Clinical and Genomic Profile of Primary Cranial Neurolymphomatosis.

Primary cranial neurolymphomatosis (PCNL) is a rare subtype of primary CNS lymphoma (PCNSL) in which infiltrative lymphomatous involvement is confined to cranial nerves. Here, we report a case of PCNL with successful genomic profiling. A 57-year-old male had a lengthy prediagnostic phase spanning approximately 30 months, characterized by multiple episodes of cranial neuropathies managed by steroids. At the time of diagnosis, the patient had right-sided cranial neuropathies involving cranial nerves (CN) V, VI, and VII. Pathological findings of the right cavernous lesion biopsy were consistent with large B-cell lymphoma-infiltrating nerve fibers. The clinical course was aggressive and refractory, characterized by relentless progression with the development of cervical spinal neurolymphomatosis, cerebrospinal fluid involvement, and ependymal and intraparenchymal cerebral involvement, despite multiple lines of therapy, including chemoimmunotherapy, Bruton's tyrosine kinase inhibitor, radiation, autologous stem cell transplant, chimeric antigen receptor T-cell therapy (CAR-T), and whole-brain radiation. The patient survived for 22 months from the time of the initial diagnosis and 52 months after the first episode of cranial neuropathy. Next-generation sequencing identified mutations (MYD88, CD79b, and PIM1) that are frequently observed in PCNSL. The unusual findings included a total of 22 mutations involving PIM1, indicating a highly active aberrant somatic hypermutation and two missense CXCR4 mutations. CXCR4 mutations have never been described in PCNSL and may have implications for disease biology and therapeutic interventions. We provide a literature review to further elucidate PCNL.

Accuracy and correlation of bed and standing scale weights in monitoring volume status in heart failure patients.

Introduction: Accurate volume status monitoring is crucial for effective diuretic therapy in patients with acute decompensated heart failure (ADHF). While guidelines recommend daily standing body weight measurement as an indicator of volume status, bed scales are commonly used in healthcare facilities. Methods: A method-comparison design was used to compare bed and standing scale weights among adults hospitalized with ADHF at Los Angeles County-University of Southern California Medical Center between March and April 2023. Results & Conclusion: Among 51 weight pairs from 43 participants, a clinically significant mean difference of 1.42 ± 1.18 kg was observed, exceeding the recommended threshold. Inaccuracies, with 71% showing differences >0.6 kg, highlight potential fluid management errors when relying on bed scales in ADHF hospitalizations.

Targets and treatments in primary CNS lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare and highly aggressive lymphoma entirely localized in the central nervous system or vitreoretinal space. PCNSL generally initially responds to methotrexate-containing chemotherapy regimens, but progressive or relapsing disease is common, and the prognosis is poor for relapsed or refractory (R/R) patients. PCNSL is often characterized by activation of nuclear factor kappa B (NF-κB) due to mutations in the B-cell receptor (BCR) or toll-like receptor (TLR) pathways, as well as immune evasion. Targeted treatments that inhibit key PCNSL mechanisms and pathways are being evaluated; inhibition of Bruton's tyrosine kinase (BTK) downstream of BCR activation has demonstrated promising results in treating R/R disease. This review will summarize the evidence and potential for targeted therapeutic agents to improve treatment outcomes in PCNSL. This includes immunotherapeutic and immunomodulatory approaches and inhibitors of the key pathways driving PCNSL, such as aberrant BCR and TLR signaling.

Hyperviscosity Syndrome Induced Bilateral Visual and Auditory Impairment in Therapy Resistant Waldenström Macroglobulinemia with MYD88 and CXCR4 Mutations.

