Outcomes of the Ross procedure in patients older versus younger than 50 years old.

OBJECTIVES: The Ross procedure is traditionally considered for young adult patients with aortic valve disease. This study compares long-term outcomes of patients undergoing the Ross procedure who are ≥50 and <50-years old. METHODS: Data were collected from 225 patients undergoing Ross procedure at a single centre from 1994 to 2019. Patients were categorized into younger (<50-years old; n = 156) and older (≥50-years old; n = 69) cohorts. Baseline demographics clinical outcomes were compared. RESULTS: The mean age was 36 ± 8.1 and 55 ± 4.2 years in the younger and older cohort, respectively. Both groups were predominantly male (58.5% vs 69.6%; P = 0.59). The younger group had a higher rate of aortic insufficiency (51% vs 26.1%; P < 0.01), and bicuspid aortic valve (81.4% vs 58.0%; P < 0.01). Aortic stenosis was more prevalent in the older cohort (25.6% vs 58.0%; P < 0.01). Operative mortality was acceptable in both groups (1.3% vs 4.3%; P = 0.15). Survival up to 10 years was not statistically different between 2 groups (96.2% vs 91.3% P = 0.16), whereas survival up to 15 years for younger patients was significantly higher (94.9% vs 85.5%; P = 0.03). After non-cardiac related deaths were excluded, survival up to 15 years (98.7% vs 91.3%; P = 0.02) was significantly lower than younger patients. In both groups, survival after the Ross procedure was similar to the age- and sex-matched US population. CONCLUSIONS: Survival up to 10 years after Ross procedure were similar, but up to 15 years was significantly higher in younger patients. The Ross procedure restored patients from both groups to expected survival. Our results suggest that at experienced centres, the Ross procedure is a safe and reasonable option for patients who are 50 years and older.

Race, neighborhood disadvantage, and survival of Medicare beneficiaries after aortic valve replacement and concomitant coronary artery bypass grafting.

BACKGROUND: Race, neighborhood disadvantage, and the interaction between these 2 social determinants of health remain poorly understood with regards to survival after aortic valve replacement with concomitant coronary artery bypass grafting (AVR+CABG). METHODS: Weighted Kaplan-Meier survival analyses and Cox proportional hazards modeling were used to evaluate the association between race, neighborhood disadvantage, and long-term survival in 205,408 Medicare beneficiaries undergoing AVR+CABG from 1999 to 2015. Neighborhood disadvantage was measured using the Area Deprivation Index, a broadly validated ranking of socioeconomic contextual disadvantage. RESULTS: Self-identified race was 93.9% White and 3.2% Black. Residents of the most disadvantaged quintile of neighborhoods included 12.6% of all White beneficiaries and 40.0% of all Black beneficiaries. Black beneficiaries and residents of the most disadvantaged quintile of neighborhoods had more comorbidities compared with White beneficiaries and residents of the least disadvantaged quintile of neighborhoods, respectively. Increasing neighborhood disadvantage linearly increased the hazard for mortality for Medicare beneficiaries of White but not Black race. Residents of the most and least disadvantaged neighborhood quintiles had weighted median overall survival of 93.0 and 82.1 months, respectively, a significant difference (P < .001 by Cox test for equality of survival curves). Black and White beneficiaries had weighted median overall survival of 93.4 and 90.6 months, respectively, a nonsignificant difference (P = .29 by Cox test for equality of survival curves). A statistically significant interaction between race and neighborhood disadvantage was noted (likelihood ratio test P = .0215) and had implications on whether Black race was associated with survival. CONCLUSIONS: Increasing neighborhood disadvantage was linearly associated with worse survival after combined AVR+CABG in White but not Black Medicare beneficiaries; race, however, was not independently associated with postoperative survival.

Vein Graft Use and Long-Term Survival Following Coronary Bypass Grafting.

