A retrospective review of the rate of sexually transmitted infections in adolescents after universal screening protocol implementation in an urban United States clinic.

Objective: Despite expanded guidelines, adolescent gonorrhea and chlamydia (GC/CT) screening rates remain low due to multiple psychosocial barriers and biases. This intervention aimed to improve screening and diagnosis rates at adolescent well visits by establishing a streamlined universal screening protocol for all patients ages 13-18 years old. Methods: A universal sexually transmitted infection (STI) screening approach was introduced at an urban clinic affiliated with an academic medical center near Philadelphia, Pennsylvania (PA) in September 2018 for all adolescent well-visits. GC/CT screening and diagnosis rates were compared two years prior to and two years after implementation, deemed the baseline and intervention groups, respectively. Results: In total, 1,168 encounters were included for analysis. The patient cohort consisted of 47% females, with an average age of 15, and were predominantly publicly insured (79%). STI screening rates increased significantly from 16.7% (89/534) to 83.6% (530/634) of adolescents with implementation of the universal screening protocol. Furthermore, there was a 1.6-fold increase in total positive cases detected after implementation of ok universal screening. Conclusion: This study demonstrates improved adolescent GC/CT capture rates by establishing a universal screening protocol and highlights a streamlined means of implementation in virtually any pediatric clinic. Limitations include sample size, as this is a single academic practice, as well as any issues with lab collection and results reporting.

Concurrent pembrolizumab with AVD for untreated classic Hodgkin lymphoma.

Concurrent administration of pembrolizumab with chemotherapy in untreated classic Hodgkin lymphoma (CHL) has not been studied previously. To investigate this combination, we conducted a single-arm study of concurrent pembrolizumab with AVD (doxorubicin, vinblastine, and dacarbazine; APVD) for untreated CHL. We enrolled 30 patients and met the primary safety end point with no observed significant treatment delays in the first 2 cycles. Twelve patients experienced grade 3 or 4 nonhematologic adverse events (AEs), most commonly febrile neutropenia and infection/sepsis. Grade 3 or 4 immune-related AEs, including alanine aminotransferase elevation and aspartate aminotransferase elevation were observed in 3 patients. One patient experienced an episode of grade 2 colitis and arthritis. Six patients missed at least 1 dose of pembrolizumab because of AEs, primarily grade 2 or higher transaminitis. Among 29 response-evaluable patients, the best overall response rate was 100% and the complete response rate was 90%. With a median follow-up of 2.1 years, the 2-year progression-free survival (PFS) and overall survival were 97% and 100%, respectively. To date, no patient who has withheld or discontinued pembrolizumab because of toxicity has progressed. Clearance of circulating tumor DNA (ctDNA) was associated with superior PFS when measured after cycle 2 and at the end of treatment (EOT). None of the 4 patients with persistent uptake by fluorodeoxyglucose positron emission tomography (PET) at EOT yet negative ctDNA have relapsed to date. Concurrent APVD shows promising safety and efficacy but may yield spurious PET findings in some patients. This trial was registered at www.clinicaltrials.gov as #NCT03331341.

Polatuzumab vedotin with infusional chemotherapy for untreated aggressive B-cell non-Hodgkin lymphomas.

The POLARIX trial demonstrated the superiority of polatuzumab vedotin (Pola) over vincristine in the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) regimen for large B-cell lymphomas, but it is unknown whether Pola can be safely incorporated into intensified regimens (eg, dose-adjusted [DA]-EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab]) typically used for the highest risk histologies. This was a single-center, open-label, prospective clinical trial of 6 cycles of Pola-DA-EPCH-R (vincristine omitted) in aggressive large B-cell lymphomas. The primary end point was to estimate the safety of Pola-DA-EPCH-R as measured by the rate of dose-limiting toxicities (DLTs) in the first 2 cycles with prespecified suspension rules. Secondary and exploratory end points included efficacy and correlation with circulating tumor DNA (ctDNA) levels. We enrolled 18 patients on study, and with only 3 DLTs observed, the study met its primary end point for safety. There were 5 serious adverse events, including grade 3 febrile neutropenia (3, 17%), grade 3 colonic perforation in the setting of diverticulitis, and grade 5 sepsis/typhlitis. Among 17 evaluable patients, the best overall response rate was 100%, and the complete response rate was 76%. With a median follow-up of 12.9 months, 12-month event-free survival was 72%, and 12-month overall survival was 94%. No patient with undetectable ctDNA at the end of treatment has relapsed to date. Using Pola to replace vincristine in the DA-EPOCH-R regimen met its primary safety end point. These data support the further evaluation and use of this approach in histologies where the potential benefit of both an intensified regimen and Pola may be desired. This trial was registered at www.clinicaltrials.gov as #NCT04231877.

