Organoids as a Robust Preclinical Model for Precision Medicine in Colorectal Cancer: A Systematic Review.

BACKGROUND: Patients with locally advanced or metastatic colorectal cancer (CRC) display heterogeneous responses to standard-of-care therapy. Robust preclinical models of malignancy in the form of patient-derived tumor organoids (PDTOs) have recently come to the fore in tailoring patient care to a personalized medicine level. This study aimed to review the literature systematically regarding PTDOs and gauge their impact on precision medicine in the management of CRC. METHODS: A PRISMA-compliant systematic review of the MEDLINE, EMBASE, Web of Science, and Cochrane Library databases was performed. The results were categorized based on the primary objective of the individual studies as follows: organoid use in predicting effective hyperthermic intraperitoneal chemotherapy (HIPEC), systemic chemotherapy in CRC, or neoadjuvant chemoradiotherapy in rectal cancer. RESULTS: The literature search found 200 publications, 16 of which met the inclusion criteria. Organoid models of primary and metastatic CRC have been increasingly used to assess clinical responses to standard therapy. Marked heterogeneity exists, matching the responses observed in clinical practice with ex vivo drug and radiation screening. Repeated correlation between organoid and patient sensitivity to forms of HIPEC, systemic chemotherapy, and chemoradiotherapy has been observed. CONCLUSION: Patient-derived tumor organoids are the latest tool in predictive translational research. Current organoid-based studies in precision medicine have shown their great potential for predicting the clinical response of patients to CRC therapy. Larger-scale, prospective data are required to fully support this exciting avenue in cancer care.

Survival after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: A systematic review and discussion of latest controversies.

INTRODUCTION: Peritoneal metastases confer the worst survival amongst all sites of metastatic colorectal cancer. The adoption of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has become an option for patients with isolated colorectal peritoneal metastases (CRPM). The aim of this study was to evaluate the outcomes following CRS and HIPEC for CRPM from published high volume cohort studies and to highlight the latest controversies and future directions of CRPM treatment. MATERIALS AND METHODS: A systematic review was performed on published studies on the treatment outcomes of CRS and HIPEC for colorectal peritoneal metastases. RESULTS: Twenty studies met the inclusion criteria for the systematic review. The median survival for all patients ranged from 14.6 to 60.1 months. The 5-year overall survival ranged from 23.4% to 52%. For patients with complete cytoreduction, the median survival was 25 to 49 months. Major morbidity and mortality ranged from 15.1% to 47.2% and 0% to 4.5%, respectively. CONCLUSION: CRS and HIPEC for the treatment of CRPM is safe and current evidence suggests it improves both median and disease-free survival. However, the efficacy of intraperitoneal chemotherapy, in particular oxaliplatin, has recently come under scrutiny. Accordingly, higher quality evidence is urgently required to contribute to multidisciplinary and international consensus on CRPM treatment strategies.

Re-do cytoreductive surgery for peritoneal surface malignancy: Is it worthwhile?

BACKGROUND AND OBJECTIVES: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) offers selected patients with peritoneal surface malignancies (PSM) an improved survival. However, a substantial proportion of patients develop peritoneal recurrence. There is limited data on the efficacy of iterative CRS and HIPEC in such patients. This study evaluates the safety, efficacy and outcomes after re-do CRS and HIPEC for PSM at a tertiary institute. METHODS: Patients undergoing re-do CRS and HIPEC for recurrent PSM were included. Cases were grouped into the first and iterative cases and compared to evaluate differences in morbidity, survival and factors influencing survival. RESULTS: One hundred and forty patients developed peritoneal recurrence after CRS and HIPEC. Thirty-seven patients underwent re-do CRS and HIPEC. The most common indication for iterative surgery was pseudomyxoma peritonei in 27 patients (73.0%). Median survival was 97 months for patients undergoing iterative surgery compared to 40 months for those who did not. Median survival following first and iterative surgery was 97 and 89 months, respectively (p = 0.15). Median progression-free survival after first and iterative surgery was 23 and 19 months, respectively (p = 0.47). At iterative CRS and HIPEC, incomplete cytoreduction (HR 12.82, 95% CI 1.64-100.35), increasing PCI (HR 1.13, 95% CI 1.04-1.22), in particular PCI >20 (HR 10.90, 95% CI 1.37-86.66) were factors associated with worse overall survival. CONCLUSION: In well selected patients, iterative CRS and HIPEC is safe, and can provide favorable survival with low morbidity. Completeness of cytoreduction and PCI are factors that influence overall survival.

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.

Evaluation of cytoreductive surgery and HIPEC for peritoneal surface malignancies: analysis of 384 consecutive cases.

