Adverse Clinical Factors Research Articles

Serum Exosomal MiR-874 as a Potential Biomarker for Nonsmall Cell Lung Cancer Diagnosis and Prognosis

AbstractLung cancer, primarily nonsmall cell lung cancer (NSCLC), is a leading cause of cancer-related fatalities globally. Due to late detection, the 5-year survival rate for NSCLC remains low. Therefore, the current research aimed to assess the diagnostic and prognostic value of serum exosomal miR-874 levels in NSCLC patients. This study involved 161 NSCLC patients and 80 control subjects. Blood samples were collected from all participants, and serum exosomal MiR-874 levels were quantified using quantitative reverse transcription-polymerase chain reaction. The study revealed a significant decrease in MiR-874 levels among NSCLC patients compared to controls. The receiver operating characteristic analysis demonstrated the diagnostic value of serum exosomal MiR-874 in effectively distinguishing NSCLC patients from controls.Furthermore, associations were observed between serum exosomal MiR-874 expression and adverse clinical factors such as young age, male sex, smoking, high tumor grade, squamous cell carcinoma histopathology, advanced tumor stage, and lymphatic involvement. Patients with high levels of MiR-874 had significantly longer overall and disease-free survival compared to those with lower levels. The study demonstrates that levels of serum exosomal miR-874 are considerably lower in NSCLC patients, indicating its potential as a diagnostic biomarker. The study's findings suggest that the expression of MiR-874 may predict the prognosis of NSCLC patients based on clinical features.

Prognostic factors and risk-stratification model of recurrent or metastatic head and neck squamous cell carcinoma treated with cetuximab containing regimen

BackgroundIn recent years, the addition of cetuximab to chemotherapy has improved treatment outcomes for patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). In this study, we present the real-world survival data of R/M HNSCC patients who received cetuximab-containing regimens from thirteen medical centers in Taiwan, as well as a three-level risk stratification model for this patient population.MethodsThis study enrolled R/M HNSCC patients from thirteen medical centers in Taiwan who received cetuximab-containing regimens from January 1, 2017 to June 6, 2022. The cases were divided into a training cohort and a validation cohort based on the start of treatment. Overall survival (OS) was evaluated in both cohorts and exploratory analysis was performed to identify associated adverse clinical and laboratory factors. The results of the exploratory analysis were used to construct a three-level risk stratification prediction model for OS.ResultsA total of 1434 patients with R/M HNSCC were enrolled in this study and received cetuximab-containing regimens. The overall population had a median OS of 8.57 months (95% CI: 8.07 – 9.08). Multivariate analysis of the training cohort identified poor ECOG performance status, heavy alcohol consumption, and prior adjuvant CCRT or lack of prior RT as adverse prognostic factors. Comparison of laboratory data between patients with OS≦6 and OS > 6 also revealed unfavorable factors, including increased white blood cell count, decreased hemoglobin level, increased platelet count, increased absolute neutrophil count, decreased absolute lymphocyte count, and increased neutrophil-to-lymphocyte ratio. Using forward prediction, a three-level risk stratification prediction model was constructed using the variables of ECOG performance status, alcohol consumption, skin metastasis, modality of radiation therapy, hemoglobin level, and neutrophil-to-lymphocyte ratio. The median OS in the low-risk, intermediate-risk, and high-risk groups were 12.02 months (95% CI 10.44–13.61), 7.5 months (95% CI 7.33–8.17), and 4.01 months (95% CI 3.94–4.08), respectively, with a log-rank test p-value < 0.001.ConclusionThis study presents a three-level risk stratification model with strong prediction ability for OS in R/M HNSCC patients who received cetuximab-containing regimens. The results are based on real-world data and may provide valuable information for clinicians in treatment planning and future drug development.

Loss of Heterozygosity and Mutations in the RAS-ERK Pathway Genes in Tumor Cells of Various Loci in Multiple Myeloma.

Multiple myeloma (MM) is a disease characterized by spatiotemporal heterogeneity of tumor clones. Different genetic aberrations can be observed simultaneously in tumor cells from different loci, and as the disease progresses, new subclones may appear. The role of liquid biopsy, which is based on the analysis of tumor DNA circulating in the blood plasma, continues to be explored in MM. Here, we present an analysis of the STR profiles and mutation status of the KRAS, NRAS, and BRAF genes, evaluated in plasma free circulating tumor DNA (ctDNA), CD138+ bone marrow cells, and plasmacytomas. The prospective single-center study included 97 patients, with a median age of 55 years. Of these, 94 had newly diagnosed symptomatic MM, and three had primary plasma cell leukemia. It should be noted that if mutations were detected only in ctDNA, "non-classical" codons were more often affected. A variety of adverse laboratory and clinical factors have been associated with the detection of rare KRAS or NRAS gene mutations in bone marrow or ctDNA, suggesting that these mutations may be factors of an unfavorable prognosis for MM. Liquid biopsy studies provide undeniable fundamental information about tumor heterogeneity and clonal evolution in MM. Moreover, we focus on using liquid biopsy to identify new high-risk factors for MM.

Prognostic impact of the high-sensitivity modified glasgow prognostic score on patients undergoing radical surgery for hepatocellular carcinoma : Authorship.