BACKGROUND: Although placement of at least 1 arterial graft during coronary artery bypass grafting (CABG) has a proven survival benefit, it is unknown what degree of revascularization with saphenous vein grafting (SVG) is associated with improved survival. OBJECTIVES: The authors sought to determine whether undergoing surgery performed by a surgeon who is liberal with vein graft utilization is associated with improved survival in patients undergoing single arterial graft CABG (SAG-CABG). METHODS: This was a retrospective, observational study of SAG-CABG performed in Medicare beneficiaries from 2001 to 2015. Surgeons were stratified by number of SVG utilized per SAG-CABG into conservative (≥1 SD below mean), average (within 1 SD of mean), and liberal (≥1 SD above mean). Long-term survival was estimated using Kaplan-Meier analysis and compared among surgeon groups before and after augmented inverse-probability weighting. RESULTS: There were 1,028,264 Medicare beneficiaries undergoing SAG-CABG from 2001 to 2015 (mean age 72.0 ± 7.9 years, 68.3% male). Over time, 1-vein and 2-vein SAG-CABG utilization increased, whereas 3-vein and ≥4-vein SAG-CABG utilization decreased (P < 0.001). Surgeons who were conservative vein graft users performed a mean 1.7 ± 0.2 vein grafts per SAG-CABG, whereas those who were liberal vein graft users performed a mean 2.9 ± 0.2 vein grafts per SAG-CABG. Weighted analysis demonstrated no difference in median survival among patients undergoing SAG-CABG by liberal vs conservative vein graft users (adjusted median survival difference 27 days). CONCLUSIONS: Among Medicare beneficiaries undergoing SAG-CABG, there is no association between surgeon proclivity for vein graft utilization and long-term survival, suggesting that a conservative approach to vein graft utilization is reasonable.

Contemporary Outcomes of Isolated Tricuspid Valve Surgery.

INTRODUCTION: Isolated tricuspid valve (TV) surgery is uncommonly performed and has historically been associated with excessive operative mortality. We previously reported improved short-term outcomes at our center. Understanding contemporary outcomes of isolated TV surgery beyond the perioperative period is essential to properly benchmark outcomes of newer transcatheter interventions. METHODS: Patients who underwent isolated TV surgery from 2007 to 2021 at a single institution were retrospectively reviewed. Survival was estimated using the Kaplan-Meier method and multivariable Cox proportional hazards regression modeling identified independent risk factors for all-cause mortality. RESULTS: Among 173 patients undergoing isolated TV surgery, 103 (60%) underwent TV repair and 70 (40%) underwent TV replacement. Mean age was 60.3 ± 18.9 y and 55 (32%) were male. The most common etiology of TV disease was functional (46%). In-hospital mortality was 4.1% (7/173), with no difference between TV repair and replacement (P = 0.06). Overall survival at 1 y and 5 y was 78.3% (111/142) and 64.5% (53/82), respectively. After median (interquartile range) follow-up of 2.0 (0.6-4.4) y, patients undergoing TV repair experienced a higher unadjusted survival as compared to those undergoing TV replacement (log-rank P = 0.02). However, after adjusting for covariates, TV replacement was not an independent predictor of all-cause mortality (hazard ratio 1.40; 95% confidence interval, 0.71-2.76; P = 0.33). CONCLUSIONS: Isolated TV surgery can be performed with lower operative mortality than historically reported. Establishing survival benchmarks from TV surgery is important in the era of developing transcatheter interventions.

Surgical treatment of infective endocarditis at comprehensive versus primary valve centers.

