Targeted therapy with nanatinostat and valganciclovir in recurrent EBV-positive lymphoid malignancies: a phase 1b/2 study.

Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 prior systemic therapy with no viable curative treatment options. In the phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 dose (RP2D) for phase 2 expansion. Phase 2 patients (n = 30) received RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) for 28-day cycles. The primary end points were safety, RP2D determination (phase 1b), and overall response rate (ORR; phase 2). Overall, 55 patients were enrolled (B-non-Hodgkin lymphoma [B-NHL], [n = 10]; angioimmunoblastic T-cell lymphoma-NHL, [n = 21]; classical Hodgkin lymphoma, [n = 11]; and immunodeficiency-associated lymphoproliferative disorders, [n = 13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR], 19% [n = 8]) with a median duration of response of 10.4 months. For angioimmunoblastic T-cell lymphoma-NHL (n = 15; all refractory to the last prior therapy), the ORR/CRR ratio was 60%/27%. The most common adverse events were nausea (38% any grade) and cytopenia (grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory phase 2 study (NCT05011058) is underway. This phase 1b/2 study is registered at www.clinicaltrials.gov as #NCT03397706.

Impact of Thiotepa-Based Autologous Hematopoietic Cell Transplantation in Primary Central Nervous System Lymphoma in First Complete Remission: A University of California Hematologic Malignancies Consortium Retrospective Analysis.

BACKGROUND: The choice between nonmyeloablative chemotherapy (NMA-C) or autologous hematopoietic cell transplantation (autoHCT) as consolidation in primary central nervous system lymphoma (PCNSL), and timing of autoHCT differs among centers. We aimed to clarify these points. METHODS: We retrospectively analyzed PCNSL adult patients who received consolidation in CR1 or underwent autoHCT during their treatment course. Cohort A included those who underwent autoHCT in CR1, cohort B included those who underwent NMA-C in CR1, and cohort C included patients who underwent autoHCT in CR2+. We compared cohorts A and B, and cohorts A and C. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS), treatment-related mortality (TRM) and cumulative incidence of relapse (CIR). RESULTS: 36 patients were included in cohort A, 30 in cohort B, and 14 in cohort C. The 5-year OS for cohorts A vs B and vs C were 90.7% vs 62.8% (P = .045) and vs 77.9% (P = .32), respectively. The 5-year PFS from diagnosis for cohorts A vs B was 87.8% vs 37.3% (P < .001). The 5-year PFS from autoHCT for cohorts A vs C was 87.6% vs 58.4% (P = .023). The 5-year TRM and CIR in cohorts A vs B was 9.4% vs 9.5% (P = .674), and 2.9% vs 53.2% (P < .001), respectively. The 5-year TRM and CIR in cohorts A vs C from the time of autoHCT was 9.5% vs 22.1% (P = .188), and 2.9% vs 19.5% (P = .104), respectively. CONCLUSION: Despite the limitations, thiotepa-based autoHCT in CR1 appears to improve outcomes in eligible patients with PCNSL.

Fosmanogepix Therapy of Disseminated Fusarium Infection.

Invasive Fusarium infections cause high mortality. Fosmanogepix, a first-in-class antifungal agent, has potent activity against Fusarium. A patient with acute leukemia with invasive fusariosis, probably involving the central nervous system and caused by Fusarium lactis resistant to currently available antifungal agents, was cured of her infection with fosmanogepix. Fosmanogepix was well tolerated.

Reducing CLABSIs in an Adult Cardiothoracic ICU.

LOCAL PROBLEM: Central line-associated bloodstream infections (CLABSIs) are associated with increased mortality and costs. In the cardiothoracic ICU (CTICU) of an academic medical center, nine CLABSIs occurred in fiscal year (FY) 2018. PURPOSE: The aim of this project was to reduce the CLABSI rate in the CTICU and sustain the results. METHODS: Nurse residents on the CTICU initiated a quality improvement project with a single intervention and expanded it into an ongoing initiative with additional interventions by the unit-based performance improvement committee. Evidence-based interventions were identified and implemented, including education; rounding; auditing; and other unit-specific interventions, which included "Central Line Sunday," accountability emails, and a blood culture algorithm with a tip sheet. RESULTS: CLABSI incidence was reduced from nine in FY 2018 to one in each of the subsequent FYs (2019 and 2020), which had similar totals of central line days, and two in FY 2021, which had a slightly higher number of central line days. The CTICU was able to achieve zero CLABSIs from August 2019 through November 2020, more than 365 days. CONCLUSIONS: Coupled with strong support from nursing leadership, nurses on the unit successfully reduced CLABSIs by adopting novel, evidence-based strategies; ongoing monitoring; and multiple interventions.

CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma.

To address antigen escape and loss of T-cell functionality, we report a phase I clinical trial (NCT04007029) evaluating autologous naive and memory T (TN/MEM) cells engineered to express a bispecific anti-CD19/CD20 chimeric antigen receptor (CAR; CART19/20) for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), with safety as the primary endpoint. Ten patients were treated with 36 × 106 to 165 × 106 CART19/20 cells. No patient experienced neurotoxicity of any grade or over grade 1 cytokine release syndrome. One case of dose-limiting toxicity (persistent cytopenia) was observed. Nine of 10 patients achieved objective response [90% overall response rate (ORR)], with seven achieving complete remission [70% complete responses (CR) rate]. One patient relapsed after 18 months in CR but returned to CR after receiving a second dose of CART19/20 cells. Median progression-free survival was 18 months and median overall survival was not reached with a 17-month median follow-up. In conclusion, CART19/20 TN/MEM cells are safe and effective in patients with relapsed/refractory NHL, with durable responses achieved at low dosage levels. SIGNIFICANCE: Autologous CD19/CD20 bispecific CAR-T cell therapy generated from TN/MEM cells for patients with NHL is safe (no neurotoxicity, maximum grade 1 cytokine release syndrome) and demonstrates strong efficacy (90% ORR, 70% CR rate) in a first-in-human, phase I dose-escalation trial. This article is highlighted in the In This Issue feature, p. 517.

Characterisation of infections in patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent.

We investigated the incidence of invasive fungal infections (IFIs) and other infectious complications in patients receiving venetoclax and hypomethylating agent therapy for acute myeloid leukaemia (AML). This retrospective, multicentre cohort study included adult patients with AML who received at least one cycle of venetoclax and either azacitidine or decitabine between January 2016 and August 2020. The primary outcome was the incidence of probable or confirmed IFI. Secondary outcomes included antifungal prophylaxis prescribing patterns, incidence of bacterial infections, and incidence of neutropenic fever hospital admissions. Among 235 patients, the incidence of probable or confirmed IFI was 5.1%. IFI incidence did not differ significantly according to age, antifungal prophylaxis use, or disease status. In the subgroup of patients with probable or confirmed IFIs, six (50%) were receiving antifungal prophylaxis at the time of infection. The overall incidence of developing at least one bacterial infection was 33.6% and 127 (54%) patients had at least one hospital admission for febrile neutropenia. This study demonstrated an overall low risk of developing probable or confirmed IFI as well as a notable percentage of documented bacterial infections and hospital admissions due to neutropenic fever.

Investigation of Combination Treatment With an Aromatase Inhibitor Exemestane and Carboplatin-Based Therapy for Postmenopausal Women With Advanced NSCLC.

INTRODUCTION: Estrogen receptors (ER) (ERα, ERß) and aromatase (key enzyme for estrogen synthesis) are expressed in most human NSCLCs. High intratumoral estrogen levels and elevated aromatase expression in NSCLC predict poor outcome. This open-label, phase 1b, single-center study evaluated the safety and tolerability of escalating doses of the aromatase inhibitor, exemestane, in combination with carboplatin and pemetrexed in postmenopausal women with stage IV nonsquamous NSCLC. METHODS: Patients received exemestane (starting 1-wk before chemotherapy) at 25 mg orally (PO) daily (cohort 1) or 50 mg PO daily (cohort 2) combined with carboplatin (area under the curve 6 mg × min/mL) and pemetrexed (500 mg/m2) intravenously every 3 weeks for four cycles. Thereafter, patients were eligible for continued therapy with exemestane and pemetrexed or pemetrexed alone. RESULTS: A total of 10 patients consented for therapy, and two patients failed in the screening. Four patients completed the therapy in cohort 1 and four patients in cohort 2. The median number of cycles administered was 15 (range: 1-54). Maximum tolerated dose was exemestane 50 mg PO daily with combination chemotherapy. Intention-to-treat analysis revealed an objective response rate (ORR) of 62.5% (five of eight patients with partial response) and a clinical benefit rate of 87.5% (seven of eight patients with either stable disease or partial response). ORR was associated with aromatase expression (p = 0.02). Circulating estrogen levels decreased with exemestane use, and quality of life measurements did not significantly change during the treatment. There were no adverse events. CONCLUSIONS: The combination of carboplatin, pemetrexed, and exemestane in postmenopausal women with metastatic NSCLC is safe and well tolerated. Biomarker studies revealed that ORR correlates with tumor aromatase expression. These findings support future clinical trials to confirm the antitumor efficacy with this combination therapy.