BACKGROUND: Peritoneal surface malignancy (PSM) was historically associated with a poor survival. The adoption of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) can now offer patients with PSM a favourable overall survival. Here, we report our single-institute outcomes following CRS and HIPEC for PSM and evaluate changes in our practice over time. METHODS: This is a retrospective review from 2009 to 2018 of all patients undergoing CRS and HIPEC for PSM at a statewide peritoneal disease centre. Cases were divided into the first half and second to compare changes in practice over time. RESULTS: Three hundred and eighty four CRS and HIPEC cases were performed during this time. The median age was 56 years with 59.6% female. The median peritoneal carcinomatosis index (PCI) was 11, with a reduction in PCI in the second cohort (9 v 15, p < 0.01). Complete cytoreduction rates were significantly higher in the second cohort (82.3% v 67.7%, p < 0.01). Overall, grade III/IV complications occurred in 101 cases (26.3%) with three (0.8%) perioperative mortalities. Median overall survival (OS) for the entire cohort was 85 months, with a 5-year survival of 52%. Median OS was 97 months for PMP, 34 months for colorectal peritoneal metastases and 27 months for other histologies. Completeness of cytoreduction, histology type, and PCI were factors independently associated with overall survival. CONCLUSION: CRS and HIPEC can offer highly favourable outcomes for PSM with low morbidity. Successful complete cytoreduction rates improved significantly with greater experience and better patient selection.

An Update on Immunotherapy for Solid Tumors: A Review.

In recent years, it has been demonstrated that immunotherapy is an effective strategy for the management of solid tumors. The origins of immunotherapy can be traced back to the work of William Coley, who elicited an immune response against sarcoma by injecting patients with a mixture of dead bacteria. Significant progress has been made since, with immune markers within the tumor now being used as predictors of cancer prognosis and manipulated to improve patient survival. While surgery remains central to the management of most patients with solid malignancies, it is important that surgeons consider the different immunotherapy strategies that can be employed to manage disease. Here, we highlight how the immune system influences tumorigenesis and bring attention to how current and future immunotherapies can serve as an adjunct to surgery.

Managing regional metastasis in patients with cutaneous head and neck melanoma - is selective neck dissection appropriate?

BACKGROUND: Neck dissection is recommended for patients with head and neck cutaneous melanoma and nodal metastasis. However, there appears to be no clear evidence to guide the extent of nodal resection. METHODS: Loco-regional recurrence (LR), overall survival (OS) and progression free survival (PFS) was retrospectively compared between patients who had Comprehensive neck dissection (CND) and Selective neck dissection (SND). RESULTS: There was no difference in LR, OS and PFS between CND (n=18) and SND groups (n=79). Extra capsular extension (ECE), frontal disease and increasing number of involved nodes resulted in worse OS and PFS but had no impact on LR. CONCLUSION: Patients with disease limited to one node without ECE can be effectively treated by SND alone. In patients who have these unfavourable pathological features more extensive nodal resection does not improve outcome if they receive radiotherapy. Extent of neck dissection or adjuvant radiotherapy has no impact on overall survival.

Surgical management of splenic flexure cancer: is there an optimal technique? A bi-national registry analysis.

BACKGROUND: Splenic flexure tumours (SFC) are uncommon and present at more advanced disease stages. The optimal surgical technique for SFC remains controversial. We sought to compare the short-term outcomes of a left hemicolectomy (LHC) versus an extended resection (subtotal colectomy, STC) for SFCs. METHODS: A retrospective analysis using the Binational Colorectal Cancer Audit (BCCA) registry was performed. All patients with SFC who underwent elective or emergency surgery for a SFC between 2010 and 2021 were included. Primary outcomes included short-term inpatient complications. Secondary outcomes included survival outcomes. RESULTS: Six hundred and ninety-nine patients underwent resections for SFCs. A LHC was more common, performed in 64.1%. Patients having a LHC were significantly older, with proportionally more LHCs done laparoscopically. Overall grade III/IV complications were similar between both operations. Prolonged ileus and return to theatre were significantly higher in patients undergoing a STC. On multivariate analysis, anastomotic leak and overall grade III/IV complications were not independently associated with the type of operation. There was no difference in medial survival based on type of operation. Higher tumour stage (Stage III/IV) were independently associated with worse survival. CONCLUSION: Segmental and extended resections are both oncologically sound procedures for SFCs. Segmental resections are associated with lower rates of prolonged ileus.

Does intra-operative humidification with warmed CO2 reduce surgical site infection in open colorectal surgery? A randomized control trial.