BACKGROUND: A recent expert consensus statement proposed designation of comprehensive and primary valve centers, with a recommendation that comprehensive centers house surgical skill and resources to treat patients with infective endocarditis (IE). We sought to compare outcomes of patients who underwent valve surgery for IE at comprehensive versus primary valve centers within a large health care system. METHODS: We reviewed 513 consecutive patients who underwent IE surgery at 8 hospitals (2 comprehensive and 6 primary valve centers) from 2014 to 2020. Outcomes from comprehensive and primary valve centers were compared after propensity score matching on the basis of patient characteristics, valve involvement, valve type, and IE treatment status. Multivariate logistic regression was used to identify risk factors for operative mortality. RESULTS: Propensity score matching generated comparable groups with similar mean Society of Thoracic Surgeons/Gaca IE risk scores among comprehensive and primary valve center cohorts. Comprehensive valve centers were more likely to perform the Bentall procedure (60.4% vs 21.7%; P < .01) when aortic root abscess was present and mitral valve repair (50.4% vs 26.3%; P < .01) in cases of mitral valve involvement. Operative mortality was significantly lower at comprehensive valve centers (6.2% vs 13.0%; P = .04), and multivariate logistic regression suggested that surgery at comprehensive valve centers was protective against operative mortality (odds ratio, 0.39; 95% confidence interval, 0.17-0.88; P = .02). Similar findings were present in a sensitivity analysis limited to patients with active IE only. CONCLUSIONS: An increased risk for operative mortality was associated with surgery performed at primary valve centers compared with comprehensive valve centers. Referral or transfer of patients with IE and surgical indications to comprehensive valve centers should be considered.

Bloodstream and respiratory coinfections in patients with COVID-19 on ECMO.

BACKGROUND: Although several studies have characterized the risk of coinfection in COVID pneumonia, the risk of the bloodstream and respiratory coinfection in patients with COVID-19 pneumonia on extracorporeal membrane oxygenation (ECMO) supports severe acute respiratory distress syndrome (ARDS) is poorly understood. METHODS: This is a retrospective analysis of patients with COVID-19 ARDS on ECMO at a single center between January 2020 and December 2021. Patient characteristics and clinical outcomes were compared. RESULTS: Of 44 patients placed on ECMO support for COVID-19 ARDS, 30 (68.2%) patients developed a coinfection, and 14 (31.8%) patients did not. Most patients underwent venovenous ECMO (98%; 43/44) cannulation in the right internal jugular vein (98%; 43/44). Patients with coinfection had a longer duration of ECMO (34 [interquartile range, IQR: 19.5, 65] vs. 15.5 [IQR 11, 27.3] days; p = .02), intensive care unit (ICU; 44 [IQR: 27,75.5] vs 31 [IQR 20-39.5] days; p = .03), and hospital (56.5 [IQR 27,75.5] vs 37.5 [IQR: 20.5-43.3]; p = .02) length of stay. When stratified by the presence of a coinfection, there was no difference in hospital mortality (37% vs. 29%; p = .46) or Kaplan-Meier survival (logrank p = .82). Time from ECMO to first positive blood and respiratory culture were 12 [IQR: 3, 28] and 10 [IQR: 1, 15] days, respectively. Freedom from any coinfection was 50 (95% confidence interval: 37.2-67.2)% at 15 days from ECMO initiation. CONCLUSIONS: There is a high rate of co-infections in patients placed on ECMO for COVID-19 ARDS. Although patients with coinfections had a longer duration of extracorporeal life support, and longer length of stays in the ICU and hospital, survival was not inferior.

A Liquid Biopsy Signature for the Detection of Patients With Early-Onset Colorectal Cancer.

BACKGROUND & AIMS: Early-onset colorectal cancer (EOCRC) is a distinct clinical and molecular entity with poor survival outcomes compared with late-onset CRC. Although the incidence of EOCRC is rising, current CRC screening strategies have several limitations in diagnostic performance for EOCRC. In view of this clinical challenge, novel and robust biomarkers for detection of EOCRC are necessary. The aim of this study was to develop a circulating micro RNA (miRNA) signature for the diagnosis of patients with EOCRC. METHODS: A systematic discovery approach by analyzing a large, publicly available, noncoding RNA expression profiling dataset (GSE115513) was used. A panel of miRNAs was identified, which was subsequently validated in blood samples from patients with EOCRC in 2 independent cohorts (n = 149) compared with controls (n = 110) and pre/postoperative plasma specimens (n = 22) using quantitative reverse-transcription polymerase chain reaction assays. RESULTS: In the discovery phase, 4 miRNAs were found to be expressed in blood samples. A combination signature of these 4 miRNAs (miR-193a-5p, miR-210, miR-513a-5p, and miR-628-3p) yielded an area under the curve of 0.92 (95% confidence interval, 0.85-0.96) for identification of EOCRC in the training cohort. The miRNA panel performance was then confirmed in an independent validation cohort (area under the curve, 0.88; 95% confidence interval, 0.82-0.93). Moreover, the miRNA panel robustly identified patients with early-stage EOCRC (P < .001). The decreased expression of miRNAs in postsurgery plasma specimens indicated their tumor specificity. CONCLUSIONS: Our novel miRNA signature for the diagnosis of EOCRC has the potential to identify patients with EOCRC with high accuracy for clinical application in the noninvasive diagnosis of EOCRC.