Telerehabilitation for Amputee Care.

Patients with amputation have unique characteristics and needs that must be considered when services are being provided through a virtual platform. The types of amputation rehabilitation services that can be provided virtually are numerous and vary from a full clinical team evaluation to individual therapy services. Whether services are being provided in person or through a virtual platform, rehabilitation of the person with amputation ideally involves a collaborative interdisciplinary team. The potential benefits of providing amputation rehabilitation care through a virtual platform include enhanced access to specialized services, reduced travel burden, and improved continuity of care.

Macrophages in SHH subgroup medulloblastoma display dynamic heterogeneity that varies with treatment modality.

Tumor-associated macrophages (TAMs) play an important role in tumor immunity and comprise of subsets that have distinct phenotype, function, and ontology. Transcriptomic analyses of human medulloblastoma, the most common malignant pediatric brain cancer, showed that medulloblastomas (MBs) with activated sonic hedgehog signaling (SHH-MB) have significantly more TAMs than other MB subtypes. Therefore, we examined MB-associated TAMs by single-cell RNA sequencing of autochthonous murine SHH-MB at steady state and under two distinct treatment modalities: molecular-targeted inhibitor and radiation. Our analyses reveal significant TAM heterogeneity, identify markers of ontologically distinct TAM subsets, and show the impact of brain microenvironment on the differentiation of tumor-infiltrating monocytes. TAM composition undergoes dramatic changes with treatment and differs significantly between molecular-targeted and radiation therapy. We identify an immunosuppressive monocyte-derived TAM subset that emerges with radiation therapy and demonstrate its role in regulating T cell and neutrophil infiltration in MB.

Asking the Right Questions About Secondhand Smoke.

INTRODUCTION: Despite knowledge about major health effects of secondhand tobacco smoke (SHS) exposure, systematic incorporation of SHS screening and counseling in clinical settings has not occurred. METHODS: A three-round modified Delphi Panel of tobacco control experts was convened to build consensus on the screening questions that should be asked and identify opportunities and barriers to SHS exposure screening and counseling. The panel considered four questions: (1) what questions should be asked about SHS exposure; (2) what are the top priorities to advance the goal of ensuring that these questions are asked; (3) what are the barriers to achieving these goals; and (4) how might these barriers be overcome. Each panel member submitted answers to the questions. Responses were summarized and successive rounds were reviewed by panel members for consolidation and prioritization. RESULTS: Panelists agreed that both adults and children should be screened during clinical encounters by asking if they are exposed or have ever been exposed to smoke from any tobacco products in their usual environment. The panel found that consistent clinician training, quality measurement or other accountability, and policy and electronic health records interventions were needed to successfully implement consistent screening. CONCLUSIONS: The panel successfully generated screening questions and identified priorities to improve SHS exposure screening. Policy interventions and stakeholder engagement are needed to overcome barriers to implementing effective SHS screening. IMPLICATIONS: In a modified Delphi panel, tobacco control and clinical prevention experts agreed that all adults and children should be screened during clinical encounters by asking if they are exposed or have ever been exposed to smoke from tobacco products. Consistent training, accountability, and policy and electronic health records interventions are needed to implement consistent screening. Increasing SHS screening will have a significant impact on public health and costs.

Filgrastim associations with CAR T-cell therapy.

