Optimization of immune checkpoint inhibitor treatment planning for relapsed or refractory extranodal NK/T cell lymphoma.

Pembrolizumab (anti-programmed cell death-ligand 1 inhibitor) is a promising salvage therapeutic option for relapsed/refractory extranodal NK/T-cell lymphoma (R/R ENKTL). However, the appropriate duration of pembrolizumab use in R/R ENKTL patients and the optimal timing for administering pembrolizumab remain undetermined. We collected and analyzed clinical information on R/R ENKTL 58 patients who received pembrolizumab to evaluate the optimal treatment durations and clinical information for considering treatment interruption. Treatment outcomes were assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and Epstein Barr virus DNA (EBV DNA) every 3 months. Nineteen (32.8%) patients had been treated with more than three chemotherapies before pembrolizumab administration. The best response rate towards the first try of pembrolizumab was 38.9% (31.5% complete response rate (CR), 7.4% partial response (PR)). During the 41.8-month median follow-up duration, the median progression-free survival (PFS) was 3.1 months, and the median overall survival (OS) was 7.1 months. The failure group, which was characterized by Deaville score (DS) 3-4 and circulating EBV detection, or DS 5 with/without EBV detection, had the worst PFS (p < 0.001) and OS (p < 0.001), followed by the high (DS 1-2 and EBV detection, or DS 3-4 and EBV not detected) and low-risk groups (DS 1-2 and EBV not detected). Among the 21 patients who achieved the best response at the first pembolizumab try, the patients who received planned 24 cycles presented better PFS than those who received incomplete cycles (57.6 months vs 20.9 months, P-value = 0.012). Among 13 patients who received avelumab or pembrolizumab in advance, a few who responded to the second trial of pembrolizumab administration had over one year of chemotherapy vacation. Determining the discontinuation or continuation of pembrolizumab would be considered in selected cases assessed by PET-CT and EBV monitoring. Disruption of pembrolizumab treatment may be advisable for the low-risk group(DS 1-2 and EBV not detected), whereas continuation could be warranted for the high-risk group (DS 1-2 and EBV detection, or DS 3-4 and EBV not detected). Moreover, it might be critical to maintain over 24 cycles to improve the survival outcome of R/R ENKTL.

Comparable outcomes for TBI-based versus treosulfan based conditioning prior to allogeneic hematopoietic stem cell transplantation in AML and MDS patients.

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a standard treatment for patients with AML and MDS. The combination of fractionated total body irradiation(8GyTBI/Flu) with fludarabine is an established conditioning regimen, but fludarabine/treosulfan(Flu/Treo) constitutes an alternative in older/comorbid patients. We conducted a retrospective analysis of 215 AML(in CR) and 96 MDS patients undergoing their first allo-HCT between 2011 and 2022, identifying 53 matched Flu/Treo and 8GyTBI/Flu patients through propensity score matching. Median follow-up of survivors was 3.3 years and 4.1 years. For the Flu/Treo group, 1-year non-relapse mortality (2% vs. 10%, p = 0.03) was lower, while 1-year relapse incidence (16% vs. 13%, p = 0.81) was similar. Three-year outcomes, including relapse-free survival and graft-versus-host disease incidence, were comparable (OS: 81% vs. 74%, p = 0.70; RFS: 78% vs. 66%, p = 0.28; chronic GvHD: 34% vs. 36%, p = 0.97; acute GvHD (100 days): 11% vs. 23%, p = 0.11). Multivariable analysis, considering age, ECOG, HCT-CI, and MRD status, revealed no associations with main outcomes. Dose-reduced conditioning with Flu/Treo or 8GyTBI/Flu demonstrated favorable and comparable survival rates exceeding 70% at 3 years with 1-year NRM rates below 10% and low relapse rates in the matched cohort. These data underline the need for further evaluation of TBI and Treo-based conditionings in prospective trials.

Chimeric antigen receptor-T cell therapy shows similar efficacy and toxicity in patients with diffuse large B-cell lymphoma aged 70 and older compared to younger patients: A multicenter cohort study.

