CLDN18.2 BiTE Engages Effector and Regulatory T Cells for Antitumor Immune Response in Preclinical Models of Pancreatic Cancer.

BACKGROUND & AIMS: BiTE (bispecific T-cell engager) immune therapy has demonstrated clinical activity in multiple tumor indications, but its influence in the tumor microenvironment remains unclear. CLDN18.2 is overexpressed in solid tumors including gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC), both of which are characterized by the presence of immunosuppressive cells, including regulatory T cells (Tregs) and few effector T cells (Teffs). METHODS: We evaluated the activity of AMG 910, a CLDN18.2-targeted half-life extended (HLE) BiTE molecule, in GC and PDAC preclinical models and cocultured Tregs and Teffs in the presence of CLDN18.2-HLE-BiTE. RESULTS: AMG 910 induced potent, specific cytotoxicity in GC and PDAC cell lines. In GSU and SNU-620 GC xenograft models, AMG 910 engaged human CD3+ T cells with tumor cells, resulting in significant antitumor activity. AMG 910 monotherapy, in combination with a programmed death-1 (PD-1) inhibitor, suppressed tumor growth and enhanced survival in an orthotopic Panc4.14 PDAC model. Moreover, Treg infusion enhanced the antitumor efficacy of AMG 910 in the Panc4.14 model. In syngeneic KPC models of PDAC, treatment with a mouse surrogate CLDN18.2-HLE-BiTE (muCLDN18.2-HLE-BiTE) or the combination with an anti-PD-1 antibody significantly inhibited tumor growth. Tregs isolated from mice bearing KPC tumors that were treated with muCLDN18.2-HLE-BiTE showed decreased T cell suppressive activity and enhanced Teff cytotoxic activity, associated with increased production of type I cytokines and expression of Teff gene signatures. CONCLUSIONS: Our data suggest that BiTE molecule treatment converts Treg function from immunosuppressive to immune enhancing, leading to antitumor activity in immunologically "cold" tumors.

National trends and outcomes of total proctocolectomy and completion proctectomy ileal pouch-anal anastomosis procedures for ulcerative colitis.

AIM: The purpose of this study is to assess US operative trends and outcomes of ulcerative colitis (UC) patients undergoing total proctocolectomy with ileal pouch-anal anastomosis (TPC-IPAA) or completion proctectomy with IPAA (CP-IPAA). METHODS: Adult UC patients who underwent TPC-IPAA or CP-IPAA were analysed retrospectively using the 2016-2020 American College of Surgeons National Surgical Quality Improvement Program database. Factors associated with 30-day overall and serious morbidity were identified using multivariable logistic regression. RESULTS: A total of 1696 patients were identified, with 958 patients (56.5%) undergoing TPC-IPAA and 738 (43.5%) undergoing CP-IPAA. A greater proportion of TPC-IPAAs were performed each year (except in 2019) compared to CP-IPAAs over the study period (P trend <0.001). Unadjusted analysis showed comparable rates of overall (20.8% vs. 24.4%, P = 0.076) and serious morbidity (14.3% vs. 12.7%, P = 0.352) between TPC-IPAA and CP-IPAA patients. Robotic TPC-IPAA had no differences in complications compared to laparoscopic and open approaches. Robotic CP-IPAA had higher anastomotic leak rates and longer hospital length of stay compared to laparoscopic and open approaches. Obesity was associated with increased odds of overall and serious morbidity for patients who underwent TPC-IPAA. Steroid/immunosuppressive therapy was associated with increased odds of overall and serious morbidity for patients who underwent CP-IPAA. CONCLUSIONS: Obese patients should be informed of their increased morbidity risk and offered counselling on weight loss prior to surgery when feasible. Patients on steroid/immunosuppressive therapy within 30 days preoperatively should not undergo CP-IPAA or should delay surgery until they can be safely off those medications.

Prevalence of cannabis use disorder and perioperative outcomes in adult colectomy patients: A propensity score-matched analysis.

