal anastomoses compared to RRH with intracorporeal anastomoses. Overall rates of conversion to open surgery were less with RRH (0%-3.9% vs 0%-18%, P < 0.001, 0.05). One study outlined significantly higher rates of incomplete resection with an open right hemicolectomy compared with minimally invasive laparoscopic and robotic resections, with positive margin rates of 2.3%, 0.9% and 0% respectively (P < 0.001). Two studies reported significantly higher lymph node harvest in RRH (P < 0.05). Overall morbidity and 30-day mortality were comparable in both approaches. CONCLUSION: Thirty-day morbidity and mortality were comparable between the two approaches, with patients undergoing RRH having lower anastomotic complications, increased lymph node harvest, and reduced LOS, conversion to open and incisional hernia rates in a number of studies. There are limited data on surgical approach and impact on quality of life and what patients deem successful surgical outcomes. There is a further need for a randomized controlled trial examining successful patient-oriented outcomes in right hemicolectomy for malignancy.

Outcomes Following Cytoreduction and HIPEC for Pseudomyxoma Peritonei: 10-Year Experience.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare clinical presentation, with considerable morbidity and mortality if left untreated. In recent decades, there is growing acceptance for the use of cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC). The aim of this study was to report on our 10-year single-center experience on outcomes following CRS and HIPEC for PMP of appendiceal origin. METHODS: A retrospective analysis of a prospectively maintained database of all patients undergoing CRS and HIPEC for PMP of appendiceal origin over a 10-year period at a statewide referral center was conducted. RESULTS: One hundred and seventy-five cytoreductive procedures were undertaken in 140 patients. The mean patient age was 57.4 years, with a female preponderance (56%). The median PCI was 16, with 73.1% of cases having a complete cytoreduction. Grade III/IV complications occurred in 36 (20.6%) cases, with no mortalities. The median overall and disease-free survival was 100 months and 40 months, respectively, with a 71% 5-year survival. High-grade histology was the main factor identified as an independent predictor of worse overall survival. CONCLUSION: CRS and HIPEC are safe with acceptable rates of morbidity. It can provide very favorable survival in patients with PMP. High-grade histology is a key prognostic factor associated with a worse overall survival.

Occurrence of Trace Metals in Food Crops Grown on the Mbale Dumpsite, Uganda, and Human Health Risks.

Food crops can be used as biomonitors to assess potential public health food safety hazards from contaminated agricultural environments. Globally, more than 800 million people grow fruits, vegetables, and grains on urban garden soils with unknown health risks. This worldwide practice has exposed consumers to pathogenic and carcinogenic risks from locally grown and imported contaminated foodstuffs such as Amaranthus cruentus and Zea mays, traditional and widely consumed crops across the globe. This study used Z. mays and A. cruentus crops to investigate the occurrence and spatial variations of aluminum (Al), chromium (Cr), iron (Fe), manganese (Mn), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), selenium (Se), cadmium (Cd), mercury (Hg), and lead (Pb) concentrations across the Mbale dumpsite, Uganda. Mean concentrations for Fe, Al, Zn, Mn, and Cu were high in both crops, whereas Pb, Cr, Co, Cd, As, Hg, Se, and Ni occurred in trace amounts. Using the 2 crops as biomonitors, significant variations for Al, Zn, Fe, Cr, and Co concentrations in individual crops were identified across the dump center, hill slope, and riverbank. The variations in Al, Zn, Fe, Cr, and Co concentrations were specific for crop types, crop parts, and location. The highest overall accumulation of metals was at the dump center and in crop leaves. Except Pb concentrations in Z. mays seeds, Cr, Pb, Zn, and Al concentrations in other crop parts were above World Health Organization/Food and Agricultural Organization consumer food safety limits. Therefore, Z. mays and A. cruentus consumption could pose health risks to consumers. Further health assessments and potential regulations are recommended to reduce potential health risks from metals in crops for human consumption. Integr Environ Assess Manag 2020;16:362-377. © 2019 SETAC.