BACKGROUNDS: Surgical site infections (SSI) are a significant cause of postoperative morbidity and mortality, contributing to a considerable financial burden on the healthcare system. Insufflation of the open surgical wound with warm, humidified carbon dioxide (CO2 ) is a novel measure aimed to reduce SSI. The local atmosphere of warm, humidified CO2 within the open surgical wound is proposed to decrease airborne contamination, bacterial growth, desiccation, and heat loss while improving tissue oxygenation and perfusion. This randomized controlled trial evaluates the impact of the HumiGard™ surgical humidification system on the incidence of SSI in patients undergoing open colorectal surgery. METHODS: We conducted a multi-site single-blinded randomized control trial on patients undergoing elective or emergency laparotomy at a single tertiary Colorectal Surgery service. The primary outcome measure was the incidence of SSI, with secondary outcomes including ICU length of stay (LOS), total LOS and mean core temperature. RESULTS: Patients who received HumiGard™ had a lower incidence of SSI, although this did not reach statistical significance (4.5% for treatment group versus 13.0% for control group; P = 0.092). There was no significant difference in ICU LOS or total LOS between cohorts. The HumiGard™ group had a higher mean core temperature than the control at the end of surgery (P < 0.001). CONCLUSION: The present study could not confirm that utilization of warm, humidified CO2 with HumiGard™ reduces SSI in open colorectal surgery. Further research is indicated to validate and extend these findings.

Mechanical bowel preparation with pre-operative oral antibiotics in elective colorectal resections: an Australian single institution experience.

BACKGROUND: Anastomotic leaks (AL) and surgical site infections (SSI) are serious complications after colorectal resection. Studies have shown the benefits of pre-operative oral antibiotics (OAB) with mechanical bowel preparation (MBP) in reducing AL and SSI rates. We aim to investigate our experience with the short-term outcomes of AL and SSI following elective colorectal resections in patients receiving OAB with MBP versus MBP only. METHODS: A retrospective analysis was performed from our database for patients who underwent elective colorectal resection between January 2019 and November 2021. Prior to August 2020, OAB was not used as part of MBP. After 2020, Neomycin and Metronidazole were used in conjunction with MBP. We evaluated differences in AL and SSI between both groups. RESULTS: Five hundred and seventeen patients were included from our database with 247 having MBP while 270 had OAB and MBP. There was a significantly lower rate of AL in patients receiving MBP and OAB as compared to MBP alone (0.4% versus 3.0%, P-value = 0.03). The SSI rate at our institution was 4.4%. It was lower in patients with MBP and OAB as compared to MBP alone, but this was not clinically significant (3.3% versus 5.7%, P-value = 0.19). CONCLUSION: The association in the reduction of AL with the addition of OAB to the MBP protocol seen here reinforces the need for future randomized controlled trials in the Australasian context. We recommend colorectal institutions in Australian and New Zealand consider OAB with MBP as part of their elective colorectal resection protocol.

Right hemicolectomy for colon cancer: does the anastomotic configuration affect short-term outcomes?

OBJECTIVES: Right hemicolectomy is a common colorectal operation for resection of cancers of the right colon. The ileocolic anastomosis may be created using a stapled end-to-side, stapled side-to-side or handsewn technique. Anastomotic leak and post-operative bleeding are uncommon but serious causes of morbidity and mortality, while post-operative ileus contributes to prolonged length of stay. The aim of this study was to evaluate differences in short-term outcomes between different anastomotic configurations following right hemicolectomy for colon cancer. METHODS: We conducted a retrospective study using data from the Bowel Cancer Outcomes Registry (BCOR), including 94 hospitals across Australia and New Zealand, of all patients who underwent right hemicolectomy or extended right hemicolectomy for colon cancer with formation of a primary anastomosis between 2007 and 2021. RESULTS: We included 8164 patients in the analysis. There was no significant difference in rates of anastomotic leak and anastomotic bleeding based on anastomotic technique. A stapled end-to-side anastomosis was associated with a lower rate of post-operative ileus than stapled side-to-side anastomosis (6.5% vs. 7.2%; P = 0.03). CONCLUSION: Both handsewn and stapled anastomosis techniques may be utilized for oncologic right hemicolectomy, with comparable rates of anastomotic leak and post-operative bleeding. Stapled end-to-side anastomosis resulted in lower rates of prolonged ileus compared to stapled side-to-side anastomoses.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases in an elderly population: outcomes from a single centre.

