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Diffuse large B-cell lymphoma is the most common subtype of lymphoma. First-line treatment with combination chemoimmunotherapy is successful in about 60% of patients. For those who have relapse, second-line therapy consists of additional chemoimmunotherapy followed by autologous stem cell transplant. But most of these patients do not have good outcomes. The U.S. Food and Drug Administration (FDA) has approved CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) for third-line treatment; CAR-T is also effective for relapsed disease. The study described in this article examines whether CAR-T could be used as second-line therapy. Visual Abstract. Second-Line Chimeric Antigen Receptor T-Cell Therapy in Diffuse Large B-Cell Lymphoma: Diffuse large B-cell lymphoma is the most common subtype of lymphoma. First-line treatment with combination chemoimmunotherapy is successful in about 60% of patients. For those who relapse, second-line therapy consists of additional chemoimmunotherapy followed by autologous stem cell transplant. But most of these patients do not have good outcomes. The U.S. Food and Drug Administration (FDA) has approved CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) for third-line treatment; CAR-T is also effective for relapsed disease. The study described in this article examines whether CAR-T could be used as second-line therapy. Background: First-line treatment of diffuse large B-cell lymphoma (DLBCL) achieves durable remission in approximately 60% of patients. In relapsed or refractory disease, only about 20% achieve durable remission with salvage chemoimmunotherapy and consolidative autologous stem cell transplantation (ASCT). The ZUMA-7 (axicabtagene ciloleucel [axi-cel]) and TRANSFORM (lisocabtagene maraleucel [liso-cel]) trials demonstrated superior event-free survival (and, in ZUMA-7, overall survival) in primary-refractory or early-relapsed (high-risk) DLBCL with chimeric antigen receptor T-cell therapy (CAR-T) compared with salvage chemoimmunotherapy and consolidative ASCT; however, list prices for CAR-T exceed $400 000 per infusion. Objective: To determine the cost-effectiveness of second-line CAR-T versus salvage chemoimmunotherapy and consolidative ASCT. Design: State-transition microsimulation model. Data Sources: ZUMA-7, TRANSFORM, other trials, and observational data. Target Population: "High-risk" patients with DLBCL. Time Horizon: Lifetime. Perspective: Health care sector. Intervention: Axi-cel or liso-cel versus ASCT. Outcome Measures: Incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (iNMB) in 2022 U.S. dollars per quality-adjusted life-year (QALY) for a willingness-to-pay (WTP) threshold of $200 000 per QALY. Results of Base-Case Analysis: The increase in median overall survival was 4 months for axi-cel and 1 month for liso-cel. For axi-cel, the ICER was $684 225 per QALY and the iNMB was −$107 642. For liso-cel, the ICER was $1 171 909 per QALY and the iNMB was −$102 477. Results of Sensitivity Analysis: To be cost-effective with a WTP of $200 000, the cost of CAR-T would have to be reduced to $321 123 for axi-cel and $313 730 for liso-cel. Implementation in high-risk patients would increase U.S. health care spending by approximately $6.8 billion over a 5-year period. Limitation: Differences in preinfusion bridging therapies precluded cross-trial comparisons. Conclusion: Neither second-line axi-cel nor liso-cel was cost-effective at a WTP of $200 000 per QALY. Clinical outcomes improved incrementally, but costs of CAR-T must be lowered substantially to enable cost-effectiveness. Primary Funding Source: No research-specific funding. [ABSTRACT FROM AUTHOR]

