How to improve RCHOP as frontline therapy for diffuse large B-cell lymphoma: a systematic review and meta-analysis of 21 randomized controlled trials.

RCHOP is the standard of care for patients with diffuse large b-cell lymphoma (DLBCL) but failures occur in approximately 40% of them. We performed a meta-analysis of 21 randomized controlled trials (RCTs) comparing experimental regimens with RCHOP. We searched the database of PubMed with proper criteria, and data of efficacy (Progression Free Survival-PFS) in the ITT population were extracted and analyzed. Cross comparisons of RCTs were performed by using the CINEMA software. Odds ratio (OR) and 95% confidence intervals (95%, CI) are reported. The literature search yielded 21 RCTs including 5785 patients in the RCHOP arm and 5648 patients in the experimental arm. Odds ratio (OR) for PFS in the total cohort was OR (95%, CI): 0.87 (0.76-0.99), p=0.02. Among different strategies to improve RCHOP, addition of a novel agent on RCHOP improved PFS. In total 1740 patients in the RCHOP arm were compared with 1755 in the RCHOP plus a novel agent arm, and the OR (95% CI) for PFS was 0.84 (0.71-0.97), p=0.02. Indirect comparisons of nine studies adding a novel agent on RCHOP does not give prominence to any agent. Subgroup analysis according to cell of origin was performed for non-GC DLBCL patients. In this subgroup, 1546 patients treated with RCHOP were compared with 1538 patients treated with experimental regimens. The OR (95% CI) for PFS was 0.86 (0.73-1.02), p=0.34. Overall survival data extracted from 18 studies showed no superiority of experimental regimens over RCHOP. Efficacy of RCHOP backbone is marginally improved when adding a novel anti-lymphoma agent.

Does the Simultaneous Introduction of Several Pharmaceuticals in the Post-Lenalidomide Era Translate to Better Outcomes in Relapse Refractory Multiple Myeloma? Findings from the Real-World Innovation in Multiple Myeloma (REAL IMM) Study.

Newer methodologies are needed to assess the real-world comparative effectiveness of a "generation" of pharmaceutical innovation versus the prior standard of care. This chart review study aimed to first evaluate the cumulative clinical benefits of pharmaceutical innovation in everyday relapse/refractory multiple myeloma before analyzing findings in the context of respective real-world outcomes from the bortezomib/lenalidomide era. Study endpoints included the 52-week PFS rate in second and third line of therapy (LOT), mPFS-2 across the first and second LOT, the ORR, reasons for discontinuation, and the treatment duration per therapeutic algorithm. Data from 107 patients were collected. The median follow-up was 2.0 years. Of the subjects who met the selection criteria for the second LOT, 72.2% maintained the PFS at 52 weeks. In the third-line setting, the PFS rate at 52 weeks was 63.5%. The mPFS across the first and second, the second, and the third LOTs were 26, 17, and 15 months, respectively. The ORR was 76.1% in the second and 69.7% in the third LOT. After non-response or progression, the main reason for drug discontinuation was treatment intolerability. The second-line ORR and the 52-week PFS rate were similar to previous real-world findings from the bortezomib/lenalidomide era. The cumulative mPFS across the second and third LOTs was higher than the respective mPFS across the first and second LOTs. Despite its limitations, the methodology and findings from this study may be used in future clinical and economic evaluations across all hematological malignancies.

P-wave duration and interatrial block as predictors of new-onset atrial fibrillation: A systematic review and meta-analysis.

BACKGROUND: Early detection of atrial fibrillation (AF) could improve patient outcomes. P-wave duration (PWD) and interatrial block (IAB) are known predictors of new-onset AF and could improve selection for AF screening. This meta-analysis reviews the published evidence and offers practical implications. METHODS: Publication databases were systematically searched, and studies reporting PWD and/or morphology at baseline and new-onset AF during follow-up were included. IAB was defined as partial (pIAB) if PWD≥120 ms or advanced (aIAB) if the P-wave was biphasic in the inferior leads. After quality assessment and data extraction, random-effects analysis calculated odds ratio (OR) and confidence intervals (CI). Subgroup analysis was performed for those with implantable devices (continuous monitoring). RESULTS: Among 16,830 patients (13 studies, mean 66 years old), 2,521 (15%) had new-onset AF over a median of 44 months. New-onset AF was associated with a longer PWD (mean pooled difference: 11.5 ms, 13 studies, p < 0.001). The OR for new-onset AF was 2.05 (95% CI: 1.3-3.2) for pIAB (5 studies, p = 0.002) and 3.9 (95% CI: 2.6-5.8) for aIAB (7 studies, p < 0.001). Patients with pIAB and devices had higher AF-detection risk (OR: 2.33, p < 0.001) than those without devices (OR: 1.36, p = 0.56). Patients with aIAB had similarly high risk regardless of device presence. There was significant heterogeneity but no publication bias. CONCLUSION: Interatrial block is an independent predictor of new-onset AF. The association is stronger for patients with implantable devices (close monitoring). Thus, PWD and IAB could be used as selection criteria for intensive screening, follow-up or interventions.