Our study aimed to assess the ability of high-sensitivity modified Glasgow prognostic Score (HS-mGPS) predicting survival in patients undergoing radical surgery for hepatocellular carcinoma (HCC) and to compare the impact with other Inflammation-Based prognostic scoring systems including Glasgow prognostic Score (GPS) and modified GPS (mGPS). Our study evaluated 293 patients with HCC who had undergone hepatectomy at the Third Affiliated Hospital of Soochow University between 2010 and 2018. The HS-mGPS, mGPS, and GPS were calculated based on particular cut-off values of preoperative C-reactive protein and albumin, and the correlations between HS-mGPS and clinicopathological parameters were evaluated. Univariate and multivariate survival analyses were conducted by Kaplan-Meier method and Cox proportional hazards model. To evaluate the discrimination ability of each prognostic score, the receiver operating characteristic (ROC) curve were generated and the areas under the curve (AUC) were measured and compared. The study results indicated a correlation between elevated HS-mGPS scores and adverse clinical factors, including higher BCLC stage, C-P grade, multiple tumors, and larger tumor diameter. Kaplan-Meier and univariate survival analyses revealed that higher scores of HS-mGPS, GPS, and mGPS were all associated with significantly reduced overall survival (OS) (all p < 0.001). In multivariate survival analysis, HS-mGPS emerged as an independent risk factor for poor OS in patients undergoing hepatectomy for HCC (p = 0.010), along with factors including maximal tumor diameter (p < 0.001), microvascular invasion (MVI) (p = 0.008), and BCLC stage (p = 0.001). The analysis of ROC curves and the AUC values indicated that HS-mGPS outperforms GPS and mGPS in predicting the long-term prognosis of patients with resectable HCC. Preoperative HS-mGPS proves superior in predicting adverse long-term outcomes in HCC patients undergoing radical surgery.

The Future of Food Allergy Management: Advancements in Therapies.

To review current and future treatment options for IgE-mediated food allergy. Recent years have seen major developments in both allergen-specific and allergen-non-specific treatment options, with the first FDA-approved peanut oral immunotherapy (OIT) product becoming available in 2020. In addition to OIT, other immunotherapy modalities, biologics, adjunct therapies, and novel therapeutics are under investigation. Food allergy is a potentially life-threatening condition associated with a significant psychosocial impact. Numerous products and protocols are under investigation, with most studies focusing on OIT. A high rate of adverse events, need for frequent office visits, and cost remain challenges with OIT. Further work is needed to unify outcome measures, develop treatment protocols that minimize adverse events, establish demographic and clinical factors that influence candidate selection, and identify patient priorities.

Clinical variables associated with major adverse cardiac events following radical cystectomy.

The objective of this study is to investigate the association between major adverse cardiac events (MACE) and clinical factors of patients undergoing radical cystectomy (RC) for bladder cancer. A retrospective analysis using the 2015-2020 National Surgical Quality Improvement Program database was performed on patients who underwent RC for bladder cancer. MACE was defined as any report of cerebrovascular accident, myocardial infarction, or thromboembolic events (pulmonary embolism or deep vein thrombosis). A multivariable-adjusted logistic regression was conducted to identify clinical predictors of postoperative MACE. A total of 10 308 (84.2%) patients underwent RC with incontinent urinary diversion (iUD), and 1938 (15.8%) underwent RC with continent urinary diversion (cUD). A total of 629 (5.1%) patients recorded a MACE, and on the multivariable-adjusted logistic regression, it was shown that MACE was significantly associated with increased age (OR = 1.035, 95% CI: 1.024-1.046, p < 0.001), obesity (OR = 1.583, 95% CI: 1.266-1.978, p < 0.001), current smokers (OR = 1.386, 95% CI: 1.130-1.700, p = 0.002), congestive heart failure before surgery (OR = 1.991, 95% CI: 1.016-3.900; p = 0.045), hypertension (OR = 1.209, 95% CI: 1.016-1.453, p = 0.043), and increase the surgical time (per 10min increase, OR = 1.010, 95% CI: 1.003-1.017, p = 0.009). We also report that increased age, obesity, and patients undergoing cUD (OR = 1.368, 95% CI: 1.040-1.798; p = 0.025) are associated with thromboembolic events. By considering the preoperative characteristics of patients, including age, obesity, smoking, congestive heart failure, and hypertension status, urologists may be able to decrease the incidence of MACE in patients undergoing RC. Urologists should aim for lower operative times as this was associated with a decreased risk of thromboembolic events.

Rituximab Combined with Chemotherapy and Acalabrutinib Prior to Autologous Stem Cell Transplantation in Mantle Cell Lymphoma: The Rectangle Trial