Hyperviscosity syndrome (HVS) is an emergent complication of Waldenström macroglobulinemia (WM) characterized by visual, neurologic, and rarely auditory impairment. We report a 69-year-old female with MYD88 and CXCR4-mutant WM who developed HVS resulting in bilateral blindness and deafness associated with neurologic manifestations including confusion, severe generalized weakness, and imbalance. Ophthalmologic evaluation revealed bilateral central retinal vein occlusion (CRVO), diffuse retinal hemorrhages, macular edema, and serous macular detachments (SMD). Magnetic resonance imaging of the brain showed bleeding in the inner ears. Management was challenging as her WM was resistant to systemic therapies including bendamustine + rituximab (BR) and rituximab + bortezomib + dexamethasone (RVD). Bruton's tyrosine kinase inhibitors could not be used initially due to ongoing lower gastrointestinal bleeding. She required five total sessions of plasma exchange and was finally initiated on zanubrutinib, achieving a partial response. She also received intravitreal bevacizumab with rapid resolution of the retinal hemorrhages but with little improvement of the SMD. She had partial restoration of her hearing in the right ear and only slight improvement in her bilateral visual deficits. The management of HVS in frail, elderly patients with therapy-resistant WM can be challenging. In these cases, plasma exchange is required until an effective systemic therapy can be safely instituted. Genomic profiling is important in the management of WM as it can predict treatment resistance and guide therapeutic decisions.

Acquired Factor VII Deficiency Associated With Chronic Myeloid Leukemia Blast Crisis.

Factor VII (FVII) is an important, vitamin K-dependent clotting factor. Acquired FVII deficiency is a rare entity that is associated with serious bleeding complications. We report a case of acquired FVII deficiency in a patient with recurrent chronic myeloid leukemia in blast crisis who developed bilateral retinal hemorrhages. The coagulopathy was corrected with the initiation of chemotherapy and subsequent reduction in peripheral blast count.

IRAK-4 inhibition: emavusertib for the treatment of lymphoid and myeloid malignancies.

Several studies have identified mutations in the MYD88L265P gene as a key driver mutation in several B-cell lymphomas. B-cell lymphomas that harbor the MYD88L265P mutation form a complex with phosphorylated Bruton's tyrosine kinase (BTK) and are responsive to BTK inhibition. However, BTK inhibition in B-cell lymphomas rarely results in a complete response and most patients experience eventual disease relapse. Persistent survival signaling though downstream molecules such as interleukin 1 receptor-associated kinase 4 (IRAK-4), an integral part of the "myddosome" complex, has been shown to be constitutively active in B-cell lymphoma patients treated with BTK inhibitors. Emerging evidence is demonstrating the therapeutic benefit of IRAK-4 inhibition in B-cell lymphomas, along with possibly reversing BTK inhibitor resistance. While MYD88 gene mutations are not present in myeloid malignancies, downstream overexpression of the oncogenic long form of IRAK-4 has been found in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), particularly in AML and MDS that harbor mutations in splicing factors U2AF1 and SF3B1. These data suggest that the anti-leukemic activity of IRAK-4 inhibition can be exploited in relapsed/refractory (R/R) AML/MDS. In this review article, we discuss the currently available pre-clinical and clinical data of emavusertib, a selective, orally bioavailable IRAK-4 inhibitor in the treatment of R/R B-cell lymphomas and myeloid malignancies.

90Yttrium Ibritumomab Tiuxetan (Zevalin) for the Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Report of 5 Cases.

Radioimmunotherapy (RIT) with radio-labeled monoclonal antibodies to CD20 produces a high response rate in patients with low-grade B-cell lymphomas. The use of this modality in patients with chronic lymphocytic leukemia (CLL) has been sporadic in clinical trials and was hampered by the extensive marrow involvement seen commonly in patients with CLL, which would produce a high risk for marrow aplasia after treatment with RIT. Herein, we report our experience with RIT in 5 patients with CLL or SLL showing short-lived responses and significant myelosuppression. After 90Y-ibritumomab tiuxetan treatment, the median time to relapse was 65 days, and no cases of MDS or AML were observed during follow-up. All patients experienced grade ≥3 thrombocytopenia and neutropenia, with median durations of 39.5 days and 107 days, respectively.