Morbidity associated with the immediate vertical rectus abdominus myocutaneous flap reconstruction after radical pelvic surgery.

AIM: Patients who undergo radical pelvic surgery often have problems with perineal wound healing and pelvic collections. While there is recognition of the perineal morbidity, there also remains uncertainty around the benefit of vertical rectus abdominus myocutaneous (VRAM) flaps due to the balance between primary healing and the complications associated with this form of reconstruction. This study aimed to evaluate factors associated with significant flap and donor site related complications following VRAM flap reconstruction for radical pelvic surgery. METHOD: A retrospective analysis of VRAM flap related complications was undertaken from prospectively maintained databases for all patients undergoing radical pelvic surgery (2001- 2017) in two cancer centres. RESULTS: In all, 154 patients were identified [median age 62 years (range 26-89 years), 80 (52%) men]. Thirty-three (21%) patients experienced significant donor or flap related complications. Major complications (Clavien-Dindo ≥ 3) related to the abdominal donor site occurred in nine (6%) patients, while those related to the flap or perineal site occurred in 28 (18%) patients. Only smoking (P = 0.003) and neoadjuvant radiotherapy (P = 0.047) were associated with the development of significant flap related complications on univariate analysis. Flap related complications resulted in a significantly longer hospital stay (P < 0.001). CONCLUSION: Careful patient selection is required to balance the risks vs the benefits of VRAM flap reconstruction. Immediate VRAM reconstruction in patients undergoing radical pelvic surgery can achieve early healing and stable perineal closure; it has a low but significant morbidity. Major flap related complications are significantly associated with smoking status and neoadjuvant radiotherapy and result in a prolonged length of hospital stay.

Laboratory Evaluation of Egg White and Milk External Biomarkers for Wasmannia auropunctata (Hymenoptera: Formicidae).

Acquisition and retention of two protein markers were tested on little fire ants, Wasmannia auropunctata Roger. Pure (100%) cow's milk and a dilution (10%) of chicken egg whites were applied to W. auropunctata directly by contact spray plus residue or indirectly via residual contact only with protein-marked plant debris. Protein-marked ants were held in plastic shoe-box-sized containers, collected at 0, 24, and 48 h after exposure to their respective marks, and then examined for the presence of the marks by a chicken egg albumin and milk casein-specific enzyme-linked immunosorbent assay. Cross-contamination rates were assessed by allowing ants marked with egg whites to interact with an equal number marked milk for 24 and 48 h, and then collected either individually or in bulk. Results indicated that the egg white biomarker was retained longer than milk and that more ants were successfully marked when the direct spray application method was employed. Cross-contamination rates were highest among bulk-collected ants and lowest among ants collected individually after 24 h. However, the rates of cross-contamination among individually collected ants increased and were similar to that of bulk-collected ants after 48 h. On the basis of our results, external protein marking may not be suitable if mass trapping is required or if the study extends beyond 24 h due to high cross-contamination rates among specimens collected in bulk and reduced marker detection rates.

Evolution of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastases: 8-Year Single-Institutional Experience.