INTRODUCTION In the European MCL Network Triangle study (Dreyling, ASH 2022) the addition of ibrutinib to frontline rituximab-containing chemotherapy and subsequent maintenance therapy improved failure-free survival in young, fit patients with mantle cell lymphoma (MCL). Ibrutinib was administered with R-CHOP, but not with R-DHAP, during the induction phase. Continuous, uninterrupted Bruton Tyrosine Kinase (BTK) inhibition could maximize the benefit of front-line therapy given that responses develop over time. Acalabrutinib has less off-target BTK inhibition than ibrutinib. We hypothesize that combining continuous acalabrutinib with R-CHOP may result in a tolerable, outpatient, highly active regimen producing favorable outcomes. METHODS NCT04566887 is a phase II, single-arm, open-label study conducted across 5 academic centres in Canada. Patients ≥ 18 years of age with previously untreated MCL, ECOG performance status 0-2, adequate organ function and considered fit for autologous stem cell transplantation (ASCT) were included. Patients received 6 cycles of R-CHOP at standard doses plus acalabrutinib 100 mg twice per day orally. Responding patients proceeded with ASCT and maintenance rituximab and acalabrutinib for a total of 2 years. The primary endpoint was the complete response (CR) rate after 6 cycles of induction with centrally reviewed PET/CT using the Lugano Criteria (Cheson, 2014). The total sample size was n=54 and the study completed accrual in May 2023. We present the results of the first 43 patients who have completed response assessment according to local investigators after 6 cycles of induction. RESULTS The median age was 62 years (range 38 - 69), 26 (60%) were male, 42 (98%) had performance status 0-1, 33 (78%) Ann Arbor stage IV, 35 (81%) bone marrow involvement, 6 (14%) high risk MIPI, 7 (16%) blastoid/pleomorphic morphology, 11 (26%) Ki67 ≥30%. All patients completed 6 cycles of induction and proceeded to ASCT. The overall response rate was 100%, and 39 (91%) patients achieved a CR. All patients started maintenance acalabrutinib + rituximab, although none have yet completed two years of protocol maintenance therapy. With a median follow up of 11.8 months (range 3.4 - 25.3) by the reverse Kaplan-Meier method, the 12-month PFS was 94% (95% CI 78.1 - 98.5), shown in Figure 1, and OS 95.5% (95% CI 71.9 - 99.3). Three subjects have developed PD so far, all with adverse clinical and biological factors: Baseline high-risk MIPI and Ki67 70%; biopsy at relapse TP53 positive by immunohistochemistry (IHC)Baseline intermediate risk MIPI and Ki67 60%; biopsy at relapse with pleomorphic morphology, TP53 positive by IHC, Ki67 100%Baseline high risk MIPI, Ki67 ≥30%, and blastoid morphology. Table 1 lists common grade 3-4 adverse events (AE) during induction and maintenance. There were no grade 5 AE. Neutropenia was the most common AE during induction and maintenance. Most infections were respiratory. Cardiovascular toxicity was uncommon. CONCLUSIONS Acalabrutinib + R-CHOP is associated with a 91% CR rate with low rates of grade 3-4 AE expected for this combination. All patients have proceeded to ASCT and subsequent maintenance therapy. Maintenance therapy in this setting is associated with additional toxicity, particularly cytopenias and infections.

The Impact of Time From Diagnosis to Initiation of Chemotherapy on Survival of Patients With Newly Diagnosed Diffuse Large B-Cell Lymphoma in the Veterans Health Administration

IntroductionOur retrospective study evaluates the impact of time from diagnosis to treatment (TDT) on outcomes of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) treated within the Veterans Health Administration (VHA). MethodsVHA patients diagnosed with DLBCL between 2011 and 2019 were included, while those with primary central nervous system lymphoma were excluded. The median overall survival and progression-free survival were estimated with the Kaplan-Meier method. Univariate, bivariate, and multivariable analyses were performed using the Cox proportional hazards model. The odds ratio for refractory outcomes was calculated using logistic regression. ResultsA total of 2448 patients were included. The median time from diagnosis to treatment of the cohort was 19 days. When comparing median progression-free survival, median overall survival, and the 2-year overall survival between the group that started treatment within 1 week and each of the other groups individually, there was a significant difference favoring improved survival in all groups with a TDT longer than 1 week (P < .0001). These patients also had a lower odds ratio for refractory outcomes. On multivariable analysis, TDT remained an independent prognostic factor. ConclusionOur study shows that a TDT equal to or less than 1 week is associated with adverse clinical factors, worse outcomes, and response in DLBCL, even after adjusting for multiple known poor prognostic factors. This was the first time that response to first-line therapy was correlated to time to treatment. Our findings support ongoing efforts to improve currently standardized prognostic tools and the incorporation of TDT into clinical trials to avoid selection bias.

Inb-100: A Pilot Study of Donor Derived, Ex-Vivo Expanded/Activated Gamma-Delta T Cell (EAGD) Infusion Following Haploidentical Hematopoietic Stem Cell Transplantation and Post-Transplant Cyclophosphamide (PTCy)

Background: Gamma-delta (gd) T cells are MHC unrestricted lymphocytes that recognize and lyse malignant cells in allogeneic settings. Although haploidentical transplant with PTCy has reduced the risk of graft-versus-host disease (GvHD); the incidence of relapse remains up to 50% at year 1. Early post-transplant infusion of haploidentical EAGD cells may decrease relapse risk through a graft-versus-leukemia (GvL) effect without severe GvHD. We present updated clinical and correlative data from our Phase I trial using our recommended phase 2 dose (RP2D). Methods: Adults with newly diagnosed or relapsed ALL, CML, AML undergoing first haploidentical transplant with reduced-intensity flu/cy/TBI conditioning received EAGD intravenously within 7 days of neutrophil engraftment. Peripheral blood was collected at EAGD infusion and monthly through day 90, with additional collections every 6 months through 1 year. Primary endpoints include dose-limiting toxicities (DLT), grade (G) 3-4 adverse events including GvHD with secondary endpoints of relapse and overall survival. Biologic parameters included multiparameter flow cytometric immunophenotyping and additional serum cytokine analysis using the Olink ® 48 target panel. Results: 14 subjects were enrolled with 4 treated at Dose Level (DL) 1 of 1 x 10 6 EAGD/kg and 6 subjects treated at the RP2D of DL2 (3 x 10 6 EAGD/kg). Untreated subjects included: One screen failure, a manufacturing failure, one subject who died prior to dosing, and one subject who received an out of study specification product. Treated subjects were 60% male, median age of 68, and primarily AML subjects in CR1. RP2D was defined by an acceptable toxicity profile, no DLT's, prolonged RFS and elevated gd levels. Peripheral lymphodepletion persisted through the first 100 days post-BMT followed by T cell recovery from a CD45+CD27-effector phenotype to central and effector memory phenotype. Notably, DL2 showed significant increases in gd T cell count recovery at days 60, 100 and 180 post-BMT vs. DL1 and historically untreated Haplo/PTCy patients, p = &amp;lt;0.05. NK cells remained within the low normal range and &amp;lt;3% of circulating T cells were Tregs. Preliminary serum cytokine analysis revealed elevated IL-6 and IL-15 in serum post- transplant prior to EAGD infusion, but dropped to normal median levels at day 60, 20-30 days after EAGD infusion. One subject received intermittent hypomethylating therapy for emergence of recipient chimerism. Treatment emergent AE's included transient WBC and ANC decreases (100% each), platelet count decrease and anemia (88.9% each) and maculopapular rash, hypomagnesemia and blood creatine increased (55.6% each). EAGD related toxicities were primarily G1-2, included G1-2 skin acute GvHD and gastrointestinal GvHD, and one case of G3 platelet count decrease. Treatment related serious AE's of G3 nausea and G2 rash were reported. No DLTs, neurotoxicity, cytokine release syndrome or treatment related deaths were reported. Conclusions: Post-BMT infusion of donor-derived, EAGD cells has demonstrated manageable safety with no infusional toxicity or ≥G3 acute GvHD or extensive chronic GvHD. Durable relapse free survival at a maximum of &amp;gt;3 years in subjects with poor risk cytogenetics and adverse clinical risk factors combined with ongoing homeostatic reconstitution of increasing gd T cell effectors post-BMT suggests this therapy may be an effective measure in mitigating relapse after HaploBMT. NCT03533816