Webtool to enhance the accuracy of diagnostic algorithms for HFpEF: a prospective cross-over study.

AIMS: Diagnosis of heart failure with preserved ejection fraction (HFpEF) can be challenging. This study aimed to evaluate the potential of a webtool to enhance the scoring accuracy when applying the complex HFA-PEFF and H2 FPEF algorithms, which are commonly used for diagnosing HFpEF. METHODS AND RESULTS: We developed an online tool, the HFpEF calculator, that enables the automatic calculation of current HFpEF algorithms. We assessed the accuracy of manual vs. automatic scoring, defined as the percentage of correct scores, in a cohort of cardiologists with varying clinical experience. Cardiologists scored eight online clinical cases using a triple cross-over design (i.e. two manual-two automatic-two manual-two automatic). Data were analysed in study completers (n = 55, 29% heart failure specialists, 42% general cardiologists, and 29% cardiology residents). Manually calculated scores were correct in 50% (HFA-PEFF: 50% [50-75]; H2 FPEF: 50% [38-50]). Correct scoring improved to 100% using the HFpEF calculator (HFA-PEFF: 100% [88-100], P < 0.001; H2 FPEF: 100% [75-100], P < 0.001). Time spent on clinical cases was similar between scoring methods (±4 min). When corrections for faulty algorithm scores were displayed, cardiologists changed their diagnostic decision in up to 67% of cases. At least 67% of cardiologists preferred using the online tool for future cases in clinical practice. CONCLUSIONS: Manual calculation of HFpEF diagnostic algorithms is often inaccurate. Using an automated webtool to calculate HFpEF algorithms significantly improved correct scoring. This new approach may impact the eventual diagnostic decision in up to two-thirds of cases, supporting its routine use in clinical practice.

Successful Anatomy Adapted Therapeutic Management and Genetic Profiling of Primary Pituitary Diffuse Large B-Cell Lymphoma.

Primary pituitary diffuse large B-cell lymphoma (PPL) has been regarded as a subtype of primary central nervous system lymphoma (PCNSL); however, the pituitary gland is located outside the blood brain barrier (BBB) with neural and vascular connections to the brain. Given its unique anatomic location, a combination of non-central nervous system (CNS)-penetrating and CNS-penetrating therapeutic agents can be employed to treat PPL. We report a female patient with PPL who was successfully managed with anatomy-adapted therapy incorporating non-CNS penetrating chemoimmunotherapy [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)] alternating with CNS-penetrating chemoimmunotherapy [rituximab, high-dose methotrexate, and high-dose cytarabine (RMA)]. She received a total of eight cycles of treatment with four cycles of each regimen following partial transsphenoidal resection. She achieved a complete response after two cycles and has remained in complete remission for the last eight years. To our knowledge, this is the longest documented survival in a patient with PPL. Targeted genomic profiling with Next-Generation Sequencing (NGS) was recently performed on the lymphoma tissue. The genomic profile of PPL in this patient is quite different from the findings typically associated with PCNSL. We suggest that PPL may be biologically distinct from PCNSL and should be treated with an anatomy adapted approach. Additional research is necessary to confirm our findings.

Multiply Relapsed Secondary CNS Non-Germinal Center Diffuse Large B-Cell Lymphoma Successfully Treated with CNS-Centric Therapy.