Evaluation of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies: Lessons learned from a 14-year retrospective study.

INTRODUCTION: Thrombotic thrombocytopenic purpura (TTP) is a clinical thrombotic microangiopathy (TMA) syndrome defined by the pentad of symptoms. Therapeutic plasma exchange with plasma replacement is an ASFA Category I modality that can reduce morbidity and mortality if initiated early. We describe a 14-year review of patients referred for plasma exchange with a suspected diagnosis of TTP. METHODS: For 70 patients referred for urgent plasma exchange, clinical, therapeutic, and laboratory data were retrospectively analyzed, and the diagnosis was determined. RESULTS: Fifteen of the patients were diagnosed with TTP based upon ADAMTS-13 activity with the other 51 patients having other non-TTP TMA diagnoses. The mortality rate was significant for both TTP and non-TTP TMAs. PLASMIC scores were also calculated retrospectively and were noted to have limited value. TMA is a diagnostic challenge and encompasses different syndromes with similar presentations. CONCLUSION: Determining an accurate diagnosis, including prompt ADAMTS-13 testing, makes it possible to initiate appropriate therapy for the multiple different TMAs that can be seen in clinical practice.

Predictors of cytopenias after treatment with axicabtagene ciloleucel in patients with large B-cell lymphoma.

Cytopenias are important but less studied adverse events following chimeric antigen receptor-engineered T cell (CAR-T) therapy. In our analysis of patients with large cell lymphoma who received axicabtagene ciloleucel (axi-cel), we sought to determine the rate and risk factors of clinically significant short term cytopenias defined as grade ≥3 neutropenia, anemia, or thrombocytopenia, or treatment with growth factors or blood product transfusions between days 20-30 after axi-cel. Fifty-three pts received axi-cel during the study period and severe cytopenias were observed in 32 (60%) pts. Significant cytopenias were more common in non-responders (stable or progressive disease) vs. responders (partial or complete response) (100% vs. 70%; p = .01). In the multivariable model, platelet transfusion within a month before leukapheresis, number of red blood cell and platelet transfusions between leukapheresis to lymphodepletion, pre-lymphodepletion absolute neurophil count, pre-lymphodepletion lactate dehydrogenase, and number of dexamethasone treatments after CAR-T were significantly associated with severe cytopenias after axi-cel.

Environmental pesticide exposure and non-Hodgkin lymphoma survival: a population-based study.

BACKGROUND: There is evidence indicating that pesticide exposure is a risk factor for non-Hodgkin lymphoma (NHL) development. However, the association between pesticide exposure and NHL survival is not well-established. METHODS: Using the California Cancer Registry, we identified patients with a first primary diagnosis of NHL from 2010 to 2016 and linked these patients with CalEnviroScreen 3.0 to obtain production agriculture pesticide exposure to 70 chemicals from the state-mandated Pesticide Use Reporting (PUR) by census tract from 2012 to 2014. In addition, data from PUR was integrated into a geographic information system that employs land-use data to estimate cumulative exposure to specific pesticides previously associated with NHL (glyphosate, organophosphorus, carbamate, phenoxyherbicide, and 2,4-dimethylamine salt) between 10 years prior up to 1 year after NHL diagnosis. Multivariable Cox proportional hazards regression models were used to evaluate the association between total pesticide exposure from CalEnviroScreen 3.0 and individual pesticide exposure from geographic land use data and lymphoma-specific and overall survival. RESULTS: Among 35,808 NHL patients identified, 44.2% were exposed to pesticide in their census tract of residence. Glyphosate, organophosphorus, carbamate, phenoxyherbicide, and 2,4-dimethylamine salt exposure was observed in 34.1%, 26.0%, 10.6%, 14.0%, and 12.8% of NHL patients, respectively. Total pesticide exposure at the time of diagnosis was not associated with lymphoma-specific or overall survival. In addition, no association was consistently found between glyphosate, organophosphorus, carbamate, phenoxyherbicide, and 2,4 dimethylamine salt exposure and lymphoma-specific or overall survival. CONCLUSIONS: Although we found no consistent associations between agricultural pesticide exposure at the neighborhood level and worse survival, these results provide a platform for designing future studies to determine the association between pesticide and NHL.