Sociodemographics, Clinical Factors, and Biological Factors Associated with Loiasis in Endemic Onchocerciasis Areas in Southern Gabon.

To implement the appropriate strategies for scale-up interventions to eliminate onchocerciasis without severe adverse events, clinical and biological factors associated with loiasis were analyzed in onchocerciasis-endemic areas. Blood was collected from volunteers after examination by a physician. Detection of microfilariae and measurement of Ov16 IgG4 were performed using direct microscopic examination of blood and onchocerciasis rapid test detection, respectively. Areas with sporadic, hypoendemic, and hyperendemic onchocerciasis endemicity were found. Participants with microfilaremia were considered microfilaremic, and those without microfilaremia were seen as amicrofilaremic. Of the 471 study participants, 40.5% (n = 191) had microfilariae. Among them, Mansonella spp. was the most common (78.2%, n = 147), followed by Loa loa (41.4%, n = 79). The association between the two species represented 18.3% (n = 35). The specific immunoglobulins of Onchocerca volvulus were detected in 24.2% of participants (n = 87/359). Overall prevalence of L. loa was 16.8%. Hypermicrofilaremia was found in 3% (N = 14), and one participant had more than 30,000 microfilaremiae per milliliter. The frequency of L. loa did not vary according to the level of onchocerciasis transmission. Pruritus was the most common clinical sign (60.5%, n = 285) reported, mainly in microfilaremic participants (72.2%, n = 138/191). The prevalence of L. loa microfilaria in the study population was below the threshold at risk for the occurrence of serious side effects due to ivermectin. Clinical manifestations frequently observed could be exacerbated by microfilaremia in areas where onchocerciasis transmission is high.

Cortisol levels are related to neonatal pain exposure in children born very preterm at age 18 months in two independent cohorts.

Exposure to pain-related stress from frequent invasive procedures in the neonatal intensive care unit (NICU) has been associated with altered physiological stress regulation, neurodevelopment, and behavior in children born very preterm (≤32 weeks gestation). Previously, in a cohort born 2003-2006 (Cohort 1), we found that, at 18 months corrected age (CA), children born extremely low gestational age (ELGA; 24-28 weeks) and very low gestational age (VLGA; 29-32 weeks), had higher pre-test cortisol levels and a different pattern of cortisol output across a developmental assessment involving cognitive challenge compared to children born full-term (FT; 39-41 weeks). Also, greater neonatal pain-related stress exposure among the preterm children was related to higher pre-test cortisol levels. Given the adverse long-term effects of neonatal pain in preterm infants and the ensuing rise in clinical concerns to appropriately manage pain in the NICU in recent years, we aimed to examine whether our findings from Cohort 1 would still be evident in an independent cohort (Cohort 2) born 2006-2011 and recruited from the same tertiary NICU in Vancouver, Canada. We also compared the cortisol patterns, clinical and socio-demographic factors, and their interrelationships between the two cohorts. In Cohort 2, our findings using multi-level modeling support and extend our earlier findings in Cohort 1, demonstrating that children born ELGA display higher pre-test cortisol levels than FT. As well, greater cortisol output across assessment was related to more anxiety/depressive behaviors in children born VLGA. Importantly, children born ELGA were exposed to less neonatal pain/stress, mechanical ventilation, and morphine in Cohort 2 than Cohort 1. In both cohorts, however, cortisol levels and patterns were related to neonatal pain/stress and clinical factors (days on mechanical ventilation, overall morphine exposure). Despite less exposure to pain/stress and adverse clinical factors in Cohort 2 compared to Cohort 1, cortisol levels and patterns across cognitive challenge in preterm children at 18-month CA were consistent across the two independent cohorts. These findings highlight that, despite improvements to neonatal care, children born extremely preterm continue to display altered HPA axis activity, which is associated with their poorer neurodevelopmental and behavioral outcomes.

Impact of diagnosis to treatment interval in patients with newly diagnosed mantle cell lymphoma.