Secondary central nervous system involvement by systemic diffuse large B-cell lymphoma (DLBCL) carries a very poor prognosis. We present a female patient who had two episodes of intracerebral central nervous system (CNS)-only relapse of systemic non-germinal center diffuse large B-cell lymphoma (NGC-DLBCL). Her treatment at initial diagnosis consisted of induction with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and intrathecal (IT) - methotrexate (MTX) followed by consolidation with autologous stem cell transplant (ASCT) after high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy. She had the first CNS-only relapse 1.5 years post-ASCT and received whole brain radiation therapy (WBRT). She developed the second intracerebral CNS-only relapse 2 years post-WBRT. A CNS-centric therapeutic approach with salvage chemoimmunotherapy incorporating rituximab, high-dose methotrexate (HD-MTX), high-dose cytarabine (HiDAC), and ibrutinib was utilized for her second CNS-only relapse. She underwent consolidation with a second ASCT following high-dose carmustine (BCNU) and thiotepa chemotherapy. Given her high risk of CNS recurrence, she was started on maintenance ibrutinib. To date, she has remained in complete remission for 3 years. In our experience, multiply relapsed secondary CNS lymphoma (SCNSL) with this response is very rare. We suggest one CNS-centric therapeutic approach that can potentially salvage patients with SCNSL who have not had prior exposure to adequate CNS-directed therapies but acknowledge that additional research is necessary to validate our findings.

Cardiovascular outcomes in breast cancer survivors: a systematic review and meta-analysis.

AIMS: It is unclear whether the future risk of cardiovascular events in breast cancer (Bc) survivors is greater than in the general population. This meta-analysis quantifies the risk of cardiovascular disease development in Bc patients, compared to the risk in a general matched cancer-free population, and reports the incidence of cardiovascular events in patients with Bc. METHODS AND RESULTS: We searched PubMed, Scopus, and Web of Science databases (up to 23 March 2022) for observational studies and post hoc analyses of randomized controlled trials. Cardiovascular death, heart failure (HF), atrial fibrillation (AF), coronary artery disease (CAD), myocardial infarction (MI), and stroke were the individual endpoints for our meta-analysis. We pooled incidence rates (IRs) and risk in hazard ratios (HRs), using random-effects meta-analyses. Heterogeneity was reported through the I2 statistic, and publication bias was examined using funnel plots and Egger's test in the meta-analysis of risk. One hundred and forty-two studies were identified in total, 26 (836 301 patients) relevant to the relative risk and 116 (2 111 882 patients) relevant to IRs. Compared to matched cancer-free controls, Bc patients had higher risk for cardiovascular death within 5 years of cancer diagnosis [HR = 1.09; 95% confidence interval (CI): 1.07, 1.11], HF within 10 years (HR = 1.21; 95% CI: 1.1, 1.33), and AF within 3 years (HR = 1.13; 95% CI: 1.05, 1.21). The pooled IR for cardiovascular death was 1.73 (95% CI 1.18, 2.53), 4.44 (95% CI 3.33, 5.92) for HF, 4.29 (95% CI 3.09, 5.94) for CAD, 1.98 (95% CI 1.24, 3.16) for MI, 4.33 (95% CI 2.97, 6.30) for stroke of any type, and 2.64 (95% CI 2.97, 6.30) for ischaemic stroke. CONCLUSION: Breast cancer exposure was associated with the increased risk for cardiovascular death, HF, and AF. The pooled incidence for cardiovascular endpoints varied depending on population characteristics and endpoint studied. REGISTRATION: CRD42022298741.

This work investigated the absolute and relative risk of cardiovascular outcomes in breast cancer survivors. Breast cancer was associated with a higher risk of cardiovascular death, heart failure (HF), and atrial fibrillation when compared to the general population.The incidence for cardiovascular death, HF, and coronary artery disease were 1.73, 4.44, and 4.29 per 1000 person-years, respectively.Clinicians should carefully assess breast cancer survivors for their cardiovascular risk factor profile and monitor their cardiovascular function.

Appraising features and outlook of women and men discharged after an acute coronary syndrome: evidence from the 23,700-patient PRAISE International Registry.

