A rare case of Philadelphia-positive (P210BCR-ABL1) T-cell acute lymphoblastic leukemia/lymphoma associated with minimal residual disease persistence after intensive chemotherapeutic approaches.

T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is a rare and aggressive leukemia. Philadelphia chromosome-positive cytogenetic abnormality is most common in CML. It is difficult to differentiate between de novo Ph+ T-ALL/LBL and T-cell lymphoblastic crises of CML. We present a case of adult Ph+ T-ALL/LBL with a likely history of antecedent CML. Initially thought to be a case of chronic-phase CML, a diagnostic quandary led to the pursuit of a lymph node biopsy that established the diagnosis of Ph+ T-LBL or T lymphoblastic blast crisis of CML, a clinical presentation extremely rare and only the second of its kind from our review of the literature. The patient was treated with an intensive chemotherapy regimen for over a year due to persistent minimal residual disease (MRD) positivity indicating aggressive disease.

Symptom burden in patients with idiopathic multicentric Castleman disease and its impact on daily life: an international patient and caregiver survey.

Background: Idiopathic Multicentric Castleman Disease (iMCD) is a rare inflammatory lymphoproliferative disorder with heterogenous clinical presentations. The symptomatology in iMCD patients remains poorly understood. The aim of this study was to identify the type, frequency and severity of iMCD-related symptoms and the impact of these on the daily lives of iMCD patients and informal-caregivers. Methods: We conducted two bespoke 45-question online surveys for iMCD patients and informal-caregivers of patients recruited from the US, UK, Australia and Canada between April 14 and November 8, 2021. Descriptive data was collected, and a Likert scale was used to quantify the impact of symptoms on various aspects of daily life. Ordinal logistic regression analysis was used to determine associations between age, gender, employment status and symptom burden with aspects of daily life. Findings: Eligible respondents included 51 iMCD patients and 11 informal-caregivers. Patients reported up to 27 unique symptoms, the mean number of symptoms experienced by a patient was 6.7 (range 0-22 symptoms). Most symptoms had a moderate to severe impact on patients' daily lives, with 'pain/discomfort', 'ability to travel', and 'sexual functioning' being the most impacted. iMCD patient characteristics such as being 40 years or older, female, and either disabled or unemployed was significantly associated with adverse impact on several aspects of daily life. Among caregivers, the aspects of daily life that were disproportionately affected was their own social life and freedom, emotional wellbeing, travel/relocation, and work. Interpretation: iMCD patients have widely varied and unappreciated symptomatology. High symptom burden adversely impacts several aspects of patient daily lives as well as their caregivers. Funding: Funding was provided by EUSA Pharma.

Strain-rate-dependent material properties of human lung parenchymal tissue using inverse finite element approach.

Automobile crashes and blunt trauma often lead to life-threatening thoracic injuries, especially to the lung tissues. These injuries can be simulated using finite element-based human body models that need dynamic material properties of lung tissue. The strain-rate-dependent material parameters of human parenchymal tissues were determined in this study using uniaxial quasi-static (1 mm/s) and dynamic (1.6, 3, and 5 m/s) compression tests. A bilinear material model was used to capture the nonlinear behavior of the lung tissue, which was implemented using a user-defined material in LS-DYNA. Inverse mapping using genetic algorithm-based optimization of all experimental data with the corresponding FE models yielded a set of strain-rate-dependent material parameters. The bilinear material parameters are obtained for the strain rates of 0.1, 100, 300, and 500 s-1. The estimated elastic modulus increased from 43 to 153 kPa, while the toe strain reduced from 0.39 to 0.29 when the strain rate was increased from 0.1 to 500 s-1. The optimized bilinear material properties of parenchymal tissue exhibit a piecewise linear relationship with the strain rate.

Computational assessment of leg response to extreme loadings using a detailed finite element model.

