Outpatient administration of CAR T-cell therapy: a focused review with recommendations for implementation in community based centers.

Chimeric Antigen Receptor T-cell (CAR-T) therapy has transformed the treatment landscape for hematological malignancies, showing high efficacy in patients with relapsed or refractory (R/R) disease and otherwise poor prognosis in the pre-CAR-T era. These therapies have been usually administered in the inpatient setting due to the risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). However, there is a growing interest in the transition to outpatient administration due to multiple reasons. We review available evidence regarding safety and feasibility of outpatient administration of CD19 targeted and BCMA targeted CAR T-cell therapy with an emphasis on the implementation of outpatient CAR-T programs in community-based centers.

DUSP22-IRF4 Rearranged CD30-Positive Primary Cutaneous Lymphoproliferative Disorder With Gamma/Delta Phenotype.

ABSTRACT: CD30-positive primary cutaneous lymphoproliferative disorders (CD30 + PCLPD) are a heterogeneous group of cutaneous T-cell lymphoma (CTCL) that includes lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma. They exist as a clinical and pathological spectrum, which display significant overlap and variability. The diagnosis is made based on correlation between clinical and histopathologic findings. LyP with 6p25.3 rearrangement subtype represents <5% of LyP cases and is defined by DUSP22-IRF4 rearrangement on 6p25.3 locus. The reported cases express the alpha/beta T-cell receptor and follow an indolent clinical behavior typical of LyP. The same rearrangement is detected in 28% of anaplastic large cell lymphoma. We hereby present an extraordinary case of CD30 + PCLPD with DUSP22-IRF4 rearrangement and novel expression of gamma/delta T-cell immunophenotype in a young patient. Although the gamma/delta T-cell immunophenotype has been described in many other T-cell lymphomas, this is the first reported association with CD30 + PCLPD with DUSP22-IRF4 rearrangement.

Partial response to venetoclax and ruxolitinib combination in a case of refractory T-prolymphocytic leukemia.

Background: T-prolymphocytic leukemia (T-PLL) is an aggressive hematologic malignancy. A portion of patients can be cured with alemtuzumab induction followed by allogeneic hematopoietic stem cell transplant, but patients who relapse after transplant have a poor prognosis, and there is no standard of care.Methods: We report a case of a 64-year-old man with relapsed JAK3-mutant T-PLL following allogeneic transplant who was treated with ruxolitinib and venetoclax.Results: Treatment with ruxolitinib and venetoclax resulted in a partial response including stabilization of the peripheral lymphocyte count, improvement in thrombocytopenia, decrease in splenomegaly, and a numerical reduction in the percentage of bone marrow involved by T-PLL. The combination was well tolerated with the exception of neutropenic infections.Conclusion: This case adds to the growing body of literature supporting venetoclax and rituximab as a viable treatment option for relapsed/refractory T-PLL with JAK-STAT alterations.

Biodiversity: the overlooked source of human health.

Biodiversity is the measure of the variation of lifeforms in a given ecological system. Biodiversity provides ecosystems with the robustness, stability, and resilience that sustains them. This is ultimately essential for our survival because we depend on the services that natural ecosystems provide (food, fresh water, air, climate, and medicine). Despite this, human activity is driving an unprecedented rate of biodiversity decline, which may jeopardize the life-support systems of the planet if no urgent action is taken. In this article we show why biodiversity is essential for human health. We raise our case and focus on the biomedicine services that are enabled by biodiversity, and we present known and novel approaches to promote biodiversity conservation.

Prevalence and Inpatient Hospital Outcomes of Malignancy-Related Ascites in the United States.

