Citations

AbstractBackgroundLeft ventricular assist device (LVAD) implantation is frequently employed in patients with end‐stage heart failure. The outcomes of addressing the repair of all substantial aortic valvular disease at the time of LVAD implantation remain unclear. We sought to assess the clinical outcomes in patients undergoing LVAD implantation concomitant with aortic valve procedures (AVPs) compared with isolated LVAD implantation.MethodsA literature search was performed using PubMed, Embase, and Cochrane library from inception till June 2022. Primary outcomes included short‐term mortality and long‐term survival. Random effects models were used to compute mean differences and odds ratios with 95% confidence intervals (CIs).ResultsA total of 14 observational studies (N = 52 693) met our inclusion criteria. Concomitant LVAD implantation and AVPs were associated with higher short‐term mortality (OR = 1.61 [95% CI, 1.06–2.42]; p = 0.02) and mean CPBt (MD = 43.25 [95% CI, 22.95–63.56]; p < 0.0001), and reduced long‐term survival (OR = 0.70 [95% CI, 0.55–0.88]; p = 0.003) compared with isolated LVAD implantation. No difference in the odds of cerebrovascular accident (OR = 1.05 [95% CI, 0.79–1.39]; p = 0.74) and mean length of hospital stay (MD = 2.89 [95% CI, −4.04 to 9.82]; p = 0.41) was observed between the two groups. On adjusted analysis, short‐term mortality was significantly higher in the LVAD group with concurrent AVPs when compared with the isolated LVAD group (aHR = 1.50 [95% CI, 1.20–1.87]; p = 0.0004).ConclusionsConcurrent AVPs were associated with higher short‐term mortality and reduced long‐term survival in patients undergoing LVAD implantation compared with isolated LVAD implantation.

PURPOSE We sought to evaluate the independent and interactive associations of planned treatment duration, celecoxib use, physical activity, body mass index (BMI), diabetes mellitus, and vitamin B6 with oxaliplatin-induced peripheral neuropathy (OIPN) among patients with stage III colon cancer enrolled in a clinical trial. METHODS We conducted a prospective, observational study of 2,450 patients with stage III colon cancer enrolled in the CALGB/SWOG 80702 trial, randomly assigned to 6 versus 12 cycles of adjuvant fluorouracil, leucovorin, and oxaliplatin chemotherapy with or without 3 years of celecoxib. OIPN was reported using the Common Terminology Criteria for Adverse Events (CTCAE) during and following completion of chemotherapy and the FACT/GOG-NTX-13 15-17 months after random assignment. Multivariate analyses were adjusted for baseline sociodemographic and clinical factors. RESULTS Patients assigned to 12 treatment cycles, relative to 6, were significantly more likely to experience higher-grade CTCAE- and FACT/GOG-NTX-13-reported neuropathy and longer times to resolution, while neither celecoxib nor vitamin B6 intake attenuated OIPN. Exercising ≥ 9 MET-hours per week after treatment relative to < 9 was associated with improvements in FACT/GOG-NTX-13-reported OIPN (adjusted difference in means, 1.47; 95% CI, 0.49 to 2.45; P = .003). Compared with patients with baseline BMIs < 25, those with BMIs ≥ 25 were at significantly greater risk of developing higher-grade CTCAE-reported OIPN during (adjusted odds ratio, 1.18; 95% CI, 1.00 to 1.40; P = .05) and following completion (adjusted odds ratio, 1.23; 95% CI, 1.01 to 1.50; P = .04) of oxaliplatin treatment. Patients with diabetes were significantly more likely to experience worse FACT/GOG-NTX-13-reported neuropathy relative to those without (adjusted difference in means, –2.0; 95% CI, –3.3 to –0.73; P = .002). There were no significant interactions between oxaliplatin treatment duration and any of these potentially modifiable exposures. CONCLUSION Lower physical activity, higher BMI, diabetes, and longer planned treatment duration, but not celecoxib use or vitamin B6 intake, may be associated with significantly increased OIPN severity.