This study focuses on evaluating the response of the Total Human Model for Safety™ lower extremity finite element model under blast loading. Biofidelity of the lower extremity model was evaluated against experiments with impact loading equivalent to underbody blast. The model response was found to match well with the experimental data for the average impactor speeds of 7 and 9.3 m/s resulting in an overall correlation and analysis rating of 0.86 and 0.82, respectively. The model response was then used to investigate response for antipersonnel mine explosion where the numerical setup consists of a charge mass of 40 g trinitrotoluene placed at a depth of 50 mm below the heel. The explosion was modeled using Multi Material-Arbitrary Lagrangian Eulerian method. The model was subjected to the graded input in terms of variation in standoff distance and mass of explosive to investigate the sensitivity of the model. The model found sensitive to the threat definition and predicted an increase of 110% in peak fluid-structure interaction force with 20% reduction in its time to peak and 29% increase in peak calcaneus axial force with a reduction of 33% in its time to peak when explosive mass varied from 40 g to 100 g. The location of the explosive below the foot was discovered to have significant effect on the injury pattern in near-field explosion. A comparative study suggested that the model predicted similar response and damage pattern compared to experimental data.

Alternating Layers of Morselized Allograft and Injectable Ceramic Bone Graft Substitute in Acetabular Reconstruction: A Novel 'Sandwich' Technique.

Background: Impaction of morselized allograft is an appealing procedure for addressing the bone defects. However, concerns remain about its suitability for massive defects. We used a novel "sandwich" technique by impacting the morselized allograft in layers with an intervening layer of injectable bone graft substitute for restoring bone defects during acetabular reconstruction in total hip arthroplasties. Methods: From August 2015 to June 2017, 17 revisions, 4 rerevisions, and 3 complex primary total hip arthroplasties were operated by this novel technique. Postoperatively, serial X-rays were evaluated at regular intervals. Clinical and functional outcomes were assessed by the Harris hip score. To examine if introducing an injectable bone substitute into allograft stock increased its load-bearing capability, simulated mechanical testing using Synbone samples was conducted in the laboratory. Results: The mean Harris hip score significantly improved from 54.6 preoperatively to 86.8 at the latest follow-up. Graft incorporation was seen in all the cases. There was no evidence of component migration or loosening as compared to the X-rays at 3 weeks and 3 months in all the cases. With revision of component as end point, the survivorship was 100% at 82 months. The mechanical testing reported a higher capability of allograft samples when compared to those without bone substitutes. Conclusions: Our data confirms that the use of the "sandwich" technique is a reliable option for major acetabular reconstruction. Early weight bearing is a significant value addition, and short-term results confirm good clinical and functional outcome. Longer follow-up is necessary to assess the status of the construct in the long term.

Cancer burden in women with HIV on Medicaid: A nationwide analysis.

BACKGROUND: Cancer is the leading cause of death in people living with HIV. In the United States, nearly 1 in 4 people living with HIV are women, more than half of whom rely on Medicaid for healthcare coverage. OBJECTIVE: The objective of this study is to evaluate the cancer burden of women living with HIV on Medicaid. DESIGN: We conducted a cross-sectional study of women 18-64 years of age enrolled in Medicaid during 2012, using data from Medicaid Analytic eXtract files. METHODS: Using International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes, we identified women living with HIV (n = 72,508) and women without HIV (n = 17,353,963), flagging the presence of 15 types of cancer and differentiating between AIDS-defining cancers and non-AIDS-defining cancers. We obtained adjusted prevalence ratios and 95% confidence intervals for each cancer and for all cancers combined, using multivariable log-binomial models, and additionally stratifying by age and race/ethnicity. RESULTS: The highest adjusted prevalence ratios were observed for Kaposi's sarcoma (81.79 (95% confidence interval: 57.11-117.22)) and non-Hodgkin's lymphoma (27.69 (21.67-35.39)). The adjusted prevalence ratios for anal and cervical cancer, both of which were human papillomavirus-associated cancers, were 19.31 (17.33-21.51) and 4.20 (3.90-4.52), respectively. Among women living with HIV, the adjusted prevalence ratio for all cancer types combined was about two-fold higher (1.99 (1.86-2.14)) in women 45-64 years of age than in women 18-44 years of age. For non-AIDS-defining cancers but not for AIDS-defining