Little is known about the benefits and risks of myeloid growth factor administration after chimeric antigen receptor (CAR) T-cell therapy for diffuse large B-cell lymphoma (DLBCL). We present a retrospective analysis among 22 relapsed/refractory DLBCL patients who received CAR T-cell therapy with axicabtagene ciloleucel. Filgrastim was administered by physician discretion to seven patients (31.8%), and the median duration of neutropenia after lymphodepleting therapy was significantly shorter for those patients who received filgrastim (5 vs 15 days, P = .016). Five patients (22.7%) developed infection in the 30 days post-CAR T-cell therapy with three patients being Grade 3 or higher. There was no difference in the incidence and severity of infection based on filgrastim use (P = .274, P = .138). Among the seven patients that received filgrastim, six patients (85.7%) and four patients (57.1%) had evidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), respectively. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) and 7 patients (46.7%) had evidence of CRS and ICANS, respectively. There was no significant difference in the incidence of developing CRS or ICANS between the group of patients that received filgrastim and those that did not (P = .193, P = .647). However, there was a significant increase in the severity of CRS for patients that received filgrastim compared to those that did not (P = .042). Filgrastim administration after CAR T-cell therapy may lead to an increase in severity of CRS without decreasing infection rates.

Results from a prospective study of individuals' symptoms and patient activation after hepatitis C treatment.

The treatment of the hepatitis C virus has been revolutionized by the discovery of direct-acting antiviral medications, which offer more effective treatment with fewer potential side effects. Few studies have examined changes in patient-reported outcomes in individuals undergoing treatment for the hepatitis C virus in the immediate time period after the first treatment (within 1 month). This study is one of the first to use quantitative and qualitative methods to investigate changes in quality of life, patient activation, and symptom burden in adults undergoing treatment for hepatitis C virus with direct-acting antiviral medications. Seventy-three patients were followed in a prospective, longitudinal mixed-methods design. Changes pre and posttreatment in quality of life, patient activation, and symptom burden were very small in magnitude when looking across the entire sample. However, patients with lower self-reported health at baseline reported improved physical and psychological functioning 1-month posttreatment. Patients with higher self-reported health at baseline reported decreased general health posttreatment, although these effects were small. Qualitative results suggested that most patients found symptoms to be manageable despite experiencing both psychological and physical symptoms during treatment. We also found that 25% of patients had low levels of patient activation and may lack the basic knowledge and confidence to be an active participant in their health care. These findings suggest that patients may benefit from tailored information based on current health status about what to expect during and immediately after beginning direct-acting antiviral medication treatment.

Ten-Year Outcomes of a Systems-Based Approach to Longitudinal Amputation Care in the US Department of Veteran Affairs.

BACKGROUND: The goal of the US Department of Veterans Affairs (VA) Amputation System of Care (ASoC) is to enhance the quality and consistency of amputation rehabilitation care for veterans with limb loss. OBJECTIVE: The ASoC provides specialized expertise in amputation rehabilitation incorporating the latest practices in medical management, rehabilitation, and artificial limbs in order to minimize disability and to enable the highest level of social, vocational, and recreational success for veterans with amputation. DISCUSSION: The ASoC serves veterans with limb amputation from any etiology. Between 2009 and 2019, the VA experienced a 34% increase in the number of veterans with amputation who received care. During the same 10-year period, the percentage of veterans with major limb amputation seen in an outpatient amputation specialty clinic each year increased from 4.8 to 26%. This article highlights how the mission of the ASoC has been accomplished over the past decade through prioritization and implementation of key strategic initiatives in learning organization creation, trust in VA care, modernization, and development of a high-performance network with enhanced access and customer service. CONCLUSIONS: This synopsis of the VA amputation care program serves as a model of amputation care that can be utilized outside the federal sector and has the potential to serve as a systems-based example for providing longitudinal care to other populations within the VA.

Counter Regulation of Spic by NF-κB and STAT Signaling Controls Inflammation and Iron Metabolism in Macrophages.

Activated macrophages must carefully calibrate their inflammatory responses to balance efficient pathogen control with inflammation-mediated tissue damage, but the molecular underpinnings of this "balancing act" remain unclear. Using genetically engineered mouse models and primary macrophage cultures, we show that Toll-like receptor (TLR) signaling induces the expression of the transcription factor Spic selectively in patrolling monocytes and tissue macrophages by a nuclear factor κB (NF-κB)-dependent mechanism. Functionally, Spic downregulates pro-inflammatory cytokines and promotes iron efflux by regulating ferroportin expression in activated macrophages. Notably, interferon-gamma blocks Spic expression in a STAT1-dependent manner. High levels of interferon-gamma are indicative of ongoing infection, and in its absence, activated macrophages appear to engage a "default" Spic-dependent anti-inflammatory pathway. We also provide evidence for the engagement of this pathway in sterile inflammation. Taken together, our findings uncover a pathway wherein counter-regulation of Spic by NF-κB and STATs attune inflammatory responses and iron metabolism in macrophages.