OBJECTIVE: Malignancy-related ascites (MRA) is the terminal stage of many advanced cancers, and the treatment is mainly palliative. This study looked for epidemiology and inpatient hospital outcomes of patients with MRA in the United States using a national database. METHODS: The current study was a cross-sectional analysis of 2015 National Inpatient Sample data and consisted of patients ≥18 years with MRA. Descriptive statistics were used for understanding demographics, clinical characteristics, and MRA hospitalization costs. Multivariate regression models were used to identify predictors of length of hospital stay and in-hospital mortality. RESULTS: There were 123 410 MRA hospitalizations in 2015. The median length of stay was 4.7 days (interquartile range [IQR]: 2.5-8.6 days), median cost of hospitalization was US$43 543 (IQR: US$23 485-US$82 248), and in-hospital mortality rate was 8.8% (n = 10 855). Multivariate analyses showed that male sex, black race, and admission to medium and large hospitals were associated with increased hospital length of stay. Factors associated with higher in-hospital mortality rates included male sex; Asian or Pacific Islander race; beneficiaries of private insurance, Medicaid, and self-pay; patients residing in large central and small metro counties; nonelective admission type; and rural and urban nonteaching hospitals. CONCLUSIONS: Our study showed that many demographic, socioeconomic, health care, and geographic factors were associated with hospital length of stay and in-hospital mortality and may suggest disparities in quality of care. These factors could be targeted for preventing unplanned hospitalization, decreasing hospital length of stay, and lowering in-hospital mortality for this population.

Recent Health Care Expenditure Trends Among Adult Cancer Survivors in United States, 2009-2016.

OBJECTIVE: The objective of this study was to understand recent trends in direct health care expenditures among cancer survivors using novel cost-estimation methods and a nationally representative database. MATERIALS AND METHODS: This study was a retrospective analysis of 193,003 adults, ≥18 years of age, using the Medical Expenditure Panel Survey during the years 2009-2016. Manning and Mullahy two-part model was used to calculate adjusted mean and incremental medical expenditures after adjusting for covariates. RESULTS: The mean direct annual health care expenditure among cancer survivors ($13,025.0 [$12,572.0 to $13,478.0]) was nearly 3 times greater than noncancer participants ($4689.3 [$4589.2 to $4789.3]) and were mainly spent on inpatient services, office-based visits, and prescription medications. Cancer survivors had an additional health care expenditure of $4407.6 ($3877.6, $4937.6) per person per year, compared with noncancer participants after adjusting for covariates (P<0.001). The total mean annual direct health care expenditure for cancer survivors increased from $12,960.0 (95% confidence interval: $12,291.0-$13,628.0) in 2009-2010 to $13,807.0 ($12,828.0 to $14,787.0) in 2015-2016. CONCLUSIONS: Given the higher health care expenditures among cancer survivors and the increasing prevalence of cancers, cost-saving measures should be planned through multidisciplinary initiatives, collaborative research, and importantly, health care planning and policy changes. Our findings could be helpful in streamlining health care resources and interventions, developing national health care coverage policies, and possibly considering radically new insurance strategies for cancer survivors.

Safety of bloodless autologous stem cell transplantation in Jehovah's Witness patients.

Due to the curative potential and improvement in progression-free survival (PFS), high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is considered the standard of care for several hematologic malignancies, such as multiple myeloma, and lymphomas. ASCT typically involves support with blood product transfusion. Thus, difficulties arise when Jehovah's Witness patients refuse blood transfusions. In order to demonstrate the safety of performing "bloodless" ASCT (BL-ASCT), we performed a retrospective analysis of 66 Jehovah's Witnesses patients who underwent BL-ASCT and 1114 non-Jehovah's Witness patients who underwent transfusion-supported ASCT (TF-ASCT) at Cedars-Sinai Medical Center between January 2000 and September 2018. Survival was compared between the two groups. Transplant-related complications, mortality, engraftment time, length of hospital stay, and number of ICU transfers were characterized for the BL-ASCT group. One year survival was found to be 87.9% for both groups (P = 0.92). In the BL-ASCT group, there was one death prior to the 30 days post transplant due to CNS hemorrhage, and one death prior to 100 days due to sepsis. Based on our data, BL-ASCT can be safely performed with appropriate supportive measures, and we encourage community oncologists to promptly refer JW patients for transplant evaluation when ASCT is indicated.