CD19-directed chimeric antigen receptor (CAR)-T cell therapy has become a standard treatment for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). While the benefits of CAR-T cell treatment are clear in the general patient population, there remains a relative scarcity of real-world evidence regarding its efficacy and toxicity in patients (pts) aged ≥70 years with DLBCL. We conducted a multicenter retrospective analysis including 172 r/r DLBCL pts with CAR-T cell treatment, axicabtagene ciloleucel or tisagenlecleucel, between 2019 and 2023 at three tertiary centers. Pts were grouped by age at CAR-T infusion (<70 vs. ≥70 years). Subsequently, descriptive and survival analyses, including propensity score matching, were performed to compare outcomes between both age groups. We identified 109 pts aged <70 and 63 pts aged ≥70 years. Overall response rates for both age groups were comparable (77.7% vs. 78.3%; p = 0.63). With a median follow-up of 8.3 months, median progression-free survival was 10.2 months (95% confidence interval [CI]: 6.5-21.8) and 11.1 months (95% CI: 4.9-NR) (p = 0.93) for both cohorts. Median overall survival reached 21.8 months (95% CI: 11.8-NR) and 34.4 months (95% CI: 10.1-NR) (p = 0.97), respectively. No significant differences in the incidence of cytokine release syndrome (p = 0.53) or grade ≥3 neurotoxicity (p = 0.56) were observed. Relapse and nonrelapse mortality were not significantly different between both groups. Our findings provide additional support that CAR-T cell therapy is feasible and effective in patients with r/r DLBCL aged 70 years or older, demonstrating outcomes comparable to those observed in younger patients. CAR-T cell therapy should be not withheld for elderly patients with r/r DLBCL.

Online searches for hepatocellular carcinoma drugs mirror prescription trends across specialties and changes in guideline recommendations.

Background & aims: The treatment options for systemically progressed hepatocellular carcinoma (HCC) have significantly expanded in recent years. In this study, we aimed to evaluate the potential of Google searches as a reflection of prescription rates for HCC drugs in the United States (US). Methods: We conducted an in-depth analysis of US prescription data obtained from the IQVIA National Prescription Audit (NPA) and corresponding Google Trends data from January 2017 to December 2022. We focused on drugs used in the first line and second or later treatment lines for HCC, collecting data on their prescriptions and search rates. Search volumes were collected as aggregated search queries for both generic drugs and their respective brand names. Results: During the study period from Q1 2017 to Q4 2022, monthly prescriptions for drugs used in HCC treatment showed an 173% increase (from 1253 to 3422). Conversely online searches increased by 3.5% (from 173 to 179 per 10 million searches). Notably, strong correlations were observed between search interest and prescriptions for newer drugs, which indicates increasing usage, while older drugs with declining usage displayed limited correlation. Our findings suggest a growing role of non-physician professions in managing systemically progressed HCC within the US healthcare system, although oncologists remained primarily responsible for drug prescriptions. Conclusions: In conclusion, online search monitoring can offer the potential to reflect prescription trends specifically related to the treatment of HCC. This approach provides a swift and accessible means of evaluating the evolving landscape of HCC treatment.

Activity of tafasitamab in combination with rituximab in subtypes of aggressive lymphoma.

Background: Despite recent advances in the treatment of aggressive lymphomas, a significant fraction of patients still succumbs to their disease. Thus, novel therapies are urgently needed. As the anti-CD20 antibody rituximab and the CD19-targeting antibody tafasitamab share distinct modes of actions, we investigated if dual-targeting of aggressive lymphoma B-cells by combining rituximab and tafasitamab might increase cytotoxic effects. Methods: Antibody single and combination efficacy was determined investigating different modes of action including direct cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) in in vitro and in vivo models of aggressive B-cell lymphoma comprising diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Results: Three different sensitivity profiles to antibody monotherapy or combination treatment were observed in in vitro models: while 1/11 cell lines was primarily sensitive to tafasitamab and 2/11 to rituximab, the combination resulted in enhanced cell death in 8/11 cell lines in at least one mode of action. Treatment with either antibody or the combination resulted in decreased expression of the oncogenic transcription factor MYC and inhibition of AKT signaling, which mirrored the cell line-specific sensitivities to direct cytotoxicity. At last, the combination resulted in a synergistic survival benefit in a PBMC-humanized Ramos NOD/SCID mouse model. Conclusion: This study demonstrates that the combination of tafasitamab and rituximab improves efficacy compared to single-agent treatments in models of aggressive B-cell lymphoma in vitro and in vivo.