Diagnostic comparison of electrical impedance spectroscopy with colposcopy and HPV mRNA-testing in the prediction of CIN2+ women in Greece.

AIM: To compare the diagnostic parameters of electrical impedance spectroscopy (EIS) via ZedScan, a device that measures spectra to differentiate between normal and abnormal cervical tissues, when used as an adjunct to colposcopies in the diagnosis of HSILs/CIN2+ in Greek women with abnormal referral cytology toward colposcopy alone and HPV mRNA-testing. METHODS: This study analyzed 86 women, patients of the Colposcopy and Cervical Pathology Clinic of 2nd Obstetrics and Gynecology Department, Aristotle University of Thessaloniki at Hippokration General Hospital, between January 2022 and September 2022. During the visits, women were subjected to cytology, colposcopy alone and then with EIS/ZedScan and histological sampling. RESULTS: Common use of colposcopies and EIS/ZedScan allowed detecting an additional 14 cases of CIN2+ (16.2%) that colposcopy alone failed to report. EIS enhanced the sensitivity of colposcopy from 80.65% to 100% equal with that of HPV-mRNA test while retaining a high specificity (94.74%) which is much higher than specificity of HPV mRNA-testing (65.45%). EIS-assisted colposcopy had the highest value combination of positive and negative predictive values (96.15% and 100%) compared to colposcopy alone (100% and 75%) and HPV mRNA-testing (72.46% and 100%). CONCLUSIONS: Colposcopies performed with EIS/ZedScan demonstrated effectiveness in the diagnosing of CIN2+ leading to a significant increase in the number of CIN2+ that would have been missed if only colposcopy was applied especially in women with LSIL referral cytology. EIS/ZedScan seems to possess the ideal diagnostic threshold for sensitivity, specificity, and predictive values for CIN2+ compared to colposcopy alone and HPV mRNA-testing.

P-wave duration and atrial fibrillation recurrence after catheter ablation: a systematic review and meta-analysis.

AIMS: Atrial fibrillation (AF) is a global health problem with high morbidity and mortality. Catheter ablation (CA) can reduce AF burden and symptoms, but AF recurrence (AFr) remains an issue. Simple AFr predictors like P-wave duration (PWD) could help improve AF therapy. This updated meta-analysis reviews the increasing evidence for the association of AFr with PWD and offers practical implications. METHODS AND RESULTS: Publication databases were systematically searched and cohort studies reporting PWD and/or morphology at baseline and AFr after CA were included. Advanced interatrial block (aIAB) was defined as PWD ≥ 120 ms and biphasic morphology in inferior leads. Random-effects analysis was performed using the Review Manager 5.3 and R programs after study selection, quality assessment, and data extraction, to report odds ratio (OR) and confidence intervals. : Among 4175 patients in 22 studies, 1138 (27%) experienced AFr. Patients with AFr had longer PWD with a mean pooled difference of 7.8 ms (19 studies, P < 0.001). Pooled OR was 2.04 (1.16-3.58) for PWD > 120 ms (13 studies, P = 0.01), 2.42 (1.12-5.21) for PWD > 140 ms (2 studies, P = 0.02), 3.97 (1.79-8.85) for aIAB (5 studies, P < 0.001), and 10.89 (4.53-26.15) for PWD > 150 ms (4 studies, P < 0.001). There was significant heterogeneity but no publication bias detected. CONCLUSION: P-wave duration is an independent predictor for AF recurrence after left atrium ablation. The AFr risk is increasing exponentially with PWD prolongation. This could facilitate risk stratification by identifying high-risk patients (aIAB, PWD > 150 ms) and adjusting follow up or interventions.

Reproductive Failure and Thrombophilia: Not Enough Evidence for a Tight Bond.