PURPOSE To determine the specific types, durations, and intensities of recreational physical activity associated with the greatest improvements in disease-free survival (DFS) of patients with colon cancer. METHODS We conducted a prospective cohort study nested within a randomized multicenter trial of stage III colon cancer that compared 3 versus 6 months of fluorouracil, leucovorin, and oxaliplatin with or without celecoxib. We measured recreational physical activity in the first 3 months of chemotherapy and again 6 months after completion of chemotherapy. The primary end point was DFS. RESULTS During a median follow-up of 5.9 years, 457 of 1,696 patients experienced disease recurrence or death. For total recreational physical activity volume, the 3-year DFS was 76.5% with < 3.0 metabolic equivalent task hours per week (MET-h/wk) and 87.1% with ≥ 18.0 MET-h/wk (risk difference [RD], 10.6%; 95% CI, 4.7 to 19.4; P < .001). For light-intensity to moderate-intensity activities, the 3-year DFS was 65.7% with 0.0 h/wk and 87.1% with ≥ 1.5 h/wk (RD, 21.4%; 95% CI, 9.2 to 37.1; P < .001). For vigorous-intensity activity, the 3-year DFS was 76.0% with 0.0 h/wk and 86.0% with ≥ 1.0 h/wk (RD, 10.0%; 95% CI, 4.5 to 18.9; P < .001). For brisk walking, the 3-year DFS was 81.7% with < 1.0 h/wk and 88.4% with ≥ 3.0 h/wk (RD, 6.7%; 95% CI, 3.0 to 13.8; P < .001). For muscle strengthening activity, the 3-year DFS was 81.8% with 0.0 h/wk and 88.8% for ≥ 0.5 h/wk (RD, 7.0%; 95% CI, 3.1 to 14.2; P = .003). CONCLUSION Among patients with stage III colon cancer enrolled in a trial of postoperative treatment, larger volumes of recreational physical activity, longer durations of light- to moderate-intensity aerobic physical activity, or any vigorous-intensity aerobic physical activity were associated with the greatest improvements in DFS.

Abstract Chronic inflammation is a well-established carcinogenic pathway for colorectal cancer (CRC), but the role of inflammation in CRC prognosis is not well understood. Since cytokines are central in extensive biological networks to regulate inflammation, it is of great importance to investigate inflammatory cytokines and CRC survival. Among an NCI-sponsored adjuvant chemotherapy trial for patients with stage III colon cancer conducted between 2010 and 2015 (CALGB/SWOG 80702), we collected serum samples from 1,498 participants at a median of 1.6 months (interquartile [IQR]: 1.3-1.9 months) after surgery. IL-6, TNFR2, and hsCRP were assayed as biomarkers of chronic inflammation and were categorized into quintiles. The primary outcome was disease-free survival, defined as