Allogeneic hematopoietic stem cell transplantation for NK/T-cell lymphoma: an international collaborative analysis.

Natural killer/T-cell lymphomas (NKTCL) represent rare and aggressive lymphoid malignancies. Patients (pts) with relapsed/refractory disease after Asparaginase (ASPA)-based chemotherapy have a dismal prognosis. To better define the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT), we conducted a retrospective analysis of data shared with the European Society for Blood and Marrow Transplantation (EBMT) and cooperating Asian centers. We identified 135 pts who received allo-HSCT between 2010 and 2020. Median age was 43.4 years at allo-HSCT, 68.1% were male. Ninety-seven pts (71.9 %) were European, 38 pts (28.1%) Asian. High Prognostic Index for NKTCL (PINK) scores were reported for 44.4%; 76.3% had >1 treatment, 20.7% previous auto-HSCT, and 74.1% ASPA-containing regimens prior to allo-HSCT. Most (79.3%) pts were transplanted in CR/PR. With a median follow-up of 4.8 years, 3-year progression-free(PFS) and overall survival were 48.6% (95%-CI:39.5-57%) and 55.6% (95%-CI:46.5-63.8%). Non-relapse mortality at 1 year was 14.8% (95%-CI:9.3-21.5%) and 1-year relapse incidence 29.6% (95%-CI:21.9-37.6%). In multivariate analyses, shorter time interval (0-12 months) between diagnosis and allo-HSCT [HR = 2.12 (95%-CI:1.03-4.34); P = 0.04] and transplantation not in CR/PR [HR = 2.20 (95%-CI:0.98-4.95); P = 0.056] reduced PFS. Programmed cell death protein 1(PD-1/PD-L1) treatment before HSCT neither increased GVHD nor impacted survival. We demonstrate that allo-HSCT can achieve long-term survival in approximately half of pts allografted for NKTCL.

mTOR inhibition amplifies the anti-lymphoma effect of PI3Kß/δ blockage in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease that exhibits constitutive activation of phosphoinositide 3-kinase (PI3K) driven by chronic B-cell receptor signaling or PTEN deficiency. Since pan-PI3K inhibitors cause severe side effects, we investigated the anti-lymphoma efficacy of the specific PI3Kß/δ inhibitor AZD8186. We identified a subset of DLBCL models within activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL that were sensitive to AZD8186 treatment. On the molecular level, PI3Kß/δ inhibition decreased the pro-survival NF-κB and AP-1 activity or led to downregulation of the oncogenic transcription factor MYC. In AZD8186-resistant models, we detected a feedback activation of the PI3K/AKT/mTOR pathway following PI3Kß/δ inhibition, which limited AZD8186 efficacy. The combined treatment with AZD8186 and the mTOR inhibitor AZD2014 overcame resistance to PI3Kß/δ inhibition and completely prevented outgrowth of lymphoma cells in vivo in cell line- and patient-derived xenograft mouse models. Collectively, our study reveals that subsets of DLBCLs are addicted to PI3Kß/δ signaling and thus identifies a previously unappreciated role of the PI3Kß isoform in DLBCL survival. Furthermore, our data demonstrate that combined targeting of PI3Kß/δ and mTOR is effective in all major DLBCL subtypes supporting the evaluation of this strategy in a clinical trial setting.

Online searches for SGLT-2 inhibitors and GLP-1 receptor agonists correlate with prescription rates in the United States: An infodemiological study.