BACKGROUND: The decriminalization of cannabis across the United States has led to an increased number of patients reporting cannabis use prior to surgery. However, it is unknown whether preoperative cannabis use disorder (CUD) increases the risk of postoperative complications among adult colectomy patients. METHODS: Adult patients undergoing an elective colectomy were retrospectively analyzed from the National Inpatient Sample database (2004-2018). To control for potential confounders, patients with CUD, defined using ICD-9/10 codes, were propensity score matched to patients without CUD in a 1:1 ratio. The association between preoperative CUD and composite morbidity, the primary outcome of interest, was assessed. Subgroup analyses were performed after stratification by age (≥50 years). RESULTS: Among 432,018 adult colectomy patients, 816 (0.19%) reported preoperative CUD. The prevalence of CUD increased nearly three-fold during the study period from 0.8/1000 patients in 2004 to 2.0/1000 patients in 2018 (P-trend<0.001). After propensity score matching, patients with CUD exhibited similar rates of composite morbidity (140 of 816; 17.2%) as those without CUD (151 of 816; 18.5%) (p = 0.477). Patients with CUD also had similar anastomotic leak rates (CUD: 5.64% vs. No CUD: 6.25%; p = 0.601), hospital lengths of stay (CUD: 5 days, IQR 4-7 vs. No CUD: 5 days, IQR 4-7) (p = 0.415), and hospital charges as those without CUD. Similar findings were seen among patients aged ≥50 years in the subgroup analysis. CONCLUSIONS: Though the prevalence of CUD has increased drastically over the past 15 years, preoperative CUD was not associated with an increased risk of composite morbidity among adult patients undergoing an elective colectomy.

Colorectal Surgery Outcomes in the United States During the COVID-19 Pandemic.

INTRODUCTION: The purpose of this study was to assess colorectal surgery outcomes, discharge destination, and readmission in the United States during the COVID-19 pandemic. METHODS: Adult colorectal surgery patients in the American College of Surgeons National Surgical Quality Improvement Program database (2019-2020) and its colectomy and proctectomy procedure-targeted files were included. The prepandemic time period was defined from April 1, 2019 to December 31, 2019. The pandemic time period was defined from April 1, 2020 to December 31, 2020 in quarterly intervals (Q2 April-June; Q3 July-September; Q4 October-December). Factors associated with morbidity and in-hospital mortality were assessed using multivariable logistic regression. RESULTS: Among 62,393 patients, 34,810 patients (55.8%) underwent colorectal surgery prepandemic and 27,583 (44.2%) during the pandemic. Patients who had surgery during the pandemic had higher American Society of Anesthesiologists class and presented more frequently with dependent functional status. The proportion of emergent surgeries increased (12.7% prepandemic versus 15.2% pandemic, P < 0.001), with less laparoscopic cases (54.0% versus 51.0%, P < 0.001). Higher rates of morbidity with a greater proportion of discharges to home and lesser proportion of discharges to skilled care facilities were observed with no considerable differences in length of stay or worsening readmission rates. Multivariable analysis demonstrated increased odds of overall and serious morbidity and in-hospital mortality, during Q3 and/or Q4 of the 2020 pandemic. CONCLUSIONS: Differences in hospital presentation, inpatient care, and discharge disposition of colorectal surgery patients were observed during the COVID-19 pandemic. Pandemic responses should emphasize balancing resource allocation, educating patients and providers on timely medical workup and management, and optimizing discharge coordination pathways.

Simultaneous resection of colorectal cancer and synchronous colorectal liver metastases: A risk stratified analysis of the NSQIP database.

BACKGROUND AND OBJECTIVES: Over 25% of patients diagnosed with colorectal cancer (CRC) will develop colorectal liver metastases (CRLM). Controversy exists over the surgical management of these patients. This study aims to investigate the safety of a simultaneous surgical approach by stratifying patients based on procedure risk and operative approach. METHODS: Using ACS-NSQIP (2016-2020), patients with CRC who underwent isolated colorectal, isolated hepatic, or simultaneous resections were identified. Colorectal and hepatic procedures were stratified by morbidity risk (high vs. low) and operative approach (open vs. minimally invasive). Thirty-day overall morbidity was compared between risk matched isolated and simultaneous resection groups. RESULTS: A total of 65 417 patients were identified, with 1550 (2.4%) undergoing simultaneous resections. A total of 1207 (77.9%) underwent a low-risk colorectal and low-risk liver resection. On multivariate analysis, there was no significant difference in overall morbidity between patients who had a simultaneous open high-risk colorectal/low-risk hepatic procedure compared to patients who had an isolated open high-risk colorectal procedure (odds ratio: 1.19; 95% confidence interval: 0.94-1.50; p = 0.148). All other combinations of simultaneous procedures had statistically significant higher rates of morbidity than the isolated group. CONCLUSIONS: Simultaneous resection of colorectal and synchronous CRLM is associated with an increased risk of morbidity in most circumstances in a risk stratified analysis, although rates of readmission and reoperation were not increased. Minimally invasive surgical approaches may significantly mitigate this morbidity.