Selective immune pressure contributes to relapse due to target antigen downregulation in patients treated with anti-CD19 chimeric antigen receptor (CAR) T cells. Bispecific lentiviral anti-CD20/anti-CD19 (LV20.19) CAR T cells may prevent progression/relapse due to antigen escape. Highly polyfunctional T cells within a CAR T-cell product have been associated with response in single-antigen-targeted anti-CD19 CAR T cells. The authors performed a single-cell proteomic analysis to assess polyfunctional cells in our LV20.19 CAR T-cell product. Analysis was limited to those treated at a fixed dose of 2.5 × 106 cells/kg (n = 16). Unused pre-infusion CAR T cells were thawed, sorted into CD4/CD8 subsets and stimulated with K562 cells transduced to express CD19 or CD20. Single-cell production of 32 individual analytes was measured and polyfunctionality and polyfunctional strength index (PSI) were calculated. Fifteen patients had adequate leftover cells for analysis upon stimulation with CD19, and nine patients had adequate leftover cells for analysis upon stimulation with CD20. For LV20.19 CAR T cells, PSI was 866–1109 and polyfunctionality was 40–45%, which were higher than previously reported values for other CAR T-cell products. Stimulation with either CD19 or CD20 antigens resulted in similar levels of analyte activation, suggesting that this product may have efficacy in CD19– patient populations. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR)-modified T-cell therapy has revolutionized outcomes for patients with relapsed/refractory B-cell malignancies. Despite the exciting results, several clinical and logistical challenges limit its wide applicability. First, the apheresis requirement restricts accessibility to institutions with the resources to collect and process peripheral blood mononuclear cells (PBMCs). Second, even when utilizing an apheresis product, failure to manufacture CAR T cells is a well-established problem in a significant subset. In heavily pre-treated patients, prior chemotherapy may impact T-cell quality and function, limiting the ability to manufacture a potent CAR T-cell product. Isolation and storage of T cells shortly after initial cancer diagnosis or earlier in life while an individual is still healthy are an alternative to using T cells from heavily pre-treated patients. The goal of this study was to determine if a CAR T-cell product could be manufactured from a small volume (50 mL) of healthy donor blood. Collaborators at Cell Vault collected 50 mL of whole peripheral venous blood from three healthy donors. PBMCs were isolated, cryopreserved and shipped to the Medical College of Wisconsin. PBMCs for each individual donor were thawed, and CAR T cells were manufactured using an 8-day process on the CliniMACS Prodigy device with a CD19 lentiviral vector. Starting doses of enriched T-cell numbers ranged from 4.0 × 107 cells to 4.8 × 107 cells, with a CD4/CD8 purity of 74–79% and an average CD4:CD8 ratio of 1.4. On the day of harvest, total CD3 cells in the culture expanded to 3.6–4.6 × 109 cells, resulting in a 74- to 115-fold expansion, an average CD4:CD8 ratio of 2.9 and a CD3 frequency of greater than 99%. Resulting CD19 CAR expression varied from 19.2% to 48.1%, with corresponding final CD19+ CAR T-cell counts ranging from 7.82 × 108 cells to 2.21 × 109 cells. The final CAR T-cell products were phenotypically activated and non-exhausted and contained a differentiated population consisting of stem cell-like memory T cells. Overall, these data demonstrate the ability to successfully generate CAR T-cell products in just 8 days using cryopreserved healthy donor PBMCs isolated from only 50 mL of blood. Notably, numbers of CAR T cells were more than adequate for infusion of an 80-kg patient at dose levels used for products currently approved by the Food and Drug Administration. The authors offer proof of principle that cryopreservation of limited volumes of venous blood with an adequate starting T-cell count allows later successful manufacture of CAR T-cell therapy. [ABSTRACT FROM AUTHOR]

Copper deficiency is a rare nutritional deficiency with hematological manifestations that mimic those found in myelodysplastic syndrome, a hematological malignancy incurable without allogeneic hematopoietic stem cell transplantation. Bone marrow biopsy findings and peripheral blood counts are oftentimes insufficient to differentiate the two conditions. Moreover, the symptoms of copper deficiency can arise years after the surgery, making diagnosis a challenge. In patients with new-onset pancytopenia, copper deficiency must be considered on the differential, especially in the setting of known risk factors such as bariatric surgery, zinc supplementation, and celiac disease. Herein, we present a case of a 61-year-old female with a remote history of gastric bypass being evaluated for MDS in the context of progressive pancytopenia and new-onset paresthesias. The patient was found to have low serum copper and ceruloplasmin. Copper supplementation largely resolved the hematological abnormalities, but the limb paresthesias remain. This case highlights the need to identify copper deficiency early and distinguish it from MDS in order to prevent permanent neurological deficits and catastrophic response should the patient undergo hematopoietic stem cell transplantation. [ABSTRACT FROM AUTHOR]