time from randomization to recurrence or death from any cause. Secondary outcomes included overall survival and time to recurrence. We estimated the associations of inflammatory biomarkers with survival using multivariable Cox proportional hazards regression. Of 1,498 participants (median follow-up: 5.9 years), mean age was 61.3 years, 82.2% were White, 55.5% were male, and 387 experienced recurrence or death. Medians (IQRs) of biomarkers were 2.6mg/L (1.2-5.6mg/L) for IL-6, 2.9×103pg/mL (2.3-3.6×103pg/mL) for TNFR2, and 2.6mg/L (1.2-5.6mg/L) for hsCRP. Compared to the lowest quintile (Q1), the highest quintile (Q5) in inflammatory biomarkers was significantly associated with worse disease-free survival (hazard ratios were 1.52 [95% CI, 1.08-2.15] for IL-6, 1.76 [95% CI, 1.22-2.54] for TNFR2, and 1.66 [95% CI, 1.17-2.35] for hsCRP). Similar patterns were observed for overall survival and time to recurrence. Our findings suggest that higher levels of inflammation after diagnosis were significantly associated with worse survival among those with stage III colon cancer, and reducing inflammation may be considered as a potential intervention to improve CRC survival. ‬‬ Associations of Inflammatory Biomarkers with Survival after Adjustment for Clinicopathologic Factors Q1 Q2 Q3 Q4 Q5 P for Trend Disease-free survival IL-6 1.00 1.14 (0.80-1.62) 1.37 (0.97-1.94) 1.44 (1.02-2.03) 1.52 (1.08-2.15) 0.02 TNFR2 1.00 1.21 (0.84-1.74) 1.43 (0.99-2.05) 1.56 (1.09-2.25) 1.76 (1.22-2.54) 0.002 hsCRP 1.00 1.34 (0.95-1.90) 1.62 (1.15-2.29) 1.26 (0.88-1.80) 1.66 (1.17-2.35) 0.04 Overall survival IL-6 1.00 1.44 (0.91-2.29) 1.56 (0.98-2.48) 1.48 (0.93-2.34) 1.68 (1.07-2.65) 0.09 TNFR2 1.00 1.57 (0.94-2.63) 1.88 (1.13-3.13) 1.92 (1.15-3.20) 2.31 (1.39-3.84) 0.003 hsCRP 1.00 1.27 (0.81-2.00) 1.72 (1.11-2.65) 1.22 (0.77-1.92) 1.73 (1.12-2.69) 0.06 Time to recurrence IL-6 1.00 1.34 (0.92-1.95) 1.48 (1.01-2.16) 1.55 (1.06-2.27) 1.54 (1.05-2.26) 0.07 TNFR2 1.00 1.14 (0.78-1.67) 1.28 (0.87-1.87) 1.48 (1.01-2.16) 1.54 (1.04-2.27) 0.02 hsCRP 1.00 1.27 (0.87-1.83) 1.64 (1.14-2.36) 1.21 (0.82-1.77) 1.55 (1.07-2.26) 0.12 Citation Format: En Cheng, Shi Qian, Anthony F. Shields, Elizabeth M. Cespedes Feliciano, Andrew B. Nixon, Ardaman P. Shergill, Katherine A. Guthrie, Felix Couture, Philip Kuebler, Pankaj Kumar, Dequincy Lewis, Benjamin Tan, Eileen M. O'Reilly, Justin C. Brown, Philip A. Philip, Bette J. Caan, Jeffrey A. Meyerhardt. Associations of inflammatory biomarkers with survival among patients with stage III colon cancer (CALGB/SWOG 80702 [Alliance]) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 682.