BACKGROUND: Colorectal cancer is the second leading cause of cancer-related mortality worldwide. Peritoneal metastases carry the worst prognosis among all sites of colorectal cancer metastases. In recent years, the advent and acceptance of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have greatly improved survival for selected patients with low-volume peritoneal metastases. OBJECTIVE: Here, we report the evolution of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases at a statewide tertiary referral center over an 8-year period. DESIGN: This is a retrospective study from 2009 to 2017. SETTING: The study was conducted at a single center over 8 years. PATIENTS: Patients with colorectal peritoneal metastases undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy were included. MAIN OUTCOMES: Main outcomes included evaluation of grade III/IV morbidity rate, mortality rate, overall and relapse-free survival, and prognostic factors influencing survival on a Cox multivariate analysis model. RESULTS: One hundred one cytoreductive surgeries were undertaken on 96 patients during this time for colorectal peritoneal metastases. The median patient age was 60 years with 55.2% being female. The median Peritoneal Carcinomatosis Index was 9, with complete cytoreduction achieved in 76 (75.2%) cases. Grade III or IV complications occurred in 26 cases (25.7%) with 2 (2%) perioperative mortalities. Median overall survival for the entire cohort was 32 months, with a 3-year survival of 38%. For patients who achieved a complete cytoreduction, median overall survival was 37 months, with a relapse-free survival of 13 months and a 3-year survival of 54%. Complete cytoreduction and nonmucinous histology were key factors independently associated with improved overall survival. LIMITATIONS: The main limitation this study is its retrospective nature. CONCLUSION: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for isolated low-volume colorectal peritoneal metastases is safe and effective, with low morbidity. It offers selected patients a highly favorable overall and relapse-free survival. See Video Abstract at http://links.lww.com/DCR/B2. EVOLUCIÓN DE LA CIRUGÍA CITORREDUCTIVA Y QUIMIOTERAPIA INTRAPERITONEAL HIPERTÉRMICA (HIPEC) PARA METÁSTASIS PERITONEALES COLORRECTALES: EXPERIENCIA INSTITUCIONAL DE 8 AÑOS: El cáncer colorrectal es la segunda causa de mortalidad relacionada con el cáncer en todo el mundo. Las metástasis peritoneales tienen el peor pronóstico entre todos los sitios de metástasis del cáncer colorrectal. En los últimos años, el advenimiento y la aceptación de la cirugía citorreductiva y la quimioterapia intraperitoneal hipertérmica ha mejorado enormemente la supervivencia de pacientes seleccionados con metástasis peritoneales de bajo volumen. OBJETIVO: Aquí, informamos sobre la evolución de la cirugía citorreductiva y la quimioterapia intraperitoneal hipertérmica para las metástasis peritoneales colorrectales en un centro de referencia terciario para todo el estado durante un período de ocho años. DISEÑO:: Estudio retrospectivo del 2009 a 2017. CONFIGURACIÓN:: Centro único a lo largo de ocho años. PACIENTES: Pacientes con metástasis peritoneales colorrectales sometidos a cirugía citorreductiva y quimioterapia intraperitoneal hipertérmica. RESULTADOS PRINCIPALES: Los resultados principales incluyeron la evaluación de la tasa de morbilidad de grado III / IV, la tasa de mortalidad, la supervivencia general y libre de recaída y los factores pronósticos que influyen en la supervivencia en el modelo de análisis multivariado Cox. RESULTADOS: Se realizaron el ciento uno cirugías citorreductivas en noventa y seis pacientes durante este tiempo por metástasis peritoneales colorrectales. La edad media de los pacientes fue de 60 años, con un 55.2% de mujeres. El Índice de Carcinomatosis Peritoneal mediano fue de 9, con una citorreducción completa lograda en 76 (75.2%) casos. Las complicaciones de grado III o IV ocurrieron en 26 casos (25.7%) con dos (2%) de mortalidad perioperatoria. La supervivencia mediana general para toda la cohorte fue de 32 meses, con una supervivencia de 3 años del 38%. Para los pacientes que lograron una citorreducción completa, la supervivencia global media fue de 37 meses, con una supervivencia sin recaída de 13 meses y una supervivencia de 3 años del 54%. La citorreducción completa y la histología no mucinosa fueron factores clave asociados de forma independiente con una mejor supervivencia general. LIMITACIONES: La principal limitación es la naturaleza retrospectiva del estudio. CONCLUSIÓN:: La cirugía citorreductiva y la quimioterapia intraperitoneal hipertérmica para las metástasis peritoneales colorrectales aisladas de bajo volumen son seguras y eficaces, con baja morbilidad. Ofrece a los pacientes seleccionados una supervivencia global altamente favorable y libre de recaída. Vea el Resumen del video en http://links.lww.com/DCR/B2.

Prognostic factors and patterns of failure after surgery for T4 rectal cancer in the beyond total mesorectal excision era.