Effect of Preincisional Liposomal Bupivacaine Sternal Blockade on Poststernotomy Opioid Use.

BACKGROUND: Prolonged and excessive opioid use in the postoperative setting is associated with multiple complications. The use of regional analgesia may reduce postoperative opioid use. METHODS: In a placebo-controlled, double-blinded trial patients undergoing sternotomy were randomly assigned in a 1:1 ratio to receive either a liposomal bupivacaine parasternal block or a normal saline parasternal injection. The primary endpoint was total morphine milligram equivalents (MMEs) used in the immediate 72-hour postoperative period. Secondary endpoints were intraoperative opioid use, pain scores, time to reach recovery milestones, and incidence of postoperative complications. RESULTS: Twenty-five patients received a normal saline injection, and 27 patients received an anesthetic sternal block. Randomization achieved excellent balance in demographics and comorbidities between the groups. Total postoperative opioid requirements at 72 hours were similar between the treatment and control groups (25.8 ± 10.4 vs 29.4 ± 16.3 MMEs, P = .60). Intraoperative opioid requirements were also similar between the 2 groups (124.8 ± 222.5 vs 114.9 ± 148.0 MMEs, P = .86). Length of stay in the intensive care unit (3.4 ± 2.5 vs 3.5 ± 2.6 days, P = .86) and hospital (8.7 ± 5.0 vs 7.5 ± 3.0 days, P = .45), time until return of bowel function (3.7 ± 1.4 vs 3.3 ± 1.4 days, P = .42), incidence of postoperative atrial fibrillation (24% vs 22.2%, P = .88), and incidence of nausea (24% vs 33.3%, P = .46) were similar. CONCLUSIONS: Preincisional sternal blockade with liposomal bupivacaine did not reduce the amount of opioid medication administered to patients in the first 72 hours after sternotomy.

Long-Term Survival After On-Pump and Off-Pump Coronary Artery Bypass Grafting.

BACKGROUND: Off-pump coronary artery bypass grafting (CABG) may be associated with increased hazard for long-term mortality as compared with on-pump CABG. We sought to evaluate risk-adjusted long-term survival after off-pump and on-pump CABG, particularly among high-volume and low-volume CABG surgeons. METHODS: We evaluated 1,235,089 isolated CABGs (off pump = 209,085; on pump = 1,026,004) performed in Medicare beneficiaries from 2001 to 2015. Long-term hazard for mortality after off-pump versus on-pump CABG was compared with Kaplan-Meier and log-rank analysis among all CABG surgeons as well as among high-volume and low-volume CABG surgeons, before and after inverse probability of treatment weighting to adjust for confounding. RESULTS: Among all surgeons, off-pump CABG was associated with a statistically significant hazard for mortality as compared with on-pump CABG before and after inverse probability of treatment weighting (median survival: off pump 9.8 years vs on pump 10.2 years; difference in median survival -134 days; log-rank P < .001). Cox regression analysis confirmed an interaction between surgeon volume and long-term mortality. The hazard for mortality associated with off-pump CABG was decreased among high-volume surgeons (difference in median survival -84 days; log-rank P < .001) and increased among low-volume surgeons (difference in median survival -240 days; long-rank P < .001). CONCLUSIONS: Off-pump CABG was associated with a significant, but clinically modest, increased hazard for mortality as compared with on-pump CABG. The hazard was reduced when off-pump CABG was performed by high-volume CABG surgeons.