The prognostic relevance of diagnosis to treatment interval (DTI) in patients with newly diagnosed mantle cell lymphoma (MCL) is unknown. Hence, we sought to evaluate the impact of DTI on outcomes in MCL using 3 large datasets (1) the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource, (2)patients enrolled in the ALL Age Asthma Cohort/CALGB 50403, and (3) a multisitecohort of patients with MCL. Patients were a priori divided into 2 groups, 0 to 14 days (short DTI) and 15 to 60 days (long DTI). The patients in whom observation was deemed appropriate were excluded. One thousand ninety-seven patients newly diagnosed with MCL and available DTI were included in the study. The majority (73%) had long DTI (n=797). Patients with short DTI had worseeastern cooperative oncology group performance status (ECOG PS ≥2), higher lactate dehydrogenase, bone marrow involvement, more frequent B symptoms, higher MCLInternational Prognostic Index (MIPI ≥6.2), and were less likely to receive intensive induction therapy than long DTI group. The median progression-free survival (2.5 years vs 4.8 years, p<0.0001) and overall survival (7.8 years vs. 11.8 years, p<0.0001) were significantly inferior in the short DTI group than the long DTI cohort and remained significant for progression-free survival and overall survival in multivariable analysis. We show that the DTI is an important prognostic factor in patients newly diagnosed with MCL and is strongly associated with adverse clinical factors and poor outcomes. DTI should be reported in all the patients newly diagnosed with MCL who are enrolling in clinical trials and steps must be taken to ensure selection bias is avoided.

Abstract MP57: Coagulation Factor IX and Incident Diabetes Risk: The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study

Introduction: A prothrombotic state is implicated in the vascular complications of type 2 diabetes (DM), and such complications disproportionately affect Black compared to White adults. However, it is not known if this is due to DM or whether coagulation factor levels are related to DM incidence. Higher coagulation factor IX (FIX) was related to increased risk of CHD and stroke among Black but not White participants in the REGARDS cohort. We hypothesized higher FIX antigen would be associated with incident DM risk, with stronger relationships in Black versus White adults. Methods: REGARDS enrolled 30,239 Black and White adults from across the contiguous US from 2003-2006 with a second in-home visit from 2013-2016. The Biomarkers as MEDiators of Racial Disparities in Risk Factors (BioMedioR) nested cohort study included 4,400 participants who completed both visits, balanced on race and sex. Modified Poisson regression models estimated the RR of incident DM per 1-SD increment log FIX. We tested for a FIX-by-race interaction a priori due to differential associations of FIX with CHD and stroke by race in REGARDS. Results: Among 3,381 participants without baseline DM (mean age 63 years, 44% Black race, 51% women), 456 (13.5%) developed incident DM over 9.5-years. Adjusting for age, sex, and race, there was a significant difference in the association of FIX with DM by race (p-interaction&lt;0.01). As shown in the Figure, adjusted for age and sex (Model 1), the RR (95% CI) for incident DM was 1.19 (1.05, 1.34) for Black adults and 1.49 (1.23, 1.81) for White adults. Adjusting for clinical risk factors (Model 2) fully attenuated this association for Black adults, and further adjusting for behavioral factors (Model 3) fully attenuated this association for Black and White adults. Conclusions: Higher FIX levels were associated with incident DM risk. Relationships between FIX and incident DM were stronger for White than Black adults. The FIX-DM association may be due to adverse clinical and behavioral risk factors.

A Novel Prognostic Score Including the CD4/CD8 for AIDS-Related Lymphoma.

BackgroundA simple and clinically applicable prognostic scoring system for AIDS-related lymphoma (ARL) in the era of combination antiretroviral therapy (cART) is needed to better stratify patients’ risks and to assist in the decision-making of therapeutic strategies.MethodsWe conducted a retrospective multicenter cohort study in 138 primary ARL patients over an 8-year period from 2013 to 2020. Survival curves were estimated using the Kaplan–Meier method. Univariate and multivariate Cox proportional hazard models were performed to identify the association between patient-, lymphoma-, and HIV-specific variables with progression-free survival (PFS) and overall survival (OS). The incremental prognostic value of novel inflammatory biomarkers in the International Prognostic Index (IPI) was evaluated by comparing the receiver operating characteristic (ROC) curves, the concordance index (C-index), and the integrated Brier score (IBS).ResultsThe median age was 49.14 ± 14.20 (range 18–79) years, 81.9% were men, and the median follow-up was 44.94 (95% CI = 37.05–52.84) months. The 3-year OS and PFS were 39.4% (95% CI = 16.3–21.2) and 38.7% (95% CI = 14.5–19.7), respectively. We found that age, extranodal sites, bulky mass, CD4 T-cell counts, CD4/CD8 ratio, and hypoalbuminemia were associated with OS (all P < 0.05) at both univariate and multivariate analyses. Of the new inflammatory markers, only the CD4/CD8 ratio was an independent prognostic parameter of OS and PFS. A lower CD4/CD8 ratio was strongly associated with adverse clinical factors, including older age, advanced Ann Arbor stage, more extranodal sites, elevated erythrocyte sedimentation rate, prior history of HIV, higher red cell distribution width ratio, hypoproteinemia, and emaciation. When the CD4/CD8 ratio was added to the IPI, the composite HIV-IPI score showed significantly better discrimination than IPI alone [AUC (95% CI): HIV-IPI, 0.83 (0.77–0.89) vs. IPI, 0.72 (0.70–0.85)]. The HIV-IPI model provided good predictive performance [C-index (95% CI): HIV-IPI, 0.82 (0.81–0.83) vs. IPI, 0.75 (0.73–0.77), P < 0.001] and a satisfactory calibration function.ConclusionsThe CD4/CD8 ratio, an inexpensive and readily available marker, is a powerful independent prognostic parameter in patients with ARL. Furthermore, when the CD4/CD8 ratio is used in combination with IPI, it increases prognostic ability. The useful prediction of expected outcomes in ARL can inform treatment decisions.