OBJECTIVES: The role of hereditary thrombophilia in reproductive failure (RF) is strongly debatable. In this retrospective single-center study, we analyzed pregnancy outcome in 175 women screened for thrombophilia after at least one event of RF. RESULTS: The prevalence of thrombophilia in our cohort was 33.4%. Pregnancy survival curves were not different according to severity (log-rank, p = 0.302) or type of thrombophilia (log-rank, p = 0.532). In total, 81.7% of 175 subsequent pregnancies were proceeded with LMWH. Concomitant use of ASA was prescribed in 75 pregnancies according to physician choice. The primary endpoint was live birth rate (LBR) that succeeded in 152/175 next pregnancies (86.8%) and late obstetric complications (LOBC) which occurred in 17/175 next pregnancies (9.8%). In logistic regression analysis, neither the severity nor the type of thrombophilia was important for any pregnancy outcome (LBR or LOBC). Considering therapeutic interventions, the use of LMWH ± ASA was not related to LBR or LOBC. The only factor inversely related to LBR was age above the cutoff value of 35.5 years (p = 0.049). CONCLUSIONS: Incidence of thrombophilia is increased among women with RF, but the severity or type of thrombophilia is not related to pregnancy outcome.

Socioeconomic Status is Globally a Prognostic Factor for Overall Survival of Multiple Myeloma Patients: Synthesis of Studies and Review of the Literature.

BACKGROUND: Socioeconomic status (SES) is reflecting differences in sociodemographic factors affecting cancer survivorship. Deprived, low SES populations have a higher prevalence of multiple myeloma and worst survival, a condition which widens over time. METHODS: We performed a meta-analysis of 16 studies (registries and cohorts) reporting myeloma patients' survival data according to SES. Ten studies reported Hazzard Ratio (H.R.) (95 % CI), and 16 studies reported p values. We combined the H.R. from 10 studies, and by using the Mosteller-Bush formula, we performed a synthesis of p values according to the area of the globe. RESULTS: Combination of H.R. from 10 studies including 85198 myeloma patients weighted to sample size of each study and adopting the hypothesis of random effect returned a combined H.R.: 1,26 (1,13-1,31) in favor of high SES patients.USA: Synthesis of p values coming from 6 studies (n=89807 pts) by using the Mosteller and Bush formula extracted a p-value of <0.0001 favoring high SES patients.Oceania: Synthesis of p values in two cohorts from Australia and New Zealand (n= 10196 pts) returned a p-value of 0,022 favoring high SES patients.Europe: The synthesis of p values from the U.K. and Greece studies (n=18533 pts) returned a p-value of <0,0001 favoring high SES patients.Asia: Synthesis of 2 studies from Asia (n=915 pts) returned a p-value of <0,0001 favoring high SES patients. CONCLUSIONS: Across the globe and widening over decades, the socioeconomic status remains a gap for equality in myeloma care.

DNA methylation patterns of RAR-ß2 and RASSF1A gene promoters in FNAB samples from Greek population with benign or malignant breast lesions.

BACKGROUND: Promoter hypermethylation is common in Breast Cancer (BC) with studies mainly in histological specimens showing frequent methylation of tumor suppressor genes (TSGs) compared with normal tissues. The aim of this study was to estimate the frequency of promoter methylation of RAR-ß2 and RASSF1A genes in breast FNAB material aiming to evaluate the methylation status of these two genes as biomarker for detecting BC in Greek population. METHODS: FNAB material from 104 patients was collected for cytological evaluation and epigenetic analysis. DNA was extracted and subjected to bisulfite conversion. A methylation-specific PCR was carried out and the final products were separated with electrophoresis in 2% agarose gels. RESULTS: From 104 samples, RASSF1A hypermethylation was observed in 78 (75%) and RAR-ß2 hypermethylation in 64 (61.6%). 84% and 78% of the cases diagnosed with breast malignancy (n = 50) were methylated for RASSF1A and RAR-ß2, respectively. Methylated RASSF1A and RAR-ß2 were also detected in 88.3% and 76.5% in samples diagnosed as suspicious for malignancy (n = 17) and in 57.2% of samples diagnosed with atypia (n = 14). The Odds Ratio for breast malignancy was 4.545 in patients with RASSF1A hypermethylation and 9.167 in patients with RAR-ß2 hypermethylation underlying their promoter's methylation positive correlation with breast malignancy. CONCLUSION: To optimize the sensitivity and specificity of this epigenetic setting, more TSGs related to BC should be gradually imported in our evaluated methylation panel and be validated in a larger study sample with the aim that the obtained epigenetic profiles will provide clinicians with valuable tools for management of BC patients in Greece.