Several clinical trials have demonstrated that many SGLT-2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1 RA) can reduce the risk of cardiovascular events in patients with Type 2 diabetes and atherosclerotic cardiovascular disease. Recent reports indicate an underutilization of new cardiometabolic drugs, including SGLT2i and GLP-1 RA. We aimed to evaluate the use of online search volumes to reflect United States prescription rates. A repeated cross-sectional analysis of Google search volumes and corresponding data from the IQVIA National Prescription Audit (NPA) of pharmacy dispensing of newly prescribed drugs was performed. Monthly data for online searches and prescription between January 1, 2016 and December 31, 2021 were collected for selected SGLT2i and GLP-1 RA. Prescription data for drugs classes (SGLT2i and GLP-1 RA) and individual drugs were calculated as the total of queried data for branded drug names. Trends were analyzed for visual and quantitative correlation as well as predictive patterns. Overall, online searches increased by 157.6% (95% CI: 142.2-173.1%) and 295.2% (95% CI: 257.7-332.6%) for SGLT2i and GLP-1RA between 2016 and 2021. Prescription rates raised by 114.6% (95% CI: 110.8-118.4%) and 221.0% (95% CI: 212.1-229.9%) for SGLT2i and GLP-1RA for this period. Correlation coefficients (range 0.86-0.99) were strongest for drugs with growing number of prescriptions, for example dapagliflozin, empagliflozin, ertugliflozin, dulaglutide, and semaglutide. Online searches might represent an additional tool to monitor the utilization trends of cardiometabolic drugs. Associations were strongest for drugs with reported cardioprotective effect. Thus, trends in online searches complement conventionally acquired data to reflect and forecast prescription trends of cardiometabolic drugs.

Clinical relevance of molecular characteristics in Burkitt lymphoma differs according to age.

While survival has improved for Burkitt lymphoma patients, potential differences in outcome between pediatric and adult patients remain unclear. In both age groups, survival remains poor at relapse. Therefore, we conducted a comparative study in a large pediatric cohort, including 191 cases and 97 samples from adults. While TP53 and CCND3 mutation frequencies are not age related, samples from pediatric patients showed a higher frequency of mutations in ID3, DDX3X, ARID1A and SMARCA4, while several genes such as BCL2 and YY1AP1 are almost exclusively mutated in adult patients. An unbiased analysis reveals a transition of the mutational profile between 25 and 40 years of age. Survival analysis in the pediatric cohort confirms that TP53 mutations are significantly associated with higher incidence of relapse (25 ± 4% versus 6 ± 2%, p-value 0.0002). This identifies a promising molecular marker for relapse incidence in pediatric BL which will be used in future clinical trials.

Association of Online Search Trends With Vaccination in the United States: June 2020 Through May 2021.

Stagnating COVID-19 vaccination rates and vaccine hesitancy remain a threat to public health. Improved strategies for real-time tracking and estimation of population-level behavior regarding vaccinations are needed. The aim of this study was to evaluate whether online search trends for COIVD-19 and influenza mirror vaccination rates. State-level weekly fraction of online searches for top vaccination-related search terms and CDC vaccination data were obtained from June 1, 2020, to May 31, 2021. Next, trends in online search and vaccination data for COVID-19 and influenza were analyzed for visual and quantitative correlation patterns using Spearman's rank correlation analysis. Online searches in the US for COVID-19 vaccinations increased 2.71-fold (95% CI: 1.98-3.45) in the 4 weeks after the FDA emergency authorization compared to the precedent 4 weeks. In March-April 2021, US online searches reached a plateau that was followed by a decline of 83.3% (95% CI: 31.2%-135.3%) until May 31, 2021. The timing of peaks in online searches varied across US states. Online searches were strongly correlated with vaccination rates (r=0.71, 95% CI: 0.45 - 0.87), preceding actual reported vaccination rates in 44 of 51 states. Online search trends preceded vaccination trends by a median of 3.0 weeks (95% CI: 2.0-4.0 weeks) across all states. For influenza vaccination searches, seasonal peaks in September-October between 2016-2020 were noted. Influenza search trends highly correlated with the timing of actual vaccinations for the 2019-2020 (r=0.82, 95% CI: 0.64 - 0.93) and 2020-2021 season (r=0.91, 95% CI: 0.78 - 0.97). Search trends and real-world vaccination rates are highly correlated. Temporal alignment and correlation levels were higher for influenza vaccinations; however, only online searches for COVID-19 vaccination preceded vaccination trends. These findings indicate that US online search data can potentially guide public health efforts, including policy changes and identifying geographical areas to expand vaccination campaigns.