Safety and Feasibility of ≤24-h Short-Stay Right Colectomies for Primary Colon Cancer.

BACKGROUND: Hospital length of stay (LOS) has been used as a surgical quality metric. This study seeks to determine the safety and feasibility of right colectomy as a ≤24-h short-stay procedure for colon cancer patients. METHODS: This was a retrospective cohort study using the ACS-NSQIP database and its Procedure Targeted Colectomy database (2012-2020). Adult patients with colon cancer who underwent right colectomies were identified. Patients were categorized into LOS ≤1 day (≤24-h short-stay), LOS 2-4 days, LOS 5-6 days, and LOS ≥7 days groups. Primary outcomes were 30-day overall and serious morbidity. Secondary outcomes were 30-day mortality, readmission, and anastomotic leak. The association between LOS and overall and serious morbidity was assessed using multivariable logistic regression. RESULTS: 19,401 adult patients were identified, with 371 patients (1.9%) undergoing short-stay right colectomies. Patients undergoing short-stay surgery were generally younger with fewer comorbidities. Overall morbidity for the short-stay group was 6.5%, compared to 11.3%, 23.4%, and 42.0% for LOS 2-4 days, LOS 5-6 days, and LOS ≥7 days groups, respectively (p < 0.001). There were no differences in anastomotic leak, mortality, and readmission rates in the short-stay group compared to patients with LOS 2-4 days. Patients with LOS 2-4 days had increased odds of overall morbidity (OR 1.71, 95% CI 1.10-2.65, p = 0.016) compared to patients with short-stay but no differences in odds of serious morbidity (OR 1.20, 95% CI 0.61-2.36, p = 0.590). CONCLUSIONS: ≤24-h short-stay right colectomy is safe and feasible for a highly-select group of colon cancer patients. Optimizing patients preoperatively and implementing targeted readmission prevention strategies may aid patient selection.

Treatment Strategies and Survival Trends for Anorectal Melanoma: Is it Time for a Change?

BACKGROUND: Immunotherapy advances for the treatment of cutaneous melanoma question its efficacy in treating anorectal mucosal melanoma (ARMM). We aimed to identify the prevalence, current management, and overall survival (OS) for ARMM. METHODS: Review of patients with ARMM from 2004 to 2015 National Cancer Database. Factors associated with immunotherapy were identified using multivariable logistic regression. The primary outcome was 2- and 5-year OS. Subgroup analysis by treatment type was performed. RESULTS: A total of 1331 patients were identified with a significant increase in prevalence (2004: 6.99%, 2015: 10.53%). ARMM patients were older, white, on Medicare, and from the South. The most common treatment was surgery (48.77%), followed by surgery + radiation (11.75%), surgery + immunotherapy (8.68%), and surgery + chemotherapy (8.68%). 16.93% of patients received immunotherapy, with utilization increasing (7.24%: 2004, 21.27%: 2015, p < 0.001). Patients who received immunotherapy had a significantly better 2-year OS (42.47% vs. 49.21%, p < 0.001), and other therapies did not reveal a significant difference. Adjusted analysis showed no difference in 2- and 5-year OS based on therapy type. CONCLUSION: The prevalence of ARMM has increased. The use of immunotherapy has increased substantially. Some survival benefit with the administration of immunotherapy may exist that has yet to be revealed. A more aggressive treatment paradigm is warranted.

Readmission Adversely Affects Survival in Surgical Rectal Cancer Patients.