Hold your needles in women with recurrent pregnancy losses with or without hereditary thrombophilia: Meta-analysis and review of the literature.

OBJECTIVES: The use of antithrombotic prophylaxis in women with recurrent pregnancy losses (RPL) remains controversial. METHODS: We performed meta-analysis of randomized controlled trials (RCTs) comparing low molecular weight heparin (LMWH) versus No LMWH in women with or without hereditary thrombophilia and RPL. Twelve RCTs met our inclusion criteria and 2298 women were included in this meta-analysis. Our primary end point was live birth and odds ratio (OR) for live birth are reported. RESULTS: In women with thrombophilia the benefit of LMWH on live birth is not significant but heterogeneity of the studies is significant (OR, 2.09; 95 % CI, 0.58-7.57; p = 0.26; I2 = 86 %, p = 0.0001). Considering women without thrombophilia there is no benefit of LMWH in OR of live birth and data from studies have low heterogeneity (OR, 1.25; 95 % CI, 0.88-1.78; p = 0 0.21; I2 = 44 %, p = 0.07). CONCLUSIONS: Hold your needles in women with RPL. Probably in some hereditary thrombophilic defects LMWH has a positive effect on OR for live birth.

Molecular evaluation of a multiplex methylation panel for epigenetic analysis of FNAB samples from Greek patients with suspicious breast lesions.

PURPOSE: Aberrant DNA methylation in promoter regions has been found in many cancers, including breast cancer (BC). A Methylation Specific PCR (MSP) was applied in breast Fine Needle Aspiration Biopsy (FNAB) material, which has been rarely used in the literature, to estimate the methylation frequencies of CND2, APC, HIN1 & CDH13 and to assess whether this multiplex methylation panel can be possibly used as an indicator-biomarker for BC detection in a Greek population. METHODS: A total of 104 participants were subjected to FNAB and both cytological evaluation and epigenetic analysis were carried out. DNA was extracted from FNAB samples and was subjected to bisulfite conversion. MSP was carried out with primers specific for either the methylated or unmethylated status for each gene. The final MSP products were analyzed in 2% agarose gels with electrophoresis. RESULTS: Hypermethylation was observed in 74%, 69.2%, 59.6% and 63.4% of the samples for CND2, HIN1, APC and CDH13, respectively. CND2 was the most hypermethylated in C5 cases (90%) and APC and HIN1 in C4 cases (88.2%). A significant correlation between histologic evaluation and the methylation frequencies for all 4 genes was calculated (p<0.001). Odds ratio for breast malignancy was 8.267 for CND2, 5.235 for APC, 7.852 for HIN1 and 22.920 for CDH13, underlying that their methylation is positively related to breast malignancy. Also, it seems that the combination of all genes into a multiplex methylation panel has significantly higher SP and PPV than any single gene methylation. CONCLUSIONS: Our study shows that breast FNAB combined with methylation data from the collected aspirates has a promising potential as a biomarker for the early detection of BC risk in women with suspicious lesions.

Socioeconomic Status Is an Independent Prognostic Factor for Overall Survival in Patients With Multiple Myeloma: Real-World Data From a Cohort of 223 Patients.

INTRODUCTION: Socioeconomic status (SES) has been shown to be a prognostic factor for overall survival in a variety of hematologic malignancies, especially for patients who require continuous care such as those with multiple myeloma (MM). PATIENTS AND METHODS: We retrospectively collected data from 223 patients with symptomatic MM diagnosed and treated in our department from January 2005 to December 2019. The modified Kuppuswamy scale, slightly modified, was used for the SES assessment. The Kaplan-Meier estimator of survival and Cox regression analysis were used. RESULTS: In our cohort of 223 patients with MM, low SES was an independent poor prognostic factor for overall survival (OS), in addition to higher International Staging System stage and high-risk cytogenetics (hazard ratio for low SES on Cox regression analysis, 2.092; 95% confidence interval [CI], 1.36-3.2; log-rank P = .000). Patients with low SES had inferior survival compared with the whole patient cohort (median OS: low SES, 28 months; 95% CI, 18-37.9; high SES, 68 months; 95% CI, 55.6-80.4; log-rank P = .000). The low SES effect on OS was more evident for the elderly patients who were not transplant eligible and in those with a diagnosis of MM International Staging System stage I. The effect of low SES on OS was attenuated by time, and ethnic origin had no effect on OS. CONCLUSIONS: The results of the present study have shown that low SES is an independent poor prognostic factor for survival of patients with MM.