Coronary artery calcium is associated with increased risk for lung and colorectal cancer in men and women: the Multi-Ethnic Study of Atherosclerosis (MESA).

AIMS: This study explored the association of coronary artery calcium (CAC) with incident cancer subtypes in the Multi-Ethnic Study of Atherosclerosis (MESA). CAC is an established predictor of cardiovascular disease (CVD), with emerging data also supporting independent predictive value for cancer. The association of CAC with risk for individual cancer subtypes is unknown. METHODS AND RESULTS: We included 6271 MESA participants, aged 45-84 and without known CVD or self-reported history of cancer. There were 777 incident cancer cases during mean follow-up of 12.9 ± 3.1 years. Lung and colorectal cancer (186 cases) were grouped based on their strong overlap with CVD risk profile; prostate (men) and ovarian, uterine, and breast cancer (women) were considered as sex-specific cancers (in total 250 cases). Incidence rates and Fine and Gray competing risks models were used to assess relative risk of cancer-specific outcomes stratified by CAC groups or Log(CAC+1). The mean age was 61.7 ± 10.2 years, 52.7% were women, and 36.5% were White. Overall, all-cause cancer incidence increased with CAC scores, with rates per 1000 person-years of 13.1 [95% confidence interval (CI): 11.7-14.7] for CAC = 0 and 35.8 (95% CI: 30.2-42.4) for CAC ≥400. Compared with CAC = 0, hazards for those with CAC ≥400 were increased for lung and colorectal cancer in men [subdistribution hazard ratio (SHR): 2.2 (95% CI: 1.1-4.7)] and women [SHR: 2.2 (95% CI: 1.0-4.6)], but not significantly for sex-specific cancers across sexes. CONCLUSION: CAC scores were associated with cancer risk in both sexes; however, this was stronger for lung and colorectal when compared with sex-specific cancers. Our data support potential synergistic use of CAC scores in the identification of both CVD and lung and colorectal cancer risk.

Coronary artery calcium is associated with long-term mortality from lung cancer: Results from the Coronary Artery Calcium Consortium.

BACKGROUND AND AIMS: Coronary artery calcium (CAC) scores have been shown to be associated with CVD and cancer mortality. The use of CAC scores for overall and lung cancer mortality risk prediction for patients in the Coronary Artery Calcium Consortium was analyzed. METHODS: We included 55,943 patients aged 44-84 years without known heart disease from the CAC Consortium. There were 1,088 cancer deaths, among which 231 were lung cancer, identified by death certificates with a mean follow-up of 12.2 ± 3.9 years. Fine-and-Gray competing-risk regression was used for overall and lung cancer-specific mortality, accounting for the competing risk of CVD death and after adjustment for CVD risk factors. Subdistribution hazard ratios (SHR) were reported. RESULTS: The mean age of all patients was 57.1 ± 8.6 years, 34.9% were women, and 89.6% were white. Overall, CAC was strongly associated with cancer mortality. Lung cancer mortality increased with increasing CAC scores, with rates per 1000-person years of 0.2 (95% CI: 0.1-0.3) for CAC = 0 and 0.8 (95% CI: 0.6-1.0) for CAC ≥400. Compared with CAC = 0, hazards were increased for those with CAC ≥400 for lung cancer mortality [SHR: 1.7 (95% CI: 1.2-2.6)], which was driven by women [SHR: 2.3 (95% CI: 1.1-4.8)], but not significantly increased for men. Risks were higher in those with positive smoking history [SHR: 2.2 (95% CI: 1.2-4.2)], with associations driven by women [SHR: 4.0 (95% CI: 1.4-11.5)]. CONCLUSIONS: CAC scores were associated with increased risks for lung cancer mortality, with strongest associations for current and former smokers, especially in women. Used in conjunction with other clinical variables, our data pinpoint a potential synergistic use of CAC scanning beyond CVD risk assessment for identification of high-risk lung cancer screening candidates.