BACKGROUND: Readmission has received attention as a potential healthcare quality metric. No studies have investigated the relationship between readmission and survival in patients undergoing rectal cancer surgery. The aims of this study were to identify factors associated with 30-day readmission after rectal cancer surgery and to determine the impact of readmission on overall survival (OS). METHODS: Patients who underwent surgical treatment for rectal/rectosigmoid adenocarcinoma stages I-IV were identified using the National Cancer Database (2004-2014). Multivariable logistic regression was used to identify factors for readmission. 2:1 nearest neighbor caliper matching without replacement was used to ensure similarity of patients being compared. Survival analyses were performed using Kaplan-Meier method along with log-rank test and Cox proportional hazards model. RESULTS: Of 110,167 patients, 7045 (6.39%) were readmitted. Factors associated with readmission included higher Charlson comorbidity score, non-private or no insurance, procedure type, hospitals in the Northeast, South, and Midwest regions, and prolonged length of stay. Within the matched cohort (13,756 non-readmitted and 6878 readmitted), readmitted patients had worse 5- and 10-year OS regardless of cancer stage (p < 0.001) and procedure type. Five- and 10-year OS were 58.98% and 41.01% for readmitted patients, 64.96% and 43.50% for non-readmitted patients. Readmitted patients had shorter OS by 13.14 months and increased risk of mortality (HR 1.20, 95% CI 1.15-1.25, p < 0.001). CONCLUSIONS: Thirty-day readmission after rectal cancer surgery is associated with decreased OS. Efforts to reduce readmissions should be considered to advance cancer care and enhance the potential for improved patient survival.

Assessing the Financial Burden Associated With Treatment Options for Resectable Pancreatic Cancer.

OBJECTIVE: The aim of this study is to assess the financial burden associated with treatment options for resectable pancreatic cancer. BACKGROUND: As the volume of cancer care increases in the United States, there is growing interest among both clinicians and policy-makers to reduce its financial impact on the healthcare system. However, costs relative to the survival benefit for differing treatment modalities used in practice have not been described. METHODS: Patients undergoing resection for pancreatic cancer were identified in the Truven Health MarketScan database. Associations between chemoradiation therapies and survival were performed using parameterized multivariable accelerated failure time models. Median payments over time were calculated for surgery, chemoradiation, and subsequent hospitalizations. RESULTS: A total of 2408 patients were included. Median survival among all patients was 21.1 months [95% confidence interval (CI): 19.8-22.5 months], whereas median follow-up time was 25.1 months (95% CI: 23.5-26.5 months). After controlling for comorbidity, receipt of neoadjuvant therapy, and nodal involvement, a longer survival was associated with undergoing combination gemcitabine and nab-paclitaxel [time ratio (TR) = 1.26, 95% CI: 1.02-1.57, P = 0.035) or capecitabine and radiation (TR = 1.25, 95% CI: 1.04-1.51, P = 0.018). However, median cumulative payments for gemcitabine with nab-paclitaxel were highest overall [median $74,051, interquartile range (IQR): $38,929-$133,603). CONCLUSIONS: Total payments for an episode of care relative to improvement in survival vary significantly by treatment modality. These data can be used to inform management decisions about pursuing further care for pancreatic cancer. Future investigations should seek to refine estimates of the cost-effectiveness of different treatments.

Predicting the Risk of Readmission From Dehydration After Ileostomy Formation: The Dehydration Readmission After Ileostomy Prediction Score.

BACKGROUND: All-cause readmission rates in patients undergoing ileostomy formation are as high as 20% to 30%. Dehydration is a leading cause. No predictive model for dehydration readmission has been described. OBJECTIVE: The purpose of this study was to develop and validate the Dehydration Readmission After Ileostomy Prediction scoring system to predict the risk of readmission for dehydration after ileostomy formation. DESIGN: Patients who underwent ileostomy formation were identified using the American College of Surgeons National Surgical Quality Improvement Program data set (2012-2015). Predictors for dehydration were identified using multivariable logistic regression analysis and translated into a point scoring system based on corresponding ß-coefficients using 2012-2014 data (derivation). Model discrimination was assessed with receiver operating characteristic curves using 2015 data (validation). SETTINGS: This study used the American College of Surgeons National Surgical Quality Improvement Program. PATIENTS: A total of 8064 (derivation) and 3467 patients (validation) were included from the American College of Surgeons National Surgical Quality Improvement Program. MAIN OUTCOME MEASURES: Dehydration readmission within 30 days of operation was measured. RESULTS: A total of 8064 patients were in the derivation sample, with 2.9% (20.1% overall) readmitted for dehydration. Twenty-five variables were queried, and 7 predictors were identified with points assigned: ASA class III (4 points), female sex (5 points), IPAA (4 points), age ≥65 years (5 points), shortened length of stay (5 points), ASA class I to II with IBD (7 points), and hypertension (9 points). A 39-point, 5-tier risk category scoring system was developed. The model performed well in derivation (area under curve = 0.71) and validation samples (area under curve = 0.74) and passed the Hosmer-Lemeshow goodness-of-fit test. LIMITATIONS: Limitations of this study pertained to those of the American College of Surgeons National Surgical Quality Improvement Program, including a lack of generalizability, lack of ileostomy-specific variables, and inability to capture multiple readmission International Classification of Diseases, 9/10 edition, codes. CONCLUSIONS: The Dehydration Readmission After Ileostomy Prediction score is a validated scoring system that identifies patients at risk for dehydration readmission after ileostomy formation. It is a specific approach to optimize patient factors, implement interventions, and prevent readmissions. See Video Abstract at http://links.lww.com/DCR/A746.