Clinical Manifestation and Short-Term Outcome of Emergency Percutaneous Revascularization of Patient with ST-Segment Elevation Myocardial Infarction at a Rural Satellite Center

Background: In Pakistan, the prevalence of acute coronary syndrome (ACS) patients is among the highest in the world. A patient's rate of morbidity and mortality depends greatly on the time that passes during ACS, especially in ST-elevation myocardial infarction patients (STEMI). Objectives: This research aimed to assess the spectrum of the acute coronary syndrome (ACS) and factors leading to delay in presentation and treatment to evaluate its impact on the short-term outcome in patients presenting to a rural satellite center of NICVD at Khairpur, Pakistan. Material &amp; Methods: This observational study was conducted on 400 patients at the Department of Adult Cardiology at Kharipur Satellite Center of National Institute of Cardiovascular Diseases (NICVD), Pakistan for six months. All patients presenting to ER with ACS whose age was ≥18 years were included. Participants' informed consents were obtained verbally and confidentiality was maintained in regards to their participation in and publication of findings from the study. Consecutive patients presenting with ACS to the satellite center of NICVD at Khairpur, Pakistan were included in this research. Baseline characteristics were analyzed using the statistical package for social sciences (SPSS 25). Results: A total of 400 (295 males and 105 females) patients with ACS were included. The mean age was 63.3 ± 11.5 (range 40-70) years, 42.5% had low SES, 35.0% had mid-SES, and 22.5% had high SES.159 (39.8%) patients were from the urban area and 241(60.2%) were from a rural region. However, age, smokers, hypertension, dyslipidemia, area of residence, obesity, diabetic Mellitus, and atrial fibrillation were found to be significant factors associated with socioeconomic status for the acute coronary syndrome. (p-value = &lt;0.05) The epicardial coronary disease was significantly less common in individuals with a high SES compared to those with a mid or low SES. We observed that mode of transport may be a significant cause of death (p-value = &lt;0.0001) because of late arrival to the hospital. In our research, we showed 7.8% 30-day mortality out of total samples. Area of residence, mode of transport, 30-day mortality, OS-ECG (in min), and inferior and anterior STEMI were found to be significantly associated factors (p-value = &lt;0.05). Conclusion: Even though the low-SES STEMI patients at the National Institute of Cardiovascular Diseases Khairpur show more adverse clinical and cardiovascular risk factors than patients from urban areas with higher SES. The 30-day mortality for these patients is comparable to the higher-SES patients. Keywords: Clinical manifestation, short-term outcome, percutaneous revascularization, STEMI, myocardial infarction, rural areas.

New-Onset Atrial Fibrillation in Patients Hospitalized With COVID-19: Results From the American Heart Association COVID-19 Cardiovascular Registry.

New-onset atrial fibrillation (AF) in patients hospitalized with COVID-19 has been reported and associated with poor clinical outcomes. We aimed to understand the incidence of and outcomes associated with new-onset AF in a diverse and representative US cohort of patients hospitalized with COVID-19. We used data from the American Heart Association COVID-19 Cardiovascular Disease Registry. Patients were stratified by the presence versus absence of new-onset AF. The primary and secondary outcomes were in-hospital mortality and major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, stroke, cardiogenic shock, and heart failure). The association of new-onset AF and the primary and secondary outcomes was evaluated using Cox proportional-hazards models for the primary time to event analyses. Of the first 30 999 patients from 120 institutions across the United States hospitalized with COVID-19, 27 851 had no history of AF. One thousand five hundred seventeen (5.4%) developed new-onset AF during their index hospitalization. New-onset AF was associated with higher rates of death (45.2% versus 11.9%) and MACE (23.8% versus 6.5%). The unadjusted hazard ratio for mortality was 1.99 (95% CI, 1.81-2.18) and for MACE was 2.23 (95% CI, 1.98-2.53) for patients with versus without new-onset AF. After adjusting for demographics, clinical comorbidities, and severity of disease, the associations with death (hazard ratio, 1.10 [95% CI, 0.99-1.23]) fully attenuated and MACE (hazard ratio, 1.31 [95% CI, 1.14-1.50]) partially attenuated. New-onset AF was common (5.4%) among patients hospitalized with COVID-19. Almost half of patients with new-onset AF died during their index hospitalization. After multivariable adjustment for comorbidities and disease severity, new-onset AF was not statistically significantly associated with death, suggesting that new-onset AF in these patients may primarily be a marker of other adverse clinical factors rather than an independent driver of mortality. Causality between the MACE composites and AF needs to be further evaluated.

An Asian multi-national multi-institutional retrospective study comparing intracavitary versus the hybrid of intracavitary and interstitial brachytherapy for locally advanced uterine cervical carcinoma.

This study is an international multi-institutional retrospective study comparing the clinical outcomes between intracavitary brachytherapy (ICBT) and the hybrid of intracavitary and interstitial brachytherapy (HBT) for locally advanced cervical cancer patients treated with definitive radiation therapy. Locally advanced cervical cancer, the initial size of which is larger than 4 cm and treated by concurrent chemoradiotherapy and image-guided adaptive brachytherapy, were eligible for this retrospective study. Patients who received HBT at least once were included in the HBT group, and patients who received only ICBT were included in the ICBT group. Anonymized data from 469 patients from 13 institutions in Japan, one from Korea and one from Thailand, were analyzed. Two hundred eighty and 189 patients were included in the ICBT group and the HBT group, respectively. Patients in the HBT group had more advanced stage, non-Scc histopathology, a higher rate of uterine body involvement, larger tumor at diagnosis, larger tumor before brachytherapy and a lower tumor reduction ratio. With a median follow-up of 51.3 months (2.1–139.9 months), 4-y local control (LC), progression-free survival (PFS) and overall survival (OS) for the entire patient population were 88.2%, 64.2% and 83%, respectively. The HBT group received a higher HR-CTV D90 than that of the ICBT group (68.8 Gy vs 65.6 Gy, P = 0.001). In multivariate analysis, the non-Scc histological subtype, HR-CTV D95 ≤ 60 Gy, reduction ratio ≤ 29% and total treatment time (TTT) ≥ 9 weeks were identified as the independent adverse prognostic factors for LC. Regarding LC, no difference was found between ICBT and HBT (4-y LC 89.3% vs 86.8%, P = 0.314). After adjustment for confounding factors by propensity score matching, no advantage of applying HBT was demonstrated regarding LC, PFS, or OS. Despite the fact that HBT patients had more adverse clinical factors than ICBT patients, HBT delivered a higher dose to HR-CTV and resulted in comparable LC.