Distal Versus Proximal Radial Artery Access for Cardiac Catheterization and Intervention: Design and Rationale of the DIPRA Trial.

BACKGROUND: Radial artery (RA) catheterization is the access of choice over femoral artery access for most interventional vascular procedures given its safety and faster patient recovery. There has been growing interest in distal radial artery (dRA) access as an alternative to the conventional proximal radial artery (pRA) access. Preserving the RA is important which serves as a potential conduit for future coronary artery bypass surgery, dialysis conduit or preserve the artery for future cardiovascular procedures. The dRA runs in close proximity to the radial nerve, which raises the concern of potential detrimental effects on hand function. STUDY DESIGN: The Distal versus Proximal Radial Artery Access for cardiac catheterization and intervention (DIPRA) trial is a prospective, randomized, parallel-controlled, open-label, single center study evaluating the outcomes of hand function and effectiveness of dRA compared to pRA access in patients undergoing cardiac catheterization. The eligible subjects will be randomized to dRA and pRA access in a (1:1) fashion. The primary end point is an evaluation of hand function at one and twelve months follow-up. Secondary end points include rates of access site hematoma, access site bleeding, other vascular access complications, arterial access success rate, and RA occlusion at one and twelve months follow up. CONCLUSION: Effects of dRA on hand function remains unknown and it's use questionable in the presence of a widely accepted pRA. DIPRA trial is designed to determine the safety and effectiveness of dRA for diagnostic and interventional cardiovascular procedures compared to the standard of care pRA.

Venovenous extracorporeal membrane oxygenation for patients with refractory coronavirus disease 2019 (COVID-19): Multicenter experience of referral hospitals in a large health care system.

BACKGROUND: The benefit of extracorporeal membrane oxygenation (ECMO) for patients with severe acute respiratory distress from coronavirus disease 2019 refractory to medical management and lung-protective mechanical ventilation has not been adequately determined. METHODS: We reviewed the clinical course of 37 patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection supported by venovenous ECMO at 4 ECMO referral centers within a large health care system. Patient characteristics, progression of hemodynamics and inflammatory markers, and clinical outcomes were evaluated. RESULTS: The patients had median age of 51 years (interquartile range, 40-59), and 73% were male. Peak plateau pressures, vasopressor requirements, and arterial partial pressure of carbon dioxide all improved with ECMO support. In our patient population, 24 of 37 patients (64.8%) survived to decannulation and 21 of 37 patients (56.8%) survived to discharge. Among patients discharged alive from the ECMO facility, 12 patients were discharged to a long-term acute care or rehabilitation facility, 2 were transferred back to the referring hospital for ventilatory weaning, and 7 were discharged directly home. For patients who were successfully decannulated, median length of time on ECMO was 17 days (interquartile range, 10-33.5). CONCLUSIONS: Venovenous ECMO represents a useful therapy for patients with refractory severe acute respiratory distress syndrome from coronavirus disease 2019.

Minimally invasive mitral valve surgery after previous sternotomy: A propensity-matched analysis.

BACKGROUND: Although the incidence of mitral valve (MV) surgery after previous open-heart surgery is increasing, there is no consensus regarding the optimal surgical approach. Reoperative MV surgery is most commonly performed via sternotomy (ST). We sought to determine whether minimally-invasive (MIS) reoperative MV surgery is safe and feasible. METHODS: All patients with a history of ST undergoing MV surgery with or without concomitant tricuspid or atrial fibrillation surgery at a single institution from 2007 to 2018 were retrospectively reviewed. ST and MIS approaches were compared using propensity-matched analysis. The coprimary endpoints were operative mortality and 1-year survival, and secondary endpoints were operative complications and length of stay. RESULTS: A total of 305 isolated MV reoperations were performed: 199 (65%) MIS and 106 (35%) ST. MIS patients were older than ST patients (71 [63, 76.5] vs. 66 [56, 72] years, p < .01), more likely to have undergone prior coronary artery bypass grafting (57% vs. 27%, p < .01), and less likely to have had prior valve surgery (55% vs. 78%, p < .01). In unmatched comparisons, operative mortality was significantly lower among MIS patients (3.0% vs. 8.5%, p = .04), but 1-year mortality was similar (14.4% vs. 15.6%, p = .8). After propensity matching, 88 pairs had excellent balance across baseline characteristics. Mortality was similar among MIS and ST patients at 30 days (3.4% vs. 8%, p = .19) and 1 year (15.9% vs. 16.5%, p = .9). RBC and fresh frozen plasma transfusions were significantly lower in the MIS group (p < .01). CONCLUSIONS: A minimally invasive approach is a safe alternative in patients with prior ST undergoing MV surgery.