Impact of Angiotensin Receptor Blocker Use on Overall Survival Among Patients Undergoing Resection for Pancreatic Cancer.

BACKGROUND: Pancreatic cancer has higher concentrations of angiotensin II compared with other cancers. This study sought to assess the effect of angiotensin II receptor blockers (ARBs) on survival of patients undergoing resection using a large, nationally representative dataset. METHODS: Patients undergoing pancreatic cancer resection were identified in the Truven Health MarketScan database. Multivariable Cox proportional hazards regression was used to assess the effect of ARB use on overall survival. RESULTS: A total of 4299 patients were identified, among whom 479 (11.1%) filled a prescription for an ARB. Mean patient age was 54.5 years (SD = 8.6 years); 2187 (51.1%) were female. Exactly 49.4% (n = 2125) of patients had a Charlson comorbidity index >2 at the time of surgery (n = 2125, 49.4%) and 59.6% (n = 2563) underwent a pancreaticoduodenectomy. Kaplan-Meier estimates of survival at 1, 2, and 4 years were 62.8% (95% CI: 61.3-64.2%), 38.2% (95% CI: 36.6-39.8%), and 19.0% (95% CI: 17.1-21.0%), respectively. On multivariable analysis, ARB use was associated with a 24% decreased risk of death over the 5-year period in which patients were under observation (HR = 0.76, 95% CI: 0.67-0.87, p < 0.001). CONCLUSIONS: ARB use was associated with improved survival in patients undergoing resection of pancreatic cancer. Further research is required into the differential effect of ARBs in the treatment of pancreatic cancer.

Readmission after major surgery: effect of the postdischarge environment.

BACKGROUND: Although uncoordinated postdischarge care has been associated with poor clinical outcomes, the effect of discharge to a low healthcare resource area (LHRA) on readmission remains undetermined. We sought to assess how the quality of discharge area health resources impact readmission following major surgery. METHODS: This cross-sectional study was performed by linking Maryland state data for 2012-2015 to the Agency for Healthcare Research and Quality Area Health-Resource File. Patients undergoing one of 11 common surgical procedures were identified. Multivariable logistic regression was performed to assess the effect of discharge area health resource quality on readmission. RESULTS: A total of 76,747 patients were identified of which 9.4% were discharged to a high healthcare resource area (HHRA), whereas 81.9% of patients were discharged to an LHRA. Perioperative morbidity and length of stay were comparable between HHRA versus LHRA patients (both P > 0.05). Among all patients, 30-d and 90-d readmission was 6.5% and 12.4%, respectively. On multivariable analysis, discharge to LHRA was independently associated with a 19% (odds ratio = 1.19; 95% CI, 1.01-1.41; P = 0.043) and 18% (odds ratio = 1.18; 95% CI, 1.04-1.33; P = 0.010) greater odds of 30-d and 90-day readmission, respectively. CONCLUSIONS: Patients discharged to an area characterized by LHRA were more likely to be readmitted at 30 d and 90 d following index discharge.

Mitochondrial ribosomal protein L12 selectively associates with human mitochondrial RNA polymerase to activate transcription.