Bone marrow transplant-associated thrombotic microangiopathy without peripheral blood schistocytes: a case report and review of the literature.

BACKGROUND: Bone marrow transplant-associated thrombotic microangiopathy (TA-TMA) is a relatively frequent but under-recognized and under-treated hematopoietic stem cell transplant (HSCT) complication that leads to significant post-transplant morbidity and mortality. Classic TMA-defining laboratory abnormalities appear at different times in the course of TA-TMA development, with schistocytes often appearing later in the disease course. In some severe TMA cases, schistocytes may be absent due to increased endothelial permeability. Unfortunately, many clinicians continue to perceive the presence of schistocytes as an absolute requirement for TA-TMA diagnosis, which leads to delayed recognition and treatment of this potentially fatal transplant complication. METHODS: Patient chart review and PubMed literature search using the term, "transplant-associated thrombotic microangiopathy". CASE PRESENTATION: A 54-year-old male IgG kappa multiple myeloma underwent a reduced intensity allogeneic HSCT from a 9/10 HLA-matched unrelated donor after conditioning with fludarabine and melphalan. On day + 27, the patient developed acute kidney injury followed by repeated episodes of diarrhea and gastrointestinal bleeding attributed to graft versus host disease (GVHD) and cytomegalovirus (CMV) colitis. Repeated colonic biopsies suggested CMV infection and GVHD. Despite appropriate treatment with antiviral therapy and immunosuppressants, the patient's condition continued to deteriorate. He experienced concomitant anemia and thrombocytopenia as well as elevated lactate dehydrogenase and low haptoglobin levels, but a TA-TMA diagnosis was not made due to an absence of schistocytes on peripheral smear. The patient expired secondary to uncontrolled gastrointestinal bleeding. A post-mortem analysis of the resection specimen revealed extensive TMA involving numerous arteries and arterioles in the ileal and colonic submucosa as well as in the muscularis propria and deep lamina propria of the mucosa. CONCLUSIONS: TA-TMA can occur in the absence of peripheral blood schistocytes. Our experience underscores the importance of considering the diagnosis of intestinal TA-TMA in patients with refractory post-transplant diarrhea and GI bleeding, even if all classic features are not present.

Targeting the Wnt Pathway in Cancer: A Review of Novel Therapeutics.

Wnt signaling is an evolutionarily conserved pathway that controls cell-to-cell interactions during embryogenesis. In adults, Wnt signaling plays a role in tissue homeostasis in almost every organ system. Aberrations within this pathway are implicated in a spectrum of human diseases. A variety of perturbations have been described in both solid and hematologic malignancies, lending way to Wnt signaling as a target for anti-cancer therapy. Of particular interest is the role of Wnt signaling in the development and maintenance of cancer stem cells, a rare population of cells that are able to maintain a tumor via self-renewal and thought to be more resistant to chemotherapy than bulk tumor cells. The ability to eradicate cancer stem cells may decrease the risk of cancer relapse and metastasis. A number of therapeutic agents specifically targeting the Wnt pathway have entered clinical trials, either as monotherapy or in combination with chemotherapy. We will provide an overview of agents that have been developed to target the Wnt pathways and a summary of pre-clinical and clinical trials.

Photobiomodulation therapy in the management of chronic oral graft-versus-host disease.