The impact of B-cell-directed therapy on SARS-CoV-2 vaccine efficacy in chronic lymphocytic leukaemia.

Prior reports evaluating SARS-CoV-2 vaccine efficacy in chronic lymphocytic leukaemia (CLL) used semiquantitative measurements of anti-S to evaluate immunity; however, neutralization assays were used to assess functional immunity in the trials leading to vaccine approval. Here, we identified decreased rates of seroconversion in vaccinated CLL patients and lower anti-S levels compared to healthy controls. Notably, we demonstrated similar results with the Roche anti-S assay and neutralization activity. Durable responses were seen at six months; augmentation with boosters was possible in responding patients. Absence of normal B cells, frequently seen in patients receiving Bruton tyrosine kinase and B-cell lymphoma 2 inhibitors, was a strong predictor of lack of seroconversion.

Long-term Follow-up and Correlative Analysis of Two Phase II Trials of Rituximab and Lenalidomide Followed by Continuous Lenalidomide in Untreated and Relapsed/Refractory Indolent Lymphoma.

PURPOSE: Rituximab and lenalidomide are effective for previously untreated and relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). However, long-term survival and predictive biomarkers are not well described. PATIENTS AND METHODS: We conducted two phase II open-label trials involving 60 patients with previously untreated and R/R advanced-stage iNHL. Patients received lenalidomide and rituximab induction followed by continuous lenalidomide until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Correlative studies included plasma cytokine monitoring, flow cytometry of peripheral blood mononuclear cells (PBMC; days 0, 15, 30, and 60), and RNA sequencing (RNA-seq) of pretreatment tumor biopsies. RESULTS: At a median follow-up of 63 months for previously untreated and 100 months for R/R, ORR was 82% for both. The 11 R/R patients who achieved complete remission remained in continuous remission for 16 to 141 months, thereafter. Median overall survival (OS) was not reached in the previously untreated and was 140 months (95% confidence interval, 53.4-140) in the R/R group. A mixed-effects linear regression model identified significant associations between Granzyme B+ (GranB+) CD8+ T cells and long-term complete response (LTCR; P = 5.3e-4). Furthermore, prior to start of therapy, treatment response could be predicted by B-cell and GranB+ CD8+ T-cell levels (% total lymphocytes). CONCLUSIONS: Rituximab plus lenalidomide followed by continuous lenalidomide is effective with manageable toxicity in patients with previously untreated and R/R iNHL. This regimen produces durable remissions, even in heavily pretreated patients, with some lasting greater than 10 years. GranB+ CD8+ T cells, B cells, and plasma IFNγ allowed prediction of LTCR but need validation in larger trials.

Second primary malignancies in multiple myeloma: A review.

As survival times of multiple myeloma (MM) patients continue to improve, second primary malignancies (SPM) have become an increasingly relevant long-term risk among MM survivors. Population studies since the 1950s have consistently observed an increased incidence of hematologic SPMs, specifically acute leukemia, among MM survivors. Prolonged treatment with alkylators, especially melphalan, was associated with an increased hematologic SPM risk; likewise, autologous stem cell transplantation appeared to minimally increase SPM risk. Immunomodulatory drugs, specifically lenalidomide, was associated with an increased SPM incidence, although most studies concluded that the benefits of therapy outweighed any risks of SPM. Newer anti-myeloma therapy such as proteasome inhibitors and monoclonal antibodies did not appear to increase SPM risk although robust long-term follow-up is lacking. This review discusses current understanding regarding SPMs among survivors of MM, how different host-, disease- and treatment-related factors contribute to SPM incidence and highlights emerging screening guidelines and prognosis for SPMs.