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory immune checkpoint that can be expressed in tumor-infiltrating lymphocytes and colorectal cancer (CRC) cells. This immune checkpoint can attenuate anti-tumoral immune responses and facilitate tumor growth and metastasis. Although capecitabine is an effective chemotherapeutic agent for treating CRC, its effect on the tumoral CTLA-4 expression remains unclear. In the current research, we applied the GSE110224 and GSE25070 datasets to characterize CTLA-4 expression in CRC patients. Then, we analyzed CTLA-4 expression in CRC samples, HT-29, HCT-166, and SW480 cell lines using real-time PCR. Our bioinformatic results have highlighted the overexpression of CTLA-4 in the CRC tissues compared to the adjacent non-tumoral tissues. Our in vitro studies have indicated that SW480 cells can substantially overexpress CTLA-4 compared to HT-29 and HCT 116 cells. In addition, capecitabine can remarkably downregulate the expression of CTLA-4 in SW480 cells. Collectively, capecitabine can inhibit the expression of CTLA-4 in CRC cells and might bridge the immunotherapy approaches with chemotherapy.

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.

10 Background: In colon cancer, tumor deposits (TD) have been associated with worse prognosis, but they are included in the TNM staging system only in the absence of lymph node metastasis (i.e., stage III pN1c tumors). Here we aimed at evaluating the prognostic value of TD and the impact of the addition of TD in the count of lymph node metastases in patients with stage III colon cancer from the CALGB/SWOG 80702 phase III trial (NCT01150045). Methods: Pathological reports of all patients were reviewed for the presence and the count of TD, primary tumor sidedness, lymphovascular invasion and perineural invasion. Cases without available pathological report or without specific information of TD were excluded. Prognostic associations were evaluated by multi-variable Cox models adjusting for treatment arm, T-stage, N-stage, lymphovascular invasion, perineural invasion and lymph node ratio. Results: Overall, 2028 patients were included, with 524 (26%) TD-positive and 1504 (74%) TD-negative stage III tumors. Of the TD-positive patients, 80 (15.4%) were node negative (i.e., pN1c), 239 (46.1%) were pN1a/b and 200 (38.55%) were pN2. 17.2% and 37.0% of all pN1a/b and pN2 tumors had TD. Overall median follow-up was 69.3 months. The presence of TD was associated with poorer DFS (adjusted hazard ratio (aHR) = 1.59, 95%CI 1.28-1.91) and OS (aHR = 1.52, 95%CI 1.18-1.95) in the overall population. The negative effect of TD on DFS and OS was observed for both pN1a/b and pN2 groups and confirmed in multivariate Cox model. Among TD-positive patients, the number of TD had a linear negative effect on DFS and OS. Adding TD to the count of lymph node metastases, 104 of 1570 (6.6%) patients initially considered as pN1 were re-staged as pN2. Re-staged pN2 patients experienced worse DFS (3-year DFS rate: 65.5% versus 80.3%, P = .0003) and OS (5-year OS rate: 69.1 versus 87.8%, P = .0005) than patients confirmed as pN1. Re-staged pN2 patients had similar DFS than patients initially staged as pN2 (3-year DFS rate: 65.5% versus 63.1%, P = .1992). OS curves of these 2 groups crossed, with better outcomes during the first 3 years of follow-up but poorer 5-year estimates for re-staged pN2 patients (5-year OS rate: 69.1% versus 74.8%, P = .0436). Conclusions: TD are found in more than one fourth of stage III colon cancer specimens. The number of TD has a linear deleterious effect on patients’ prognosis. Adding the number of TD to the count of lymph node metastases improves the prognostication accuracy of the TNM staging. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01150045.

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.

LBA3 Background: Bortezomib (btz) combined with lenalidomide (len) and dexamethasone (dex) (VRd) is a standard initial therapy for NDMM. Carfilzomib (cfz), a next-generation proteasome inhibitor, in combination with len-dex (KRd) has shown higher efficacy in phase II trials. This randomized phase III trial was designed to examine if KRd improves progression free survival (PFS) compared to VRd in NDMM (current results), and whether indefinite maintenance with len improves OS compared with two-year maintenance (to be analyzed once data matures). Methods: Patients (Pts) with NDMM, were randomized to receive VRd or KRd in a 1:1 fashion for 36 weeks followed by a second randomization (1:1) to indefinite versus two years of len maintenance. Pts without del17p, t (14;16), t(14;20), plasma cell leukemia or high-risk GEP70 profile, were enrolled. VRd arm included btz 1.3 mg/m2 on days(d) 1, 4, 8, and 11 (d 1, 8 for cycles 9-12), len 25 mg d 1-14, and dex 40 mg d 1, 2, 4, 5, 8, 9, 11, 12 of a 3-week (wk) cycle for 12 cycles, while pts in the KRd arm received cfz 36 mg/m2 d 1, 2, 8, 9, 15, 16 with len 25 mg daily on d 1-21 and dex 40 mg wkly, in 4 wk cycles for 9 cycles. Maintenance included len 15mg d 1-21 every 4 wks. The study was designed to detect a hazard ratio (HR)=0.75 with 80% power at 1-sided 2.5% alpha and 399 PFS events (progression or death regardless of intervening therapy). Results: The study accrued 1087 pts (VRd=542, KRd=545). The median age was 65y. Treatment, efficacy, and toxicity data are in the table. At the second of 3 planned interim analyses, with PFS HR=1.04 (95% CI, 0.8 to 1.3, p=0.74), futility was met. Median PFS was VRd=34.4m and KRd=34.6m; no differences were seen based on age (<65 or ≥65), presence or absence of t(4;14) or ISS stage. The three-year OS (95% CI) was similar: VRd 84% (80 to 88) and KRd 86% (82 to 89). Conclusions: In this randomized phase 3 trial, KRd did not improve PFS compared with VRd in NDMM. A significantly higher rate of cardio-pulmonary and renal toxicity was observed with KRd, while neuropathy rates were higher with VRd. VRd remains the standard triplet induction regimen in standard and intermediate risk NDMM, and a suitable backbone for 4 drug combinations. Clinical trial information: NCT01863550 . [Table: see text]