AIM: Patients treated with allogeneic hematopoietic stem cell transplantation (HSCT) may experience oral complications associated with chronic graft-versus-host disease (cGVHD). These complications may significantly affect quality of life, even many years post-HSCT. Current treatment options for oral cGVHD are limited and often include steroid or other immunomodulatory medications, which may not adequately control the oral condition. A non-immunosuppressive intervention for symptomatic relief in oral cGVHD would thus be a welcome addition to the treatment paradigm. MATERIALS AND METHODS: We report seven cases of oral cGVHD that were treated with photobiomodulation therapy (PBM), previously known as low-level laser therapy (LLLT). Patients underwent at least two PBM treatments per week in addition to local treatment with steroids, and if on systemic therapies, these were either unchanged or dosage was reduced during the period of PBM therapy. Follow-up data is presented for 4 weeks of treatment. RESULTS: Oral pain, sensitivity, and dry mouth improved in most patients. These findings suggest PBM therapy may represent an additional approach for management of oral cGVHD, and suggest that controlled studies should be conducted to confirm the efficacy and safety of PBM therapy in oral cGVHD and to determine optimal PBM therapy protocols.

Current therapy of myelodysplastic syndromes.

After being a neglected and poorly-understood disorder for many years, there has been a recent explosion of data regarding the complex pathogenesis of myelodysplastic syndromes (MDS). On the therapeutic front, the approval of azacitidine, decitabine, and lenalidomide in the last decade was a major breakthrough. Nonetheless, the responses to these agents are limited and most patients progress within 2 years. Allogeneic stem cell transplantation remains the only potentially curative therapy, but it is associated with significant toxicity and limited efficacy. Lack or loss of response after standard therapies is associated with dismal outcomes. Many unanswered questions remain regarding the optimal use of current therapies including patient selection, response prediction, therapy sequencing and combinations, and management of resistance. It is hoped that the improved understanding of the underpinnings of the complex mechanisms of pathogenesis will be translated into novel therapeutic approaches and better prognostic/predictive tools that would facilitate accurate risk-adaptive therapy.

Glomerular hemophagocytic macrophages in a patient with proteinuria and clinical and laboratory features of hemophagocytic lymphohistiocytosis (HLH).

Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous disorder characterized by excessive activation and proliferation of nonmalignant histiocytes, which are commonly found in bone marrow, lymph nodes, spleen and liver in affected patients. Here, we report the presence of glomerular macrophages, including one showing erythrophagocytosis, on renal biopsy in a 25-year-old patient with clinical presentation and laboratory changes consistent with HLH. The clinical course was marked by persistent fever for 2 months, pleural and pericardial effusion, splenomegaly, lymphadenopathy, pancytopenia, cardiac arrhythmias, multiple organ dysfunction, and proteinuria, with demise after a 2-month hospitalization. Positive assay for Epstein-Barr virus (EBV), marked hyperferritinemia, hypofibrinogenemia, hypertriglyceridemia, elevated anti-nuclear antibody, proteinuria, and decreased circulating NK cells by flow cytometry were compatible with the diagnosis of HLH. We suggest that the glomerular hemophagocytic macrophages, which have not heretofore been described in the kidney of a patient with HLH, may have contributed to renal dysfunction manifest as proteinuria.

Semaphorin 3E initiates antiangiogenic signaling through plexin D1 by regulating Arf6 and R-Ras.

Recent studies revealed that a class III semaphorin, semaphorin 3E (Sema3E), acts through a single-pass transmembrane receptor, plexin D1, to provide a repulsive cue for plexin D1-expressing endothelial cells, thus providing a highly conserved and developmentally regulated signaling system guiding the growth of blood vessels. We show here that Sema3E acts as a potent inhibitor of adult and tumor-induced angiogenesis. Activation of plexin D1 by Sema3E causes the rapid disassembly of integrin-mediated adhesive structures, thereby inhibiting endothelial cell adhesion to the extracellular matrix (ECM) and causing the retraction of filopodia in endothelial tip cells. Sema3E acts on plexin D1 to initiate a two-pronged mechanism involving R-Ras inactivation and Arf6 stimulation, which affect the status of activation of integrins and their intracellular trafficking, respectively. Ultimately, our present study provides a molecular framework for antiangiogenesis signaling, thus impinging on a myriad of pathological conditions that are characterized by aberrant increase in neovessel formation, including cancer.