Background: Reducing diagnostic delays in cancer has been a major interest worldwide; however, the literature on diagnostic delays in lymphoma remains scarce. Diffuse large B‐cell lymphoma (DLBCL) is the most common non‐Hodgkin's lymphoma. We aimed to determine whether certain structural factors predicted diagnostic delays in DLBCL and whether diagnostic delays impacted overall survival (OS). Methods: Data were extracted via a retrospective cohort design from a single academic tertiary care referral center. A total of 104 patients were included. Time from first symptoms to diagnosis of <3 months was defined as "early diagnosis" and ≥3 months as "delayed diagnosis". Analysis was performed with student's t‐test, chi‐square testing, binomial logistic regression, and Kaplan‐Meier log‐rank testing. Results: "Delayed diagnosis" was more likely with lower stage, lower international prognostic index (IPI), and further distance from referral center (OR 0.66, CI 0.46‐0.95; OR 0.69, CI 0.51‐0.94; OR 1.008, CI 1.001‐1.015). Patients of "other" ethnicity and without medical insurance were more likely to have significant diagnostic delays and worse overall survival (P = 0.002 and P = 0.007, respectively). Diagnostic delays of ≥3 months did not predict worse OS. However, delays of >6 months did predict worse OS. Conclusion: Our data suggest that excessive diagnostic delays of more than 6 months, ethnic minority status, and uninsured status in DLBCL may lead to worse outcomes. Efforts should be undertaken to reduce excessive diagnostic delays. More investigation needs to be done on the impacts of diagnostic delays in both DLBCL and other aggressive lymphomas. [ABSTRACT FROM AUTHOR]

Objectives: To identify the frequency of micafungin resistance among clinically significant isolates of Candida stored at our institution from 2005 to 2015. Chart review of patients with resistant isolates then informed the clinical setting and outcomes associated with these infections.Methods: Clinical Candida isolates had been stored at -80°C in Brucella broth with 20% glycerol from 2005. Isolates were tested using broth microdilution to determine micafungin MICs. All Candida glabrata isolates and all isolates demonstrating decreased susceptibility to micafungin were screened for FKS mutations using a Luminex assay.Results: In total, 3876 Candida isolates were tested for micafungin resistance, including 832 C. glabrata isolates. Of those, 33 isolates from 31 patients were found to have either decreased susceptibility to micafungin and/or an FKS mutation. C. glabrata accounted for the majority of these isolates. While bloodstream infections were found to have a very high mortality rate, isolates from other sites were uncommonly associated with 30-day mortality. Overall resistance rates were very low.Conclusions: Echinocandin resistance in C. glabrata has been increasingly reported but rates at our institution remain very low. We hypothesize that a focus on antifungal stewardship may have led to these observations. Knowledge of local resistance patterns is key to appropriate empirical treatment strategies. [ABSTRACT FROM AUTHOR]

Objective: Autologous peripheral nerve grafts are commonly used clinically as a treatment for peripheral nerve injuries. However, in research using an autologous graft is not always feasible due to loss of function, which in many cases is assessed to determine the efficacy of the peripheral nerve graft. In addition, using allografts for research require the use of an immunosuppressant, which creates unwanted side effects and another variable within the experiment that can affect regeneration. The objective of this study was to analyze graft rejection in peripheral nerve grafts and the effects of cyclosporine A (CSA) on axonal regeneration. Methods: Peripheral nerve grafts in inbred Lewis rats were compared with Sprague-Dawley (SD) rats to assess graft rejection, CSA side effects, immune responses, and regenerative capability. Macrophages and CD8+ cells were labeled to determine graft rejection, and neurofilaments were labeled to determine axonal regeneration. Results: SD rats without CSA had significantly more macrophages and CD8+ cells compared to Lewis autografts, Lewis isografts, and SD allografts treated with CSA. Lewis autografts, Lewis isografts, and SD autografts had significantly more regenerated axons than SD rat allografts. Moreover, allografts in immunosuppressed SD rats had significantly less axons than Lewis rat autograft and isografts. Discussion: Autografts have long been the gold standard for treating major nerve injuries and these data suggest that even though CSA is effective at reducing graft rejection, axon regeneration is still superior in autografts versus immunosuppressed allografts. [ABSTRACT FROM AUTHOR]

Candidemia has a high attributable mortality. The objective of this study was to determine the impact of infectious disease consultation on mortality and clinical outcomes in candidemia. Infectious disease consultation was associated with better adherence to guidelines and improved survival, even in patients with high Acute Physiology and Chronic Health Evaluation II scores. [ABSTRACT FROM AUTHOR]