BACKGROUND: Acute coronary syndromes (ACS) are a common cause of morbidity and mortality. Several studies have focused on ACS at admission, but limited evidence is available on sex-based comparison of patients discharged after ACS. We appraised the outlook of women and men discharged after ACS. METHODS: Details on women enrolled in the PRAISE registry, an international cohort study spanning 23,700 patients included between 2003 and 2019, were systematically collected. We focused on patient and procedural features, medications at discharge, and 1-year outcomes. The primary endpoint was the composite of death, myocardial infarction, or major bleeding after discharge. RESULTS: A total of 17,804 (76.5%) men and 5466 (23.5%) women were included. Several baseline differences were found, including risk factors and prior revascularization (all P<0.05). Men underwent more frequently radial access, and at discharge they received more commonly dual antiplatelet therapy and guideline-directed medical therapy (P<0.001). At 1-year follow-up, risks of death, reinfarction, major bleeding, and non-fatal major bleeding, jointly or individually, were all significantly higher in women (all P≤0.01). All such differences however did not hold true at multivariable analysis, with the exception of major bleeding, which appeared surprisingly less common in females at fully adjusted analysis (P=0.017). CONCLUSIONS: Women, albeit only apparently, had worse outcomes 1 year after discharge for ACS, but adjusted analysis suggested instead that they faced a lower risk of major bleeding after discharge. These findings support the call for more aggressive management of women after ACS.

Bilateral pulmonary embolism associated with peripheral blood eosinophilia and positive antiphospholipid antibodies in a patient with cellulitis.

Key Clinical Message: This report described the pathophysiology, diagnostic workup, and management of thrombosis possibly associated with peripheral blood eosinophilia and transient positive antiphospholipid antibodies in the setting of cellulitis. Abstract: Peripheral blood eosinophilia is a risk factor for thrombosis and the presence of other prothrombotic factors such as antiphospholipid antibodies can potentiate that risk. The authors present a case of acute pulmonary embolism which developed at the peak of eosinophilia, later found to have transient positive antiphospholipid antibodies in a male patient with right lower limb cellulitis and a history of intravenous drug abuse. This report illustrates the pathophysiology, diagnosis workup, and therapeutic options of thrombosis possibly associated with peripheral blood eosinophilia and positive antiphospholipid antibodies, which include anticoagulants, corticosteroids, and immunosuppressants. Clinicians should be aware of this possible association which may guide the choice and duration of anticoagulants. Although direct oral anticoagulants are effective anticoagulants in various thromboembolic events, studies showed unfavorable outcomes for their use in antiphospholipid syndrome.

The addition of evolocumab to maximal tolerated statin therapy improves walking performance in patients with peripheral arterial disease and intermittent claudication (Evol-PAD study).

OBJECTIVE: To test the hypothesis that in patients with peripheral arterial disease (PAD) and claudication, treated with maximal tolerated statin therapy, the addition of a monthly subcutaneous injection of evolocumab for 6 months improves treadmill walking performance. BACKGROUND: Lipid lowering therapy improves walking parameters in patients with PAD and claudication. Evolocumab decreases cardiac and limb adverse events in patients with PAD; however, the effect of evolocumab on walking performance is not known. METHODS: We performed a double-blind, randomized, placebo-controlled study to compare maximal walking time (MWT) and pain free walking time (PFWT) in patients with PAD and claudication treated with monthly subcutaneous injections of evolocumab 420 mg (n = 35) or placebo (n = 35). We also performed measurements of lower limb perfusion, brachial flow mediated dilatation (FMD), carotid intima media thickness (IMT), and serum biomarkers of PAD disease severity. RESULTS: After six-months of treatment with evolocumab MWT increased by 37.7 % (87.5 ± 24 s) compared to 1.4 % (-21.7 ± 22.9 s) in the placebo group, p = 0.01. PFWT increased by 55.3 % (67.3 ± 21.2 s) in the evolocumab group compared to 20.3 % (8.5 ± 20.3 s) in the placebo group, p = 0.051. There was no difference in lower extremity arterial perfusion measurements. FMD increased by 42.0 ± 73.9 % (1.01 ± 0.7 %) in the evolocumab group and decreased by 16.29 ± 20.06 % (0.99 ± 0.68 %) in the placebo group (p < 0.001). IMT decreased by 7.16 ± 4.6 % (0.06 ± 0.04 mm) in the evolocumab group and increased by 6.68 ± 4.9 % (0.05 ± 0.03 mm) in the placebo group, (p < 0.001). CONCLUSIONS: The addition of evolocumab to maximal tolerated statin therapy improves maximal walking time in patients with PAD and claudication, increases FMD, and decreases IMT. CONDENSED ABSTRACT: Peripheral arterial disease (PAD) impairs quality of life by causing lower extremity intermittent claudication, rest pain, or amputation. Evolocumab is a monthly injectable monoclonal antibody medication that reduces cholesterol. In this study, we randomly treated patients with PAD and claudication, and on background statin therapy, with evolocumab or placebo, and found that evolocumab improves walking performance on a treadmill test by increasing maximal walking time. We also found that evolocumab decreases plasma MRP-14 levels, a marker of PAD severity.