Belinostat in Relapsed/Refractory T-Cell Large Granular Lymphocyte Leukemia.

T-cell large granular lymphocyte (LGL) leukemia is a rare indolent neoplasm primarily treated with immunosuppression. Few therapies and no consensus exist for the optimal treatment of T-cell LGL leukemia refractory to immunosuppressive therapy. Here, we report a case of relapsed/refractory T-cell LGL treated with belinostat. A 57-year-old male presented with lymphocytosis and anemia and was found to have T-cell LGL, requiring frequent packed red blood cell transfusions. He was initially treated with methotrexate with no response after 7 months. He was then switched to cyclosporine and cyclophosphamide and experienced transfusion independence for 42 months before disease relapse. He was then started on belinostat with noted subsequent transfusion independence for greater than 15 months to date and decreased disease involvement on bone marrow biopsy. To our knowledge, this is the first reported case of belinostat use in relapsed/refractory T-cell LGL leukemia which resulted in a durable clinical and biologic response.

Incidence of Upper Extremity Deep Vein Thrombosis in Acute Leukemia and Effect on Mortality.

The cumulative incidence, risk factors, rate of subsequent venous thromboembolism (VTE) and bleeding and impact on mortality of isolated upper extremity deep vein thrombosis (UE DVT) in acute leukemia are not well-described. The California Cancer Registry, used to identify treated patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) diagnosed between 2009 and 2014, was linked with the statewide hospitalization database to determine cumulative incidences of UE DVT and subsequent VTE and bleeding after UE DVT diagnosis. Cox proportional hazards regression models were used to assess the association of UE DVT on the risk of subsequent pulmonary embolism (PE) or lower extremity deep vein thrombosis (LE DVT) and subsequent bleeding, and the impact of UE DVT on mortality. There were 5,072 patients identified: 3,252 had AML and 1,820 had ALL. Three- and 12-month cumulative incidences of UE DVT were 4.8% (95% confidence interval [CI]: 4.1-5.6) and 6.6% (95% CI: 5.8-7.5) for AML and 4.1% (95% CI: 3.2-5.1) and 5.9% (95% CI: 4.9-7.1) for ALL, respectively. Twelve-month cumulative incidences of subsequent VTE after an incident UE DVT diagnosis were 5.3% for AML and 12.2% for ALL. Twelve-month cumulative incidences of subsequent bleeding after an incident UE DVT diagnosis were 15.4% for AML and 21.1% for ALL. UE DVT was associated with an increased risk of subsequent bleeding for both AML (hazard ratio [HR]: 2.07; 95% CI: 1.60-2.68) and ALL (HR: 1.62; 95% CI: 1.02-2.57) but was not an independent risk factor for subsequent PE or LE DVT for either leukemia subtype. Isolated incident UE DVT was associated with increased leukemia-specific mortality for AML (HR: 1.42; 95% CI: 1.16-1.73) and ALL (HR: 1.80; 95% CI: 1.31-2.47). UE DVT is a relatively common complication among patients with AML and ALL and has a significant impact on bleeding and mortality. Further research is needed to determine appropriate therapy for this high-risk population.

Ofatumumab and Complement Replacement in Relapsed/Refractory Chronic Lymphocytic Leukemia.

BACKGROUND: While many humanized monoclonal antibodies utilize complement-dependent cytotoxicity, the complement depleting effects of these antibodies and the impact of complement replacement on treatment response are not well-described. METHODS: We conducted a phase 2 trial involving patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Patients were treated with ofatumumab with fresh frozen plasma (FFP) used as a source of complement replacement. The primary endpoint was objective response rate. Correlative endpoints included complement levels (C3 and C4) and complement activity (CH50) which was drawn at baseline and after ofatumumab with FFP administration. RESULTS: Among 12 enrolled patients, overall response rate was 83% with two patients (17%) achieving a complete response. While only two (17%) patients had low complement activity at baseline, eight (67%) developed low levels of complement activity after ofatumumab treatment with FFP replacement. The magnitude of complement depletion did not correlate with response. Adverse events were minimal. The combination of ofatumumab and FFP demonstrated tolerability and surprising activity in high-risk CLL patients. CONCLUSIONS: The combination of ofatumumab and FFP demonstrated tolerability and surprising activity in high-risk CLL patients. Complement replacement should be studied further as a minimally toxic approach to improve efficacy of monoclonal antibody-based regimens.