Assessment of Circulating Tumor DNA in Newly Diagnosed DLBCL Patients Randomly Treated By R-CHOP or R-High Dose Chemotherapy Plus Autologous Stem Cell Support

PurposeDiffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. The association of rituximab to CHOP chemotherapy is nowadays the standard of care for de novo DLBCL patients; however 40% of these patients relapse or are refractory to treatment within 2 years. Before rituximab, patients treated by high dose chemotherapy plus autologous stem-cell support (HDT) had a significantly better outcome than by CHOP alone 1. Between 2005 and 2008, the GOELAMS 075 French multicentric clinical trial (NCT00561379) enrolled 323 de novo DLBCL patients randomly treated by R-CHOP or R-HDT, and showed that rituximab erases the survival difference between the two arms of frontline treatment 2.The main objective of this study was to evaluate circulating tumor DNA (ctDNA) concentration measured by an easy-to-collect and cost-effective method in the GOELAMS 075 de novo DLBCL patients, in regards of the two frontline treatments.MethodsPlasma samples were collected at inclusion for 123 patients and 6 months after the end-of-treatment (EOT) for 50 patients in complete remission (CR) at EOT. The 123 patients were representative of the 323 eligible patients. Among the 123 patients, 68 were assigned to the R-CHOP arm and 55 to the R-HDT arm, of which, respectively, 59 and 51 achieved CR at EOT. Baseline characteristics, overall (OS) and progression free survivals were not different between randomization arms for the 123 patients. No difference in baseline characteristics was found between both studied cohorts.ctDNA concentration in ng per ml of plasma was measured as the enrichment of DNA fragments between 100 and 300 base pairs. For survival analysis, the ctDNA threshold was defined as equal to 10 times the maximum cell-free DNA concentration measured in healthy subjects. For paired samples, mutation profiles at baseline and 6 months after EOT were assessed by capture-based targeted DNA sequencing using a panel of 43 genes known to be associated to DLBCL in the literature. Intention-to-treat (ITT) analysis was performed, unless otherwise mentioned.ResultsElevated ctDNA at diagnosis was found significantly associated with adverse clinical factors (R-IPI ≥3 ; number of extranodal sites ≥2), as well as intake of salvage therapy. Patients with ctDNA ≥ 54.9 ng/ml had significantly worse OS (HR=2.4, 95 th CI : 1.1-5.2 ; Pvalue=0.029). Patients with elevated ctDNA were more likely to require a salvage therapy, regardless of the randomisation arm. Only for ITT R-CHOP patients, elevated ctDNA was associated with a significantly shorter OS (HR=4.4, 95th CI : 1.6-12.3 ; Pvalue=0.004; Figure 1). Patients with elevated ctDNA who received the initially planned 8 R-CHOP cures (no salvage therapy) had a significantly worse OS than any other patients (67% deaths ; 5-years OS : 33% ; Pvalue=0.0002).Focusing on the cohort of 50 patients in CR at the EOT, we found a significant decrease of ctDNA 6 months after EOT compared to baseline only for ITT R-HDT patients (Pvalue=0.006). Noticeably, out of the 7 patients with higher ctDNA 6 months after EOT, six had been assigned to the R-CHOP arm, and five of those did not benefit salvage therapy. Mutation profiling was performed for 46 CR patients (ITT, R-CHOP, n=23 ; R-HDT, n=23) at baseline and 6 months after EOT. Mutations were detected in 48% of R-CHOP patients and 61% of R-HDT patients. The tumor mutational burden, defined as the number of gene mutations found on the total of 164 Kb sequenced, was significantly decreased 6 months after EOT only for R-HDT patients (Pvalue=0.005). The number of mutations, especially the number of new variants, and the number of deleterious and likely oncogenic variants, increased significantly in the R-CHOP arm 6 months after EOT while decreasing in the R-HDT arm (Pvalue<0.001; Figure 2). All 46 patients in CR at EOT remained in CR 5 to 10 years after treatment, except for 3 patients, who did not receive salvage therapy and relapsed more than 5 years after EOT. All 3 patients belonged to the R-CHOP arm patients with higher ctDNA 6 months after EOT compared to baseline.ConclusionUsing an easy-to-measure and low-cost method, ctDNA concentration at diagnosis was shown, in an intention-to-treat analysis, to be an adverse prognostic factor only for de novo DLBCL patients treated by standard R-CHOP. Furthermore ctDNA was not significantly cleared in plasma at CR only for ITT R-CHOP patients, with the number of mutations increased 6 months after EOT compared to baseline. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abstract 3036: ALK protein expression and its prognostic significance in MYCN non amplified neuroblastoma