AbstractSpinal cord injury (SCI) is a devastating condition affecting 270,000 people in the United States. A potential treatment for decreasing the secondary inflammation, excitotoxic damage, and neuronal apoptosis associated with SCI, is the anti-inflammatory cytokine interleukin-10. The best characterized effects of IL-10 are anti-inflammatory—it downregulates pro-inflammatory species interleukin-1β (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6), tumor necrosis factor-α, interferon-γ, matrix metalloproteinase-9, nitric oxide synthase, myeloperoxidase, and reactive oxygen species. Pro-apoptotic factors cytochrome c, caspase 3, and Bax are downregulated by IL-10, whereas anti-apoptotic factors B-cell lymphoma 2 (Bcl-2) and Bcl-2–associated X, B-cell lymphoma-extra large (Bcl-xl) are upregulated by IL-10. IL-10 also provides trophic support to neurons through the IL-10 receptor. Increased tissue sparing, functional recovery, and neuroprotection are seen with an immediate post-SCI systemic administration of IL-10. Treatment of SCI with IL-10 has been used successfully in combination with Schwann cell and olfactory glial cell grafts, as well as methylprednisolone. Minocycline, tetramethylpyrazine, and hyperbaric oxygen treatment all increase IL-10 levels in a SCI models and result in increased tissue sparing and functional recovery. A chronic systemic administration of IL-10 does not appear to be beneficial to SCI recovery and causes increased susceptibility to septicemia, pneumonia, and peripheral neuropathy. However, a localized upregulation of IL-10 has been shown to be beneficial and can be achieved by herpes simplex virus gene therapy, injection of poliovirus replicons, or surgical placement of a slow-release compound. IL-10 shows promise as a treatment for SCI, although research on local IL-10 delivery timeline and dosage needs to be expanded. [ABSTRACT FROM AUTHOR]

Simple Summary: In relapsed, refractory B cell malignancies and multiple myeloma, chimeric antigen receptor (CAR) T cell therapy has represented a major scientific advancement with high response rates and durable responses for many. Nonetheless, target antigen downregulation in tumor cells can lead to poor responses and relapsed disease. Current FDA approved CAR T cell therapies only target a single B-cell specific cell marker. While effective, single targeted CAR T cell therapy can lead selective pressure against the target antigen leading to loss of expression and tumor cell escape. Simultaneous dual antigen targeting CAR therapy has been evaluated in multiple early phase clinical trials in response to these clinical challenges in hopes of improving response rates and preventing relapse. This article discusses the limitations of single targeted CAR T cell therapy, approaches to dual antigen targeting, and the results of early phase trials utilizing dual antigen targeting CAR T cell therapy. Chimeric antigen receptor (CAR) modified T cell therapy offers a targeted immunotherapeutic approach to patients with refractory hematological malignancies. This technology is most advanced in B cell malignancies and multiple myeloma and is rapidly evolving as more data become available regarding clinical efficacy and response durability. Despite excellent initial response rates with single antigen targeting CARs, failure to respond to therapy and relapse due to target antigen downregulation remain clinical challenges. To mitigate immunophenotypic selective pressures, simultaneous dual antigen targeting with bispecific CAR T cells or multiple administration of different populations of CAR T cells may prevent relapse by addressing one resistance mechanism attributed to antigenic loss. This article will review recently published data on the use of dual targeting with CAR T cells from early phase clinical trials aimed at treating B cell malignancies and multiple myeloma. [ABSTRACT FROM AUTHOR]

Background Enterococcus species frequently cause health care–associated bacteremia, with high attributable mortality. The benefit of consultation with infectious disease (ID) specialists has been previously illustrated with Staphylococcus aureus bacteremia. Whether ID consultation (IDC) improves mortality in enterococcal bacteremia is unknown. Methods This is a retrospective cohort single-center study from January 1, 2015, to June 30, 2016, that included all patients >18 years of age admitted with a first episode of Enterococcus bacteremia. Patients were excluded if death or transfer to palliative care occurred within 2 days of positive blood culture. Results Two hundred five patients were included in the study, of whom 64% received IDC. Participants who received IDC were more likely to undergo repeat cultures to ensure clearance (99% vs 74%; P  < .001), echocardiography (79% vs 45%; P  < .001), surgical intervention (20% vs 7%; P  = 0.01), and have appropriate antibiotic duration (90% vs 46%; P  < .001). Thirty-day mortality was significantly higher in the no-IDC group (27 % vs 12 %; P  < .007). In multivariate analysis, 30-day in-hospital mortality was associated with both E. faecium bacteremia (adjusted odds ratio [aOR], 2.39; 95% confidence interval [CI], 1.09–5.23) and IDC (aOR, 0.35; 95% CI, 0.16–0.76). Conclusions Patients who received IDC for Enterococcus bacteremia had significantly lower 30-day mortality. Further prospective studies are necessary to determine if these outcomes can be validated in other institutions for patients who receive IDC with Enterococcus bacteremia. [ABSTRACT FROM AUTHOR]