Exploring Disparities in Mortality Rates Among Heart Failure Patients With Primary Diagnosis of Cardiac Arrest: A Nationwide Analysis of 2016-2020 Data.

Cardiac arrest is a dangerous threat to patients with heart failure. In this analysis, the authors aim to investigate the disparities between patients with heart failure who died with a diagnosis of cardiac arrest in terms of race, income, sex, hospital location, hospital size, hospital region, and insurance. Do social determinants of life impact cardiac arrest in patients with heart failure? A total of 8840 patients with heart failure who had a primary diagnosis of cardiac arrest, were admitted non-elective, were adults, and died during the admission were included in this study. A total of 215 (2.43%) patients had cardiac arrest due to cardiac cause, 95 (1.07%) had cardiac arrest due to other specified causes, and 8530 (96.49%) patients had cardiac arrest due to unspecified cause. The study group had a mean age of 69 years and had more males (53.91%). In terms of cardiac arrest due to any cause among adult patients with heart failure, the difference was significantly different in female patients (OR 0.83, p-value = 0.001, 95% CI 0.74-0.93), Black patients (OR 1.44, p-value < 0.001, 95% CI 1.25-1.67), Asian patients (OR 1.66, p-value = 0.002, 95% CI 1.20-2.29), Native American patients (OR 1.96, p-value = 0.022, 95% CI 1.10-3.48), other race patients (OR 1.59, p-value = 0.007, 95% CI 1.14-2.23), patients on hospital from south region (OR 1.59, p-value = 0.007, 95% CI 1.14-2.23), patients from large hospitals (OR 1.21, p-value = 0.015, 95% CI 1.04-1.41), and patients from teaching hospitals (OR1.19, p-value = 0.018, 95% CI 1.03-1.37). In terms of cardiac arrest due to cardiac cause among adult patients with heart failure, there was no significant difference in the variables analyzed. In terms of cardiac arrest due to other specified causes among adult patients with heart failure, the difference was significantly different in female patients (OR 0.19, p-value = 0.024, 95% CI 0.04-0.80), and urban-based hospitals (OR 0.10, p-value = 0.015, 95% CI 0.02-0.64). In terms of cardiac arrest due to unspecified causes among adult patients with heart failure, the difference was significantly different in female patients (OR 0.84, p-value = 0.004, 95% CI 0.75-0.95), Black patients (OR 1.46, p-value < 0.001, 95% CI 1.26-1.69), Asian patients (OR 1.60, p-value = 0.006, 95% CI 1.14-2.23), Native American patients (OR 2.06, p-value = 0.014, 95% CI 1.16-3.67), other race patients (OR 1.58, p-value = 0.010, 95% CI 1.12-2.23), patients on the hospital from the south region (OR 1.25, p-value = 0.014, 95% CI 1.05- 1.48), patients on the hospital from Midwest region (OR 1.22, p-value = 0.033, 95% CI 1.02-1.46), patients from large hospitals (OR 1.21, p-value = 0.016, 95% CI 1.04-1.41), patients from teaching hospitals (OR 1.18, p-value = 0.022, 95% CI 1.02-1.36), patients from urban hospitals (OR 1.37, p-value = 0.023, 95% CI 1.04-1.80). In conclusion, it is imperative for physicians to remain cognizant of health disparities while assessing patients to preempt bias during the evaluation process. The present analysis convincingly demonstrates the influence of gender, race, and hospital location on the incidence of cardiac arrest in individuals afflicted with heart failure. Nonetheless, the paucity of cases pertaining to cardiac arrest attributed to cardiac causes or other specified etiologies considerably compromises the analytical robustness for this particular subtype of cardiac arrest. Thus, further investigations are warranted to ascertain the underlying factors contributing to such disparities among patients with heart failure, while concurrently necessitating physicians' awareness regarding the potential existence of bias in their evaluative endeavors.