Abstract Anaplastic lymphoma kinase (ALK) point mutations (within the kinase domain), gene amplification and protein overexpression are identified (8-14%) both in familial and sporadic high-risk neuroblastoma (HR-NB). ALK mutations are much more frequent at time of relapse and were associated with poor clinical outcomes for children with HR-NB. Evidently, ALK is near exclusively co-amplified with MYCN, and the cooperative activity of ALK and MYCN are known to drive HR-NB pathogenesis. However, the ALK protein expression and its role in the prognosis of MYCN non-amplified NB remained unexplored. In this study, NB tumors representing varied stages, ages, sites, diagnosis/progressive disease, primary/metastatic site from a cohort MYCN non-amplified NB patients (n=92) were custom archived in TMAs and stained with ALK (immunohistochemistry) antibody. The correlations between ALK protein expression, and clinico-pathological and biological variables of MYCN non-amplified NB tumors were analyzed. Assessing the strong positivity, high expression of ALK protein could be detected in 47 (51%) of the 92 NB tumors. The majority of NBs with evident of ALK protein high expression exhibited undifferentiated or poorly differentiated histology (39/47, 82.9%). ALK protein high expression significantly predicted worse survival outcomes for NB (and HR-NB subset) patients with MYCN non-amplified status. Transcriptional data mining (R2: Genomics Analysis and Visualization Platform) across multiple cohorts of MYCN non-amplified NB patients revealed unique and defined associations of ALK to the adverse clinical prognostic factors (e.g. advanced disease stage, risk) and poor survival outcomes. Our study recognized the prognostic role of ALK protein expression in MYCN non-amplified NB. Since, ALK is indicated to transactivate MYCN, increase MYCN protein expression, and coordinate disease progression; further studies are warranted to define the mechanism(s) of ALK high-expression associated disease evolution in MYCN non-amplified HR-NB.Funding: This work was partially or in full, funded by Oklahoma Center for the Advancement of Science and Technology, OCAST-HR19-04; National Institutes of Health, NIH-P20GM103639 and; NIH-NCI- Cancer Center Support Grant P30CA225520 Citation Format: Natarajan Aravindan, Dinesh Babu Somasundaram, Santny Shanmugarama, Sheeja Aravindan. ALK protein expression and its prognostic significance in MYCN non amplified neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3036.

Diagnosis-to-Treatment Interval (DTI) Remains Associated with Adverse Clinical Characteristics and Outcome in Newly Diagnosed Patients with Diffuse Large B-Cell Lymphoma Treated on Clinical Trials

Diagnosis-to-Treatment Interval (DTI) remains associated with adverse clinical characteristics and outcome in newly diagnosed patients with diffuse large B-cell lymphoma treated on clinical trials. PURPOSE A number of therapy combinations showing promise in nonrandomized studies in newly diagnosed diffuse large B-cell lymphoma (DLBCL) failed to demonstrate improvement over the control arm in randomized studies. Moreover, better than expected outcomes on the control (standard therapy arm) have been observed. Selection bias in clinical trials has consequences for scientific validity and applicability of study results to the general population. In an aggressive malignancy such as DLBCL, real or perceived urgency of initiation of therapy is weighed against the time required for trial consenting, screening, pathology review and biomarker assessment. The resulting exclusion of patients with rapidly progressive or symptomatic disease may lead to selection of patients with less aggressive disease enrolled on clinical trials. We recently examined the time from diagnosis to treatment initiation (DTI) and its association with clinical factors and outcome in a clinic-based observational cohort of patients with DLBCL from the US. Here we replicate those results in an independent clinical trial based cohort from Europe. PATIENTS AND METHODS Newly diagnosed patients with DLBCL were prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) or the LYSA LNH-2003 clinical trials program. All enrolled cases from LYSA were used in analysis as intent to treat approach. Pathological diagnosis was centrally reviewed and all patients received anthracycline-based immunochemotherapy (IC) at initial diagnosis. DTI was defined as the time in days from date of first lymphoma-containing biopsy to the initiation of IC therapy. Associations of DTI with clinical factors and outcome were examined using the median DTI split (0-14 days) from the MER dataset and as using a continuous variable for DTI based on examination of functional form. Outcome was assessed using event-free survival at 24 months from diagnosis (EFS24) where events were defined as progression/relapse, initiation of new anti-lymphoma therapy, or death due to any cause. RESULTS 990 patients were enrolled in the MER from 2002-2012 and 1446 patients were enrolled in the LYSA cohort from 2003-2009. Median (range) DTI was 15 days (0-155) days in the MER and 23 days (0-215) in LYSA. Short DTI (0-14 days) was strongly associated with adverse clinical factors including elevated LDH, poor performance status, presence of B symptoms, and higher aaIPI and IPI in both cohorts (all p 0.10) and DTI and age (p>0.068) were not statistically significant in both cohorts. There was no association between DTI and distance from enrollment center in the MER (p=0.99). Functional form analysis demonstrated a linear association between DTI and EFS24 in both cohorts. Longer DTI was associated with improved EFS24 in both the MER (per-week OR=0.80, 95%CI:0.74-.0.87, p CONCLUSION A short diagnosis-to-treatment interval is strongly associated with adverse clinical factors and poor outcome in newly diagnosed DLBCL. Conversely, patients with longer DTI have less aggressive clinical characteristics and better outcomes. This association has been replicated in a large cohort of patients enrolled on clinical trials. Clinical trials must take steps to avoid the bias of enrolling patients with expected good outcome due to their ability to delay treatment. Disclosures Ghesquieres: Celgene and Mundipharma: Consultancy, Honoraria; Roche: Research Funding. Haioun: PFIZER: Consultancy, Honoraria; GILEAD: Consultancy, Honoraria; JANSSEN: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Delarue: Gilead: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Molina: Takeda: Other: travel support to the ASH meeting; Novartis: Honoraria; Merck Serono: Honoraria. Ansell: Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Affimed: Research Funding. Cerhan: Janssen: Other: Scientific Advisory Board (REMICADELYM4001); Janssen: Other: Multiple Myeloma Registry Steering . Salles: morphosys: Consultancy, Honoraria; BMS: Consultancy; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding. Witzig: Novartis: Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Kura: Research Funding; Acerta: Research Funding. Tilly: Takeda: Consultancy, Honoraria; Immunogen: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Gilead: Honoraria. Nowakowski: celgene: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Genetech: Consultancy, Research Funding; Abbvie: Consultancy; pharmacyclics: Consultancy; Nanostring: Research Funding.