Introduction: In this retrospective matched case control study, we aim to identify breast cancer-related risk factors associated with developing COVID-19 and describe outcomes of patients with breast cancer diagnosed with COVID-19., Methods: Women with breast cancer treated at the Medical College of Wisconsin and diagnosed with COVID-19 from March through December 2020 served as cases, and those without COVID-19 within the same timeframe served as controls. Univariate and multivariate comparisons were performed., Results: Twenty-five cases and 77 controls were identified. All cases were fully matched by age, obesity, county, and race. Mean age was 54.6 versus 54.9, body mass index 31.0 versus 31.6, 48% lived in Milwaukee County, and 68% were White. Regarding COVID-19 outcomes, 24.0% (n = 6) of cases were hospitalized, median length of stay was 2 days, 8% (n=2) needed oxygen, 4% (n = 6) were intubated, and 4% (n = 6) died. COVID-19 led to treatment delays in 40% of cases. On univariate analysis, there was no statistically significant difference in hormone receptor status or breast cancer stage. Being on active chemotherapy (OR 5.8, P  = 0.043) significantly increased the likelihood of developing COVID-19., Conclusions: In this matched case control study of patients with breast cancer, active chemotherapy was significantly associated with an increased likelihood of developing COVID-19, with a trend seen for triple negative disease. These findings support continued strict precautions for those on active chemotherapy and warrant further analysis in those with triple negative disease., (Copyright© Board of Regents of the University of Wisconsin System and The Medical College of Wisconsin, Inc.)

Background: Prior literature demonstrates internal medicine residents have suboptimal competence in critical appraisal. Journal clubs are a common intervention to address this skill, but engagement and critical appraisal skill improvement are variable., Objective: We evaluated journal club engagement and critical appraisal skills after implementation of a gamified format., Methods: This was a single-arm study, conducted from July 1, 2020 to June 30, 2021, involving internal medicine residents at 2 US programs. Residents participated in a 12-month gamified journal club that sorted residents into 2 teams. Residents attended an orientation followed by 6 to 10 monthly, hour-long competitions. In each competition, a subset of the resident teams competed to answer a clinical prompt by critically appraising an original article of their choice. A chief medical resident or faculty member moderated each session and chose the winning team, which received a nominal prize of candy. The primary outcome was engagement, measured by a 7-question survey developed de novo by the authors with Likert scale responses at baseline and 12 months. The secondary outcome was critical appraisal skills assessed by the Berlin Questionnaire., Results: Sixty-one of 72 eligible residents (84.7%) completed both engagement surveys. Residents reported statistically significant improvements in most dimensions of engagement, including a higher likelihood of reading articles before sessions (posttest minus pretest score -1.08; 95% CI -1.34 to -0.82; P <.001) and valuing time spent (posttest minus pretest score -0.33; 95% CI -0.55 to -0.11; P =.004). Critical appraisal skills marginally improved at 12 months (posttest minus pretest score -0.84; 95% CI -1.54 to -0.14; P =.02)., Conclusions: Our study demonstrates a gamified journal club was associated with improvements in engagement and minimal change in critical appraisal skills., Competing Interests: Conflict of interest: The authors declare they have no competing interests.

Allogeneic hematopoietic cell transplantation (alloHCT) can potentially salvage large B-cell lymphoma (LBCL) patients experiencing treatment failure after chimeric antigen receptor T-cell therapy (CAR T). Nonetheless, data on the efficacy and toxicities of alloHCT after receipt of CAR T are limited. We report a multicenter retrospective study assessing the safety, toxicities, and outcomes of alloHCT in LBCL patients following CAR T failure. Eighty-eight patients with relapsed, refractory LBCL received an alloHCT following anti-CD19 CAR T failure. The median number of lines of therapy between CAR T infusion and alloHCT was one (range, 0-7). Low intensity conditioning was used in 77% (n=68) and peripheral blood was the most common graft source (86%, n=76). The most common donor types were matched unrelated donor (39%), followed by haploidentical (30%) and matched related donor (26%). Median follow-up of survivors was 15 months (range, 1-72). One-year overall survival, progression-free survival, and graft-versus-host disease-free relapse-free survival were 59%, 45%, and 39% respectively. One-year non-relapse mortality and progression/relapse were 22% and 33% respectively. On multivariate analysis, <2 lines of intervening therapy between CAR T and alloHCT and complete response at time of alloHCT were associated with better outcomes. In conclusion, alloHCT after CAR T failure can provide durable remissions in a subset of patients.