Outcomes of Patients With Classic Hodgkin Lymphoma Who Relapsed After Autologous Stem Cell Transplant.

Immune checkpoint inhibitors (ICIs) and brentuximab vedotin (BV) are novel agents for classic Hodgkin lymphoma, including relapse after autologous stem cell transplant (ASCT). However, their impact on survival post-ASCT relapse, in comparison with conventional therapy, is less known due to the lack of randomized controlled trials. Clinical characteristics and outcomes of 115 patients with relapse (or progression) after ASCT are studied. After a median follow-up of 8.59 years from post-ASCT relapse, the median progression-free survival (PFS) and overall survival (OS) were 0.91 and 5.07 years, respectively. Median lines of therapy after post-ASCT relapse was 2 (range, 1-12). The median PFS was not reached (NR) versus 1.11 versus 0.50 versus 0.85 versus 0.78 years (P = 0.006) and OS was NR versus 7.60 versus 3.08 versus 3.51 versus 3.17 years (P = 0.28) in patients first treated with ICIs versus BV versus investigational agents versus chemotherapy versus radiation therapy (RT). First-line treatment with novel agents (ie, ICIs and BV) was associated with superior outcomes compared with investigational agents and chemotherapy/RT with a median PFS of 1.65 versus 0.50 versus 0.79 years (P = 0.003) and a median OS of 7.60 versus 3.08 versus 3.32 years (P = 0.08). Regardless of lines of therapy, the treatment with ICIs had the most favorable outcome with a median PFS and OS of 3.98 and NR years, respectively. Allogeneic stem cell transplant (allo-SCT) was done in 23 patients (20%), and the median post-allo-SCT PFS and OS were 1.31 and 2.35 years, respectively. In conclusion, survival following post-ASCT relapse improves significantly when patients receive novel agents.

New Dual Endothelin Receptor Antagonist Aprocitentan in Hypertension: A Systematic Review and Meta-Analysis.

Hypertension is one of the most common disorders encountered, yet pharmacotherapy for resistant hypertension has limited effective options. Aprocitentan is postulated to be a novel antihypertensive. The main goal was to determine the effect of aprocitentan on blood pressure among patients with hypertension. A thorough search of 5 electronic databases, including PubMed Central, PubMed, EMBASE, Springer, and Google Scholar, was carried out. The study included eight articles. With doses exceeding 25 mg, plasma ET-1(endothelin-1) concentrations, which show ETB (Endothelin receptor type B) receptor antagonism, significantly rose. Aprocitentan significantly reduced systolic and diastolic blood pressure with both doses of 10mg and 25mg in patients with hypertension. Further research is warranted to evaluate the efficacy, safety, and long-term outcomes of aprocitentan and its synergistic effect with other antihypertensives.

Yttrium-90 Ibritumomab Tiuxetan is Cost-Effective Compared to Bendamustine + Rituximab in Low-grade Lymphomas.