Sfr1, a Tetrahymena thermophila Sfi1 Repeat Protein, Modulates the Production of Cortical Row Basal Bodies.

Basal bodies are essential microtubule-based structures that template, anchor, and orient cilia at the cell surface. Cilia act primarily in the generation of directional fluid flow and sensory reception, both of which are utilized for a broad spectrum of cellular processes. Although basal bodies contribute to vital cell functions, the molecular contributors of their assembly and maintenance are poorly understood. Previous studies of the ciliate Tetrahymena thermophila revealed important roles for two centrin family members in basal body assembly, separation of new basal bodies, and stability. Here, we characterize the basal body function of a centrin-binding protein, Sfr1, in Tetrahymena. Sfr1 is part of a large family of 13 proteins in Tetrahymena that contain Sfi1 repeats (SFRs), a motif originally identified in Saccharomyces cerevisiae Sfi1 that binds centrin. Sfr1 is the only SFR protein in Tetrahymena that localizes to all cortical row and oral apparatus basal bodies. In addition, Sfr1 resides predominantly at the microtubule scaffold from the proximal cartwheel to the distal transition zone. Complete genomic knockout of SFR1 (sfr1Δ) causes a significant increase in both cortical row basal body density and the number of cortical rows, contributing to an overall overproduction of basal bodies. Reintroduction of Sfr1 into sfr1Δ mutant cells leads to a marked reduction of cortical row basal body density and the total number of cortical row basal bodies. Therefore, Sfr1 directly modulates cortical row basal body production. This study reveals an inhibitory role for Sfr1, and potentially centrins, in Tetrahymena basal body production. IMPORTANCE Basal bodies and centrioles are structurally similar and, when rendered dysfunctional as a result of improper assembly or maintenance, are associated with human diseases. Centrins are conserved and abundant components of both structures whose basal body and centriolar functions remain incompletely understood. Despite the extensive study of centrins in Tetrahymena thermophila, little is known about how centrin-binding proteins contribute to centrin's roles in basal body assembly, stability, and orientation. The sole previous study of the large centrin-binding protein family in Tetrahymena revealed a role for Sfr13 in the stabilization and separation of basal bodies. In this study, we found that Sfr1 localizes to all Tetrahymena basal bodies and complete genetic deletion of SFR1 leads to overproduction of basal bodies. The uncovered inhibitory role of Sfr1 in basal body production suggests that centrin-binding proteins, as well as centrins, may influence basal body number both positively and negatively.

Diffusion tensor imaging reveals visual pathway damage in patients with mild cognitive impairment and Alzheimer's disease.

Visual deficits are commonly seen in patients with Alzheimer's disease (AD), but postmortem histology has not found substantial damage in visual cortex regions, leading to the hypothesis that the visual pathway, from eye to the brain, may be damaged in AD. Diffusion tensor imaging (DTI) has been used to characterize white matter abnormalities. However, there is a lack of data examining the optic nerves and tracts in patients with AD. In this study, we used DTI to analyze the visual pathway in healthy controls, patients with mild cognitive impairment (MCI) and AD using scans provided by the Alzheimer's Disease Neuroimaging Initiative (ADNI). We found significant increases in the total diffusivity and radial diffusivity and reductions in fractional anisotropy in optic nerves among AD patients. Similar but less extensive changes in these metrics were seen in MCI patients as compared to controls. The differences in DTI metrics between groups mirrored changes in the splenium of the corpus callosum, which has commonly been shown to exhibit white matter damage during AD and MCI. Our findings indicate that white matter damage extends to the visual system, and may help explain the visual deficits experienced by AD patients.