BACKGROUND: Despite advances in the rates of total mesorectal excision (TME) for rectal cancer surgery, decreased local recurrence rates and increased 5-year survival, there still exists large variation in the quality of treatment received. Up to 30 per cent of rectal cancers are locally advanced at presentation and approximately 5-10 per cent still breach the mesorectal plane and invade adjacent structures despite neoadjuvant therapy. With the evolution of extended resections for rectal cancers beyond the TME plane, proponents advocate that these resections should be performed only in specialist centres. The aim was to assess the prognostic factors and patterns of failure after beyond TME surgery for T4 rectal cancers. METHODS: Data were collected from prospective databases at three high-volume institutions specializing in beyond TME surgery for T4 rectal cancers between 1990 and 2013. The primary outcome measures were overall survival, local recurrence and patterns of first failure. RESULTS: Three hundred and sixty patients were identified. The negative resection margin (R0) rate was 82·8 per cent (298 patients) and the local recurrence rate was 12·5 per cent (45 patients). The type of surgical procedure (Hartmann's: hazard ratio (HR) 4·49, 95 per cent c.i. 1·99 to 10·14; P = 0·002) and lymphovascular invasion (HR 2·02, 1·08 to 3·77; P = 0·032) were independent predictors of local recurrence. The 5-year overall survival rate for all patients was 61 (95 per cent c.i. 55 to 67) per cent. The 5-year cumulative incidence of first failure was 8 per cent for local recurrence, 6 per cent for local and distant disease, and 18 per cent for distant disease. CONCLUSION: This study has demonstrated that a coordinated approach in specialist centres for beyond TME surgery can offer good oncological and long-term survival in patients with T4 rectal cancers.

ANTECEDENTES: A pesar de las mejoras en los porcentajes de extirpación total del mesorrecto (total mesorectal excision, TME) en la cirugía de cáncer de recto, la disminución de los porcentajes de recidiva local y el aumento de la supervivencia a 5 años, todavía existe una gran variabilidad en la calidad del tratamiento recibido. Hasta el 30% de los cánceres de recto están localmente avanzados en el momento del diagnóstico y aproximadamente el 5-10% sobrepasarán el plano mesorrectal e invadirán las estructuras adyacentes a pesar del tratamiento neoadyuvante. Con la evolución de las resecciones ampliadas para los cánceres de recto que sobrepasan el plano de la TME, los defensores recomiendan que estas resecciones solo se realicen en centros especializados. El objetivo fue evaluar los factores pronósticos y los patrones de recidiva después de la cirugía ampliada más allá de la TME para los cánceres de recto T4. MÉTODOS: Los datos se recogieron a partir de bases de datos prospectivas de tres instituciones de alto volumen especializadas en resecciones ampliadas más allá de la TME para el cáncer de recto T4 entre 1990 y 2013. Los criterios de valoración principal fueron la supervivencia global, la recidiva local y los patrones de la primera recidiva. RESULTADOS: Se identificaron 360 pacientes. El margen de resección fue negativo (R0) en el 82,8% (n = 298) y el porcentaje de recidiva local fue de 12,5% (n = 45). El tipo de cirugía realizada (Hartmann: cociente de riesgos instantáneos, hazard ratio, HR 4,49; i.c. del 95%: 1,99-10,14; P = 0,002) y la invasión linfovascular (HR 2,02; i.c. del 95%: 1,08-3,77; P = 0,032) fueron factores predictivos independientes de recidiva local. La supervivencia global a 5 años para todos los pacientes fue del 61% (i.c. del 95%: 55-67). La incidencia acumulada a los 5 años de la primera recidiva fue de 8% para la recidiva local, 6% para la recidiva local y a distancia, y 18% para la recidiva a distancia. CONCLUSIÓN: Este estudio demuestra que un abordaje coordinado en centros especializados para cirugía más allá de la TME puede ofrecer una buena supervivencia oncológica y a largo plazo en pacientes con cáncer de recto T4.

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.