BACKGROUND: Yttrium-90 ibritumomab tiuxetan [(90)Y-IT] is a CD20-targeted radio-immunotherapeutic agent. It has shown an excellent therapeutic activity with high tolerability against previously untreated follicular lymphoma (FL) and marginal zone B cell lymphoma (MZL). It is an attractive therapeutic option as the treatment schedule is short and convenient. The aim of our study is to determine the cost-effectiveness of (90)Y-IT in comparison to the standard-of-care bendamustine + rituximab (BR) in the first-line treatment of low-grade FL (LG-FL) and MZL in the real world. PATIENTS AND METHODS: We included all patients who were treated with standard-dose (90)Y-IT for previously untreated LG-FL and MZL at the Mayo Clinic Cancer Center (N = 51). A comparator arm with a historical cohort of previously untreated LG-FL and MZL patients who received BR was used (N = 92). RESULTS: Inverse propensity weighting was utilized to balance the 2 study arms. There were no differences in terms of overall response rate (100% vs. 98%, P = .18), complete response rate (94% vs. 95%, P = .91), or 5 years progression-free survival (76% vs. 75%, P = .63) between patients who received (90)Y-IT and BR, respectively. Within the first year, patients who received (90)Y-IT required an average of 4.5 fewer oncology clinic visits (P < .001), an average of 10 fewer days of therapeutic use (P < .001), and 40% less use of growth factors (P < .001) as compared to the BR group. The direct therapeutic cost of (90)Y-IT treatment was 54% less than that of 6 cycles of BR. CONCLUSION: The findings suggest that (90) Y-IT is more cost-effective than BR and is a viable alternative in up-front management of LG-FL and MZL.

DTRMWXHS-12, a novel Bruton tyrosine kinase inhibitor, in combination with everolimus and pomalidomide in patients with relapsed/refractory lymphomas: An open-label, multicenter, phase 1a/1b study.

Preclinical studies have shown augmented activity when combining Bruton tyrosine kinase inhibitors (BTKi) with inhibitors of mammalian target of rapamycin (mTOR) and immunomodulatory agents (IMiD). We conducted a phase 1, open-label study at five centers in USA to evaluate the safety of triplet BTKi/mTOR/IMiD therapy. Eligible patients were adults aged 18 years or older with relapsed/refractory CLL, B cell NHL, or Hodgkin lymphoma. Our dose escalation study used an accelerated titration design and moved sequentially from single agent BTKi (DTRMWXHS-12), doublet (DTRMWXHS-12 + everolimus), and then to triplet therapy (DTRMWXHS-12 + everolimus + pomalidomide). All drugs were dosed once daily on days 1-21 of each 28-day cycle. The primary goal was to establish the recommended phase 2 dose of the triplet combination. Between September 27, 2016, and July 24, 2019, a total of 32 patients with a median age of 70 years (range 46 to 94 years) were enrolled. No MTD was identified for monotherapy and the doublet combination. The MTD for the triplet combination was determined to be DTRMWXHS-12 200 mg + everolimus 5 mg + pomalidomide 2 mg. Responses across all studied cohorts were seen in 13 of 32 (41.9%). Combining DTRMWXHS-12 with everolimus and pomalidomide is tolerable and shows clinical activity. Additional trials could confirm benefit of this all-oral combination therapy for relapsed/refractory lymphomas.

Conduction system pacing: promoting the physiology to prevent heart failure.

Cardiac conduction system pacing provides physiological ventricular activation by directly stimulating the conduction system. This review describes the two types of conduction system pacing: His bundle pacing (HBP) and left bundle area pacing (LBAP). The most significant advantage of HB pacing is that it can provide a regular, narrow QRS; however, the disadvantages are challenging implantation and a high risk of re-intervention due to lead dislodgement and the development of high pacing threshold. LBAP provides optimum physiological activation of the left ventricle by engaging the left bundle/fascicular fibers. LBAP is more physiological than traditional RV apical pacing and could be an attractive alternative to conventional cardiac resynchronization therapy (CRT). The advantages of LBAP are a relatively more straightforward implantation technique than HBP, better lead stability and pacing thresholds. HBP and LBAP are more physiological than right ventricular pacing and may be used instead of conventional pacemakers. Both HBP and LBBP are being investigated as alternatives to conventional CRT.