Internet Search Trends Relevant to Interventional Oncology: A Google Trends Study (2004-2020).

Interventional Radiology (IR) procedures addressing cancer have been grouped in the subspecialty of interventional oncology and represent an important component of modern multidisciplinary cancer care. This study pinpoints temporal and geographical trends of public online searches for terms related to the field, as well as IR-related cancer therapies. Google Trends data were analyzed for long-term (2004-2020) trends in the United States and worldwide. Overall, search interest for IR increased throughout the United States but decreased globally. Specific search volumes for cancer-related IR techniques such as radioembolization and chemoembolization therapies increased by 2.8- and 2.5-fold, respectively, in the United States, whereas the search volumes for ablation techniques remained steady or decreased. Future research and advocacy may focus on increasing public awareness of the field.

Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma.

Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.

The role of autologous stem cell transplantation (ASCT) in aggressive B-cell lymphomas: real-world data from a retrospective single-center analysis.

Patients with high-risk or relapsed aggressive B-cell lymphomas are characterized by poor prognosis. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) can induce durable remissions in these patients and is potentially curative. Two hundred forty-seven patients with aggressive B-cell lymphomas treated with high-dose chemotherapy and ASCT, either as consolidation after first-line therapy or after salvage therapy for relapsed disease, between 2002 and 2019 at the University Hospital Muenster, were analyzed. The median follow-up of surviving patients was 36 months (range 0-163). Progression-free survival (PFS) and overall survival (OS) after 3 years was 63% and 68%, respectively. After ASCT, 28% of all patients experienced a relapse. The cumulative incidence of non-relapse mortality at day 100 after ASCT was 4%. Multivariate analysis identified remission status at ASCT, age at ASCT, and the numbers of infused CD34+ cells as independent prognostic factors for both PFS and OS. Patients with mantle cell lymphoma (MCL) or primary CNS lymphoma (PCNSL) treated with ASCT in first-line had a superior OS and PFS when compared to patients treated with ASCT in relapsed disease. For patients with diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), early relapse (< 12 months) after first-line therapy showed a trend towards an inferior PFS and OS. Deaths after ASCT were predominantly caused by lymphoma relapse and/or progression (64%) or due to infections (23%). In conclusion, high-dose chemotherapy followed by ASCT in the era of novel targeted agents remains a feasible and effective approach for patients with high-risk or relapsed aggressive B-cell lymphomas. Remission status and age at ASCT, and the number of infused stem cells were of prognostic relevance.

Understanding myocardial infarction trends during the early COVID-19 pandemic: an infodemiology study.

During the first months of the coronavirus disease 2019 (COVID-19) pandemic in early 2020, Google Trends data in the United States showed a strong increase in search query frequency for chest pain symptoms despite a concurrent decrease in search interest for myocardial infarction. This suggests a reduced attention to acute coronary syndrome (ACS) and chest pain as its main symptom during this time period. These observations could help explain why cardiovascular mortality rose dramatically despite a strong decrease in hospitalisation rates for ACS.

Targeting B-cell receptor and PI3K signaling in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous diagnostic category comprising distinct molecular subtypes characterized by diverse genetic aberrations that dictate patient outcome. As roughly one-third of patients with DLBCL are not cured by current standard chemoimmunotherapy, a better understanding of the molecular pathogenesis is warranted to improve outcome. B-cell receptor (BCR) signaling is crucial for the development, growth, and survival of normal B cells and a substantial fraction of malignant B cells. Various analyses revealed genetic alterations of central components of the BCR or its downstream signaling effectors in some subtypes of DLBCL. Thus, BCR signaling and the downstream NF-κB and phosphatidylinositol 3-kinase (PI3K) cascades have been proposed as potential targets for the treatment of patients with DLBCL. As one of the main effectors of BCR activation, PI3K-mediated signals play a crucial role in the pathogenesis and survival of DLBCL. In this review, we summarize our current understanding of BCR signaling with a special focus on the PI3K pathway in DLBCL and how to use this knowledge therapeutically.