Enhanced anti-cancer activity of andrographis with oligomeric proanthocyanidins through activation of metabolic and ferroptosis pathways in colorectal cancer.

The high degree of morbidity and mortality in colorectal cancer (CRC) patients is largely due to the development of chemoresistance against conventional chemotherapeutic drugs. In view of the accumulating evidence that various dietary botanicals offer a safe, inexpensive and multi-targeted treatment option, herein, we hypothesized that a combination of Andrographis paniculata and Oligomeric Proanthocyanidins (OPCs) might interact together with regard to anti-tumorigenic activity in CRC. As a result, we demonstrated the enhanced anti-cancer activity between these two botanical extracts in terms of their ability to inhibit cancer cell growth, suppress colony formation and induce apoptosis. Furthermore, we validated these findings in subcutaneous xenograft model and in patient derived primary epithelial 3D organoids. Transcriptomic profiling identified involvement of metabolic pathways and ferroptosis-associated genes, including HMOX1, GCLC and GCLM, that may be responsible for the increased anti-tumorigenic activity by the two compounds. Collectively, our study provides novel evidence in support of the combinatorial use of andrographis and OPCs as a potential therapeutic option, perhaps as an adjunctive treatment to classical drugs, in patients with colorectal cancer.

A Transcriptomic Signature for Risk-Stratification and Recurrence Prediction in Intrahepatic Cholangiocarcinoma.

BACKGROUND AND AIMS: Tumor recurrence is frequent even in intrahepatic cholangiocarcinoma (ICC), and improved strategies are needed to identify patients at highest risk for such recurrence. We performed genome-wide expression profile analyses to discover and validate a gene signature associated with recurrence in patients with ICC. APPROACH AND RESULTS: For biomarker discovery, we analyzed genome-wide transcriptomic profiling in ICC tumors from two public data sets: The Cancer Genome Atlas (n = 27) and GSE107943 (n = 28). We identified an eight-gene panel (BIRC5 [baculoviral IAP repeat containing 5], CDC20 [cell division cycle 20], CDH2 [cadherin 2], CENPW [centromere protein W], JPH1 [junctophilin 1], MAD2L1 [mitotic arrest deficient 2 like 1], NEIL3 [Nei like DNA glycosylase 3], and POC1A [POC1 centriolar protein A]) that robustly identified patients with recurrence in the discovery (AUC = 0.92) and in silico validation cohorts (AUC = 0.91). We next analyzed 241 specimens from patients with ICC (training cohort, n = 64; validation cohort, n = 177), followed by Cox proportional hazard regression analysis, to develop an integrated transcriptomic panel and establish a risk-stratification model for recurrence in ICC. We subsequently trained this transcriptomic panel in a clinical cohort (AUC = 0.89; 95% confidence interval [CI] = 0.79-0.95), followed by evaluating its performance in an independent validation cohort (AUC = 0.86; 95% CI = 0.80-0.90). By combining our transcriptomic panel with various clinicopathologic features, we established a risk-stratification model that was significantly superior for the identification of recurrence (AUC = 0.89; univariate HR = 6.08, 95% CI = 3.55-10.41, P < 0.01; and multivariate HR = 3.49, 95% CI = 1.81-6.71, P < 0.01). The risk-stratification model identified potential recurrence in 85% of high-risk patients and nonrecurrence in 76% of low-risk patients, which is dramatically superior to currently used pathological features. CONCLUSIONS: We report a transcriptomic signature for risk-stratification and recurrence prediction that is superior to currently used clinicopathological features in patients with ICC.