Basal transcription of human mitochondrial DNA (mtDNA) in vitro requires the single-subunit, bacteriophage-related RNA polymerase, POLRMT, and transcription factor h-mtTFB2. This two-component system is activated differentially at mtDNA promoters by human mitochondrial transcription factor A (h-mtTFA). Mitochondrial ribosomal protein L7/L12 (MRPL12) binds directly to POLRMT, but whether it does so in the context of the ribosome or as a "free" protein in the matrix is unknown. Furthermore, existing evidence that MRPL12 activates mitochondrial transcription derives from overexpression studies in cultured cells and transcription experiments using crude mitochondrial lysates, precluding direct effects of MRPL12 on transcription to be assigned. Here, we report that depletion of MRPL12 from HeLa cells by shRNA results in decreased steady-state levels of mitochondrial transcripts, which are not accounted for by changes in RNA stability. We also show that a significant "free" pool of MRPL12 exists in human mitochondria not associated with ribosomes. "Free" MRPL12 binds selectively to POLRMT in vivo in a complex distinct from those containing h-mtTFB2. Finally, using a fully recombinant mitochondrial transcription system, we demonstrate that MRPL12 stimulates promoter-dependent and promoter-independent transcription directly in vitro. Based on these results, we propose that, when not associated with ribosomes, MRPL12 has a second function in transcription, perhaps acting to facilitate the transition from initiation to elongation. We speculate that this is one mechanism to coordinate mitochondrial ribosome biogenesis and transcription in human mitochondria, where transcription of rRNAs from the mtDNA presumably needs to be adjusted in accordance with the rate of import and assembly of the nucleus-encoded MRPs into ribosomes.

Short-Stay Left Colectomy for Colon Cancer: Is It Safe?

BACKGROUND: Advances in surgical practices have decreased hospital length of stay (LOS) after surgery. This study aimed to determine the safety of short-stay (≤24-hour) left colectomy for colon cancer patients in the US. STUDY DESIGN: Adult colon cancer patients who underwent elective left colectomies were identified using the American College of Surgeons NSQIP database (2012 to 2021). Patients were categorized into 4 LOS groups: LOS 1 day or less (≤24-hour short stay), 2 to 4, 5 to 6, and 7 or more. Primary outcomes were 30-day postoperative overall and serious morbidity. Secondary outcomes were 30-day mortality and readmission. Multivariable logistic regression was performed to explore the association between LOS and overall and serious morbidity. RESULTS: A total of 15,745 patients who underwent left colectomies for colon cancer were identified with 294 (1.87%) patients undergoing short stay. Short-stay patients were generally younger and healthier with lower 30-day overall morbidity rates (LOS ≤1 day: 3.74%, 2 to 4: 7.38%, 5 to 6: 16.12%, and ≥7: 37.64%, p < 0.001). Compared with patients with LOS 2 to 4 days, no differences in mortality and readmission rates were observed. On adjusted analysis, there was no statistical difference in the odds of overall (LOS 2 to 4 days: odds ratio 1.90, 95% CI 1.01 to 3.60, p = 0.049) and serious morbidity (LOS 2 to 4 days: odds ratio 0.86, 95% CI 1.42 to 1.76, p = 0.672) between the short-stay and LOS 2 to 4 days groups. CONCLUSIONS: Although currently performed at low rates in the US, short-stay left colectomy is safe for a select group of patients. Attention to patient selection, refinement of clinical pathways, and close follow-up may enable short-stay colectomies to become a more feasible reality.

Impact of preoperative chemotherapy on perioperative morbidity in combined resection of colon cancer and liver metastases.

BACKGROUND: Preoperative chemotherapy, or neoadjuvant therapy (NAC) can be used to improve resectability but can also have hepatotoxic effects on the future liver remnant. The purpose of this study was to investigate the impact of NAC on 30-day morbidity among patients undergoing a resection of primary colon cancer and synchronous liver metastases (sLM). METHODS: This was a retrospective study using the National Surgical Quality Improvement Program database (2012-2020). The association between NAC and 30-day overall morbidity, the primary outcome, was assessed. Subgroup analyses for low and high-risk procedures were performed. RESULTS: Among 968 patients who underwent the combined resection, 571 (58.99%) received NAC. There was a lower rate of 30-day overall morbidity among patients who received NAC (34.50% vs. 41.56%, p = 0.026) and no difference in rates of postoperative liver failure, bile leak, need for invasive intervention for hepatic procedure, and anastomotic leak. On adjusted analyses, patients who received NAC had decreased odds of overall morbidity (OR 0.73, 95% CI 0.55-0.97, p = 0.031) compared to patients who did not receive NAC. On subgroup analyses, patients who received NAC prior to a low risk combined resection had lower rates of overall morbidity on both adjusted and unadjusted analyses. Among those undergoing high-risk combined resections, there was no difference in overall morbidity. DISCUSSION AND CONCLUSION: Patients who are deemed to be candidates for preoperative chemotherapy can proceed with planned neoadjuvant chemotherapy prior to combined resection of primary colon cancer and sLM as preoperative neoadjuvant chemotherapy does not appear to be associated with increased postoperative morbidity.