BACKGROUND: The prevalence of elderly patients with resectable colorectal peritoneal metastases (CRPM) is increasing. This study aimed to compare short and long-term outcomes of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for CRPM in patients above and below 70 years of age. METHODS: This was a retrospective, 10-year analysis of 90-day major morbidity and mortality, and long-term survival. RESULTS: Thirty-two (21.3%) of 150 consecutive patients who underwent CRS and HIPEC during the study period were aged 70 and older. PCI (P = 0.04), perioperative chemotherapy use (P < 0.01) and organ resections (rectum P = 0.04, diaphragm P = 0.03) were less in the over 70 group. There was no significant differences in major morbidity (P = 0.19) and mortality (P = 0.32). There was also no difference in 5-year overall survival (OS) (≥70: 26% vs. <70: 39%; P = 0.68) and disease-free survival (DFS) (≥70: 25% vs. <70: 14%; P = 0.22). Age above 70 was not independently associated with worse OS (HR 1.55, P = 0.20) and DFS (HR 1.07, P = 0.81). CONCLUSION: The surgical management of CRPM appears safe and feasible in this elderly population. Appropriate selection of elderly patients for such radical intervention is reinforced by the comparable survival with those under 70.

Small bowel evisceration from vagina.

Vaginal evisceration is a rare condition where abdominal contents herniate through a vaginal wall defect. The estimated incidence is 0.032-1.2% after hysterectomy, trachelectomy or upper vaginectomy. We present a 78-year-old lady who developed vaginal evisceration 2 years after radical cystectomy and hysterectomy for bladder cancer. It is rare surgical emergency that requires prompt recognition and damage control with bowel reduction and packing. We discuss the initial management and surgical options for definitive repair.

Management of primary and metastatic malignant small bowel obstruction, operate or palliate. A systematic review.

BACKGROUND: The management of patients presenting with malignant small bowel obstruction is a challenging paradigm. The aim of this systematic review was to examine different management strategies in these complex patients. The primary outcomes evaluated were the type of intervention, 30-day morbidity and mortality and overall survival rates. METHODS: A systematic literature review of EMBase, Medline, PubMed and the Cochrane Library was performed using Preferred Reporting Items for Systematic reviews and Meta-Analyses for studies reporting on conservative and operative management of malignant small bowel obstruction. RESULTS: Fifteen studies (n = 882 patients) reporting on outcomes for malignant small bowel obstruction were analysed. Outcomes measured were primarily survival and relief of obstructive symptoms. The median age ranged from 52 to 66 years. The most common cause of malignant small bowel obstruction was gynaecological in nature (56%), followed by colorectal (19%). Four hundred and eighty-six patients underwent primary surgical management and the remaining 396 patients were assigned to non-surgical intervention. Median overall survival in the operative studies ranged from 2.5 to 7.4 months compared with 0.9 to 1.9 months (P < 0.05). The 30-day mortality ranged from 13% to 28% in those who underwent surgical interventions versus 2% to 61% in the non-surgical group (P = 0.09). No significant difference in median survival in gastrointestinal (GI) and gynaecological malignancies was observed (4.3 versus 5.0 months, P = 0.12). Morbidity ranged from 21% to 85% in the surgical group and 12% to 29% in the percutaneous groups (P < 0.05). CONCLUSION: Surgical intervention in malignant small bowel obstruction is associated with significant morbidity, although it may improve survival in selected patients with gynaecological and colorectal malignancy. It is imperative that realistic goals and expectations are discussed with patients preoperatively.

Robotic complete mesocolic excision and central vascular ligation for right-sided colon cancer: short-term outcomes from a case series.

BACKGROUND: Despite conflicting data regarding oncological outcomes, studies demonstrate that complete mesocolic excision (CME) and central vascular ligation (CVL) for right-sided colon cancer removes significantly more tissue and yields higher lymph node counts when compared to conventional resection. This study aims to report the safety profile of CME and CVL in patients undergoing robotic surgery for right-sided colon cancer during the introduction of this technique across two institutions. METHODS: Patients who underwent an elective robotic right colectomy with CME and CVL for right-sided colon cancer in a public quaternary and a private tertiary healthcare centre between November 2018 and April 2020 were included. Demographic, clinical, perioperative and histopathological variables were recorded and analysed. RESULTS: Twenty patients (13 females) with a median age of 69 (23-83) years and median body mass index of 27 (19-46) were included. All of them had a pre-operative diagnosis of right-sided colon adenocarcinoma. Median operative time and blood loss were 140 (130-300) min and 30 (20-100) mL, respectively. There were no conversions or intra-operative complications. There were two post-operative complications recorded (one ileus and one intra-abdominal collection treated with intravenous antibiotics) and no re-interventions. Median length of stay was 4 (2-8) days. All patients had an R0 resection, and the median lymph node yield was 36 (22-80) lymph nodes. CONCLUSION: This series demonstrates a safe introduction of robotic CME and CVL in patients with right-sided colon cancer. The lymph node harvest obtained with CME and CVL in this setting was high.