Andrographis-mediated chemosensitization through activation of ferroptosis and suppression of ß-catenin/Wnt-signaling pathways in colorectal cancer.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality in the USA. As much as 50-60% of CRC patients develop resistance to 5-fluorouracil (5FU)-based chemotherapeutic regimens, attributing the increased overall morbidity and mortality. In view of the growing evidence that active principles in various naturally occurring botanicals can facilitate chemosensitization in cancer cells, herein, we undertook a comprehensive effort in interrogating the activity of one such botanical-andrographis-by analyzing its activity in CRC cell lines [both sensitive and 5FU resistant (5FUR)], a xenograft animal model and patient-derived tumor organoids. We observed that combined treatment with andrographis was synergistic and resulted in a significant and dose-dependent increase in the efficacy of 5FU in HCT116 and SW480 5FUR cells (P < 0.05), reduced clonogenic formation (P < 0.01) and increased rates of caspase-9-mediated apoptosis (P < 0.05). The genomewide expression analysis in cell lines led us to uncover that activation of ferroptosis and suppression of ß-catenin/Wnt-signaling pathways were the key mediators for the anti-cancer and chemosensitizing effects of andrographis. Subsequently, we validated our findings in a xenograft animal model, as well as two independent CRC patient-derived organoids-which confirmed that combined treatment with andrographis was significantly more effective than 5FU and andrographis alone and that these effects were in part orchestrated through dysregulated expression of key genes (including HMOX1, GCLC, GCLM and TCF7L2) within the ferroptosis and Wnt-signaling pathways. Collectively, our data highlight that andrographis might offer a safe and inexpensive adjunctive therapeutic option in the management of CRC patients.

A MicroRNA Signature Identifies Pancreatic Ductal Adenocarcinoma Patients at Risk for Lymph Node Metastases.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinomas (PDACs) frequently metastasize to the lymph nodes; strategies are needed to identify patients at highest risk for lymph node metastases. We performed genome-wide expression profile analyses of PDAC specimens, collected during surgery or endoscopic ultrasound-guided fine-need aspiration (EUS-FNA), to identify a microRNA (miRNA) signature associated with metastasis to lymph nodes. METHODS: For biomarker discovery, we analyzed miRNA expression profiles of primary pancreatic tumors from 3 public data sets (The Cancer Genome Atlas, GSE24279, and GSE32688). We then analyzed 157 PDAC specimens (83 from patients with lymph node metastases and 74 without) from Japan, collected from 2001 through 2017, for the training cohort and 107 PDAC specimens (63 from patients with lymph node metastases and 44 without) from a different medical center in Japan, from 2002 through 2016, for the validation cohort. We also analyzed samples collected by EUS-FNA before surgery from 47 patients (22 patients with lymph node metastases and 25 without; 17 for the training cohort and 30 from the validation cohort) and 62 specimens before any treatment from patients who received neoadjuvant chemotherapy (9 patients with lymph node metastasis and 53 without) for additional validation. Multivariate logistic regression analyses were used to evaluate the statistical differences in miRNA expression between patients with vs without metastases. RESULTS: We identified an miRNA expression pattern associated with diagnosis of PDAC metastasis to lymph nodes. Using logistic regression analysis, we optimized and trained a 6-miRNA risk prediction model for the training cohort; this model discriminated patients with vs without lymph node metastases with an area under the curve (AUC) of 0.84 (95% confidence interval [CI], 0.77-0.89). In the validation cohort, the model identified patients with vs without lymph node metastases with an AUC of 0.73 (95% CI, 0.64-0.81). In EUS-FNA biopsy samples, the model identified patients with vs without lymph node metastases with an AUC of 0.78 (95% CI, 0.63-0.89). The miRNA expression pattern was an independent predictor of PDAC metastasis to lymph nodes in the validation cohort (odds ratio, 17.05; 95% CI, 2.43-119.57) and in the EUS-FNA cohort (95% CI, 0.65-0.87). CONCLUSIONS: Using data and tumor samples from 3 independent cohorts, we identified an miRNA signature that identifies patients at risk for PDAC metastasis to lymph nodes. The signature has similar levels of accuracy in the analysis of resected tumor specimens and EUS-FNA biopsy specimens. This model might be used to select treatment and management strategies for patients with PDAC.