Procedure-specific risks of robotic simultaneous resection of colorectal cancer and synchronous liver metastases.

An estimated 25% of patients with colorectal cancer (CRC) present with distant metastases at the time of diagnosis, the most common site being the liver. Although prior studies have reported that a simultaneous approach to resections in these patients can lead to increased rates of complications, emerging literature shows that minimally invasive surgical (MIS) approaches can mitigate this additional morbidity. This is the first study utilizing a large national database to investigate colorectal and hepatic procedure-specific risks in robotic simultaneous resections for CRC and colorectal liver metastases (CRLM). Utilizing the ACS-NSQIP targeted colectomy, proctectomy, and hepatectomy files, 1,721 patients were identified who underwent simultaneous resections of CRC and CRLM from 2016 to 2021. Of these patients, 345 (20%) underwent resections by an MIS approach, defined as either laparoscopic (n = 266, 78%) or robotic (n = 79, 23%). Patients who underwent robotic resections had lower rates of ileus compared to those who had open surgeries. The robotic group had similar rates of 30-day anastomotic leak, bile leak, hepatic failure, and post-operative invasive hepatic procedures compared to both the open and laparoscopic groups. The rate of conversion to open (8% vs. 22%, p = 0.004) and median LOS (5 vs. 6 days, p = 0.022) was significantly lower for robotic compared to laparoscopic group. This study, which is the largest national cohort of simultaneous CRC and CRLM resections, supports the safety and potential benefits of a robotic approach in these patients.

Factors associated with not undergoing surgery for locally advanced rectal cancers: An NCDB propensity-matched analysis.

BACKGROUND: The traditional treatment paradigm for patients with locally advanced rectal cancers has been neoadjuvant chemoradiation followed by curative intent surgery and adjuvant chemotherapy. This study aimed to assess surgery trends for locally advanced rectal cancers, factors associated with forgoing surgery, and overall survival outcomes. METHODS: Adults with locally advanced rectal cancers were retrospectively analyzed using the National Cancer Database (2004-2019). Propensity score matching was performed. Factors associated with not undergoing surgery were identified using multivariable logistic regression. Kaplan-Meier and log-rank tests were used for 5-year overall survival analysis, stratified by stage and treatment type. RESULTS: A total of 72,653 patients were identified, with 64,396 (88.64%) patients undergoing neoadjuvant + surgery ± adjuvant therapy, 579 (0.80%) chemotherapy only, 916 (1.26%) radiation only, and 6,762 (9.31%) chemoradiation only. The proportion of patients who underwent surgery declined over the study period (95.61% in 2006 to 92.29% in 2019, P trend < .001), whereas the proportion of patients who refused surgery increased (1.45%-4.48%, P trend < .001). Factors associated with not undergoing surgery for locally advanced rectal cancers included older age, Black race (odds ratio 1.47, 95% CI 1.35-1.60, P < .001), higher Charlson-Deyo score (score ≥3: 1.79, 1.58-2.04, P < .001), stage II cancer (1.22, 1.17-1.28, P < .001), lower median household income, and non-private insurance. Neoadjuvant + surgery ± adjuvant therapy was associated with the best 5-year overall survival, regardless of stage, in unmatched and matched cohorts. CONCLUSION: Despite surgery remaining an integral component in the management of locally advanced rectal cancers, there is a concerning decline in guideline-concordant surgical care for rectal cancer in the United States, with evidence of persistent socioeconomic disparities. Providers should seek to understand patient perspectives/barriers and guide them toward surgery if appropriate candidates. Continued standardization, implementation, and evaluation of rectal cancer care through national accreditation programs are necessary to ensure that all patients receive optimal treatment.

Feasibility of robotic multivisceral resections in colorectal cancer patients: a NSQIP-based study.