B-cell lymphomas associated with breast implants: Report of three cases and review of the literature.

Since the first reported case in 1997, over 600 women with breast implant-associated anaplastic large cell lymphoma (BI ALCL) have been reported. BI ALCL is a CD30-positive T-cell lymphoma that carries clonal T-cell receptor gene rearrangements, and a subset of cases harbors mutations in the JAK-STAT signaling pathway. Rarely, other histologic types of lymphoma have been reported in association with breast implants, including fewer than 10 cases of B-cell origin. Here, we describe three additional patients with B-cell lymphoma occurring around breast implants. Two of these patients developed extranodal marginal zone lymphoma in the peri-implant capsule, one of which had a concurrent ALCL within the superficial lining of the capsule. The third patient presented with diffuse large B-cell lymphoma inside the breast parenchyma surrounding her implant. Determining the etiology and risk factors for the development of B-cell lymphomas associated with breast implants remains challenging, given the wide spectrum of histologic features and the rarity of these neoplasms. Ultimately, we document three new cases of B-cell lymphoma arising around breast implants and highlight their clinical and pathologic features in order to expand our understanding of this rare disease presentation.

Durable Survival Outcomes in Primary and Secondary Central Nervous System Lymphoma After High-dose Chemotherapy and Autologous Stem Cell Transplantation Using a Thiotepa, Busulfan, and Cyclophosphamide Conditioning Regimen.

BACKGROUND: High-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been investigated in patients with primary central nervous system lymphoma (PCNSL) and non-Hodgkin lymphoma (NHL) with CNS involvement and has shown promising results. PATIENTS AND METHODS: A retrospective analysis was performed of 48 consecutive patients who had undergone HDC/ASCT with TBC (thiotepa, busulfan, cyclophosphamide) conditioning for PCNSL (27 patients), secondary CNS lymphoma (SCNSL) (8 patients), or relapsed disease with CNS involvement (13 patients) from July 2006 to December 2017. Of the 27 patients with PCNSL, 21 had undergone ASCT at first complete remission (CR1). RESULTS: The 2-year progression-free survival (PFS) rate was 80.5% (95% confidence interval [CI], 69.9-92.9) and the 2-year overall survival (OS) rate was 80.1% (95% CI, 69.2%-92.7%) among all patients. The 2-year PFS and OS rate for patients with PCNSL in CR1 was 95.2% (95% CI, 86.6%-100%) and 95.2% (95% CI, 86.6%-100%), respectively. On univariate analysis of the patients with PCNSL, ASCT in CR1 was the only variable statistically significant for outcome (P = .007 for PFS; P = .008 for OS). Among patients with SCNSL or CNS relapse, the 2-year PFS and OS rate were comparable at 75.9% (95% CI, 59.5%-96.8%) and 75.3% (95% CI, 58.6%-98.6%), respectively. The most common side effects were febrile neutropenia (89.6%; of which 66.7% had an infectious etiology identified), nausea/vomiting (85.4%), diarrhea (93.8%), mucositis (89.6%), and electrolyte abnormalities (89.6%). Four patients (8.3%) died of treatment-related overwhelming infection; of these patients, 3 had SCNSL. CONCLUSION: HDC and ASCT using TBC conditioning for both PCNSL and secondary CNS NHL appears to have encouraging long-term efficacy with manageable side effects.

Adjusting to sex and intimacy: Gynecological cancer survivors share about their partner relationships.

This study describes what gynecological (GYN) cancer survivors relate about their intimate partners and adjustments in their sexual lives following diagnosis and treatment. Conventional descriptive content analysis was used to examine participant responses about partner relationships following their diagnosis. Responses revealed three clusters and 15 codes of data. Findings report the influence of cancer treatment on sexual activity and functioning, women's sex lives, and their relationships. Health-care providers have a vital role in supporting women and their partners during the cancer care trajectory and should include both the survivor and the partner in conversations focused on sexual concerns and sexual well-being.