Temporal Trends and Interest in Coronary Artery Calcium Scoring Over Time: An Infodemiology Study.

OBJECTIVE: To evaluate interest in coronary artery calcium (CAC) among the general public during the past 17 years and to compare trends with real-world data on number of CAC procedures performed. METHODS: We used Google Trends, a publicly available database, to access search query data in a systematic and quantitative fashion to search for CAC-related key terms. Search terms included calcium test, heart score, calcium score, coronary calcium, and calcium test score. We accessed Google Trends in January 2021 and analyzed data from 2004 to 2020. RESULTS: From 2004 to December 31, 2020, CAC-related search interest (in relative search volume) increased continually worldwide (+201.9%) and in the United States (+354.8%). Three main events strongly influenced search interest in CAC: reports of a CAC scan of the president of the United States led to a transient 10-fold increase in early January 2018. American College of Cardiology/American Heart Association guideline release led to a sustained increase, and lockdown after the global pandemic due to COVID-19 led to a transient decrease. Real-world data on performed CAC scans showed an increase between 2006 and 2017 (+200.0%); during the same time period, relative search volume for CAC-related search terms increased in a similar pattern (+70.6%-1511.1%). For the search term coronary calcium scan near me, a potential representative of active online search for CAC scanning, we found a +28.8% increase in 2020 compared with 2017. CONCLUSION: Google Trends, a valuable tool for assessing public interest in health-related topics, suggests increased overall interest in CAC during the last 17 years that mirrors real-world usage data. Increased interest is seemingly linked to reports of CAC testing in world leaders and endorsement in major guidelines.

Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL.

Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a substantial therapeutic challenge. DLBCL can be classified into at least 2 major subtypes (germinal center B cell [GCB]-like and activated B cell [ABC]-like DLBCL), each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad antitumor effect of dimethyl fumarate (DMF) on both DLBCL subtypes, which is mediated by the induction of ferroptosis, a form of cell death driven by the peroxidation of phospholipids. As a result of the high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induces lipid peroxidation and thus ferroptosis, particularly in GCB DLBCL. In ABC DLBCL cells, which are addicted to NF-κB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and Janus kinases. Interestingly, the BCL-2-specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL. Collectively, our findings identify the clinically approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCLs.

Decreased public pursuit of cancer-related information during the COVID-19 pandemic in the United States.

BACKGROUND: In response to the prioritization of healthcare resources towards the COVID-19 pandemic, routine cancer screening and diagnostic have been disrupted, potentially explaining the apparent COVID-era decline in cancer cases and mortality. In this study, we identified temporal trends in public interest in cancer-related health information using the nowcasting tool Google Trends. METHODS: We used Google Trends to query search terms related to cancer types for short-term (September 2019-September 2020) and long-term (September 2016-September 2020) trends in the US. We compared average relative search volumes (RSV) for specified time ranges to detect recent and seasonal variation. RESULTS: General search interest declined for all cancer types beginning in March 2020, with changes in search interest for "Breast cancer," "Colorectal cancer," and "Melanoma" of - 30.6%, - 28.2%, and - 26.7%, respectively, and compared with the mean RSV of the two previous months. In the same time range, search interest for "Telemedicine" has increased by + 907.1% and has reached a 4-year peak with a sustained increased level of search interest. Absolute cancer mortality has declined and is presently at a 4-year low; however, search interest in cancer has been recuperating since July 2020. CONCLUSION: We observed a marked decline in searches for cancer-related health information that mirrors the reduction in new cancer diagnoses and cancer mortality during the COVID-19 pandemic. Health professions need to be prepared for the coming demand for cancer-related healthcare, foreshadowed by recovering interest in cancer-related information on Google Trends.