Multivisceral robotic surgery may be an alternative to sequential procedures in select patients with colorectal cancer who are diagnosed with synchronous lesions or in those who require additional procedures at the time of resection. The aim of this study was to assess utilization of the robot for multivisceral resections and compare the surgical outcomes of this approach to laparoscopic resections. Adult colorectal surgery patients who underwent a colectomy or proctectomy and a concurrent abdominal surgery procedure in the American College of Surgeons NSQIP database (2016-2021) were included. The primary outcomes were 30-day postoperative overall and serious morbidity. Factors associated with morbidity were assessed using a multivariable logistic regression. Of the 3875 patients who underwent simultaneous multivisceral resections, 397 (10.3%) underwent a robotic approach and 962 (24.8%) a laparoscopic approach. Gynecological procedures (38%) comprised the largest proportion of concurrent procedures followed by hepatic resections (18%). On unadjusted analysis, rates of overall morbidity (25.4% vs. 30.0%) and serious morbidity (12.1% vs 12.0%) did not differ between the robotic and laparoscopic approach groups, respectively. The rate of conversion to open was lower for the robotic compared to laparoscopic approach (9.3% vs. 28.8%, p < 0.001), and length of stay was shorter (4 vs. 5, p < 0.001). On adjusted analysis, there was no significant difference in overall (OR 0.87, 95% CI 0.65-1.16, p = 0.34) or serious morbidity (OR 1.12, 95% CI 0.75-1.65, p = 0.59) between the two approaches even after concurrent procedure risk stratification. Robotic multivisceral resections can be performed with acceptable overall and serious morbidity in select patients with colorectal cancer. Rates of conversion and length of stay may be decreased with a robotic approach, and future research is needed to determine the optimal operative approach in this patient population.

Procedure-Specific Risks of Robotic Simultaneous Resection of Colorectal Cancer and Synchronous Liver Metastases.

An estimated 25% of patients with colorectal cancer (CRC) present with distant metastases at the time of diagnosis, the most common site being the liver. Controversy exists regarding the safety of a simultaneous versus staged approach to resections in these patients, but reports have shown that minimally invasive surgery (MIS) approaches can mitigate morbidity. This is the first study utilizing a large national database to investigate colorectal and hepatic procedure-specific risks in robotic simultaneous resections for CRC and colorectal liver metastases (CRLM). Utilizing the ACS-NSQIP targeted colectomy, proctectomy, and hepatectomy files, 1,550 patients were identified who underwent simultaneous resections of CRC and CRLM from 2016-2020. Of these patients, 311 (20%) underwent resections by an MIS approach, defined as an either laparoscopic (n = 241, 78%) or robotic (n = 70, 23%). Patients who underwent robotic resections had lower rates of ileus compared to those who had an open surgery. The robotic group had similar rates of 30-day anastomotic leak, bile leak, hepatic failure, and post operative invasive hepatic procedures compared to both the open and laparoscopic groups. The rate of conversion to open was significantly lower for robotic compared to laparoscopic group (9% vs. 22%, p = 0.012). This report is the largest study to date of robotic simultaneous CRC and CRLM resections reported in the literature and supports the safety and potential benefits of this approach.

HMGA1 induces FGF19 to drive pancreatic carcinogenesis and stroma formation.

High mobility group A1 (HMGA1) chromatin regulators are upregulated in diverse tumors where they portend adverse outcomes, although how they function in cancer remains unclear. Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors characterized by dense desmoplastic stroma composed predominantly of cancer-associated fibroblasts and fibrotic tissue. Here, we uncover an epigenetic program whereby HMGA1 upregulates FGF19 during tumor progression and stroma formation. HMGA1 deficiency disrupts oncogenic properties in vitro while impairing tumor inception and progression in KPC mice and subcutaneous or orthotopic models of PDAC. RNA sequencing revealed HMGA1 transcriptional networks governing proliferation and tumor-stroma interactions, including the FGF19 gene. HMGA1 directly induces FGF19 expression and increases its protein secretion by recruiting active histone marks (H3K4me3, H3K27Ac). Surprisingly, disrupting FGF19 via gene silencing or the FGFR4 inhibitor BLU9931 recapitulates most phenotypes observed with HMGA1 deficiency, decreasing tumor growth and formation of a desmoplastic stroma in mouse models of PDAC. In human PDAC, overexpression of HMGA1 and FGF19 defines a subset of tumors with extremely poor outcomes. Our results reveal what we believe is a new paradigm whereby HMGA1 and FGF19 drive tumor progression and stroma formation, thus illuminating FGF19 as a rational therapeutic target for a molecularly defined PDAC subtype.