A 15-Gene Immune, Stromal, and Proliferation Gene Signature that Significantly Associates with Poor Survival in Patients with Pancreatic Ductal Adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with dismal survival rates. Tumor microenvironment (TME), comprising of immune cells and cancer-associated fibroblasts, plays a key role in driving poor prognosis and resistance to chemotherapy. Herein, we aimed to identify a TME-associated, risk-stratification gene biomarker signature in PDAC. EXPERIMENTAL DESIGN: The initial biomarker discovery was performed in The Cancer Genome Atlas (TCGA, n = 163) transcriptomic data. This was followed by independent validation of the gene signature in the International Cancer Genome Consortium (ICGC, n = 95), E-MTAB-6134 (n = 288), and GSE71729 (n = 123) datasets for predicting overall survival (OS), and for its ability to detect poor molecular subtypes. Clinical validation and nomogram establishment was undertaken by performing multivariate Cox regression analysis. RESULTS: Our biomarker discovery effort identified a 15-gene immune, stromal, and proliferation (ISP) gene signature that significantly associated with poor OS [HR, 3.90; 95% confidence interval (CI), 2.36-6.41; P < 0.0001]. This signature also robustly predicted survival in three independent validation cohorts ICGC [HR, 2.63 (1.56-4.41); P < 0.0001], E-MTAB-6134 [HR, 1.53 (1.14-2.04); P = 0.004], and GSE71729 [HR, 2.33 (1.49-3.63); P < 0.0001]. Interestingly, the ISP signature also permitted identification of poor molecular PDAC subtypes with excellent accuracy in all four cohorts; TCGA (AUC = 0.94), ICGC (AUC = 0.91), E-MTAB-6134 (AUC = 0.80), and GSE71729 (AUC = 0.83). The ISP-derived high-risk patients exhibited significantly poor OS in a clinical validation cohort [n = 119; HR, 2.62 (1.50-4.56); P = 0.0004]. A nomogram was established which included the ISP, CA19-9, and T- and N-stage for eventual clinical translation. CONCLUSIONS: We report a novel gene signature for risk-stratification and robust identification of patients with PDAC with poor molecular subtypes.

Pan-Cancer Analysis Reveals the Diverse Landscape of Novel Sense and Antisense Fusion Transcripts.

Gene fusions that contribute to oncogenicity can be explored for identifying cancer biomarkers and potential drug targets. To investigate the nature and distribution of fusion transcripts in cancer, we examined the transcriptome data of about 9,000 primary tumors from 33 different cancers in TCGA (The Cancer Genome Atlas) along with cell line data from CCLE (Cancer Cell Line Encyclopedia) using ChimeRScope, a novel fusion detection algorithm. We identified several fusions with sense (canonical, 39%) or antisense (non-canonical, 61%) transcripts recurrent across cancers. The majority of the recurrent non-canonical fusions found in our study are novel, unexplored, and exhibited highly variable profiles across cancers, with breast cancer and glioblastoma having the highest and lowest rates, respectively. Overall, 4,344 recurrent fusions were identified from TCGA in this study, of which 70% were novel. Additional analysis of 802 tumor-derived cell line transcriptome data across 20 cancers revealed significant variability in recurrent fusion profiles between primary tumors and corresponding cell lines. A subset of canonical and non-canonical fusions was validated by examining the structural variation evidence in whole-genome sequencing (WGS) data or by Sanger sequencing of fusion junctions. Several recurrent fusion genes identified in our study show promise for drug repurposing in basket trials and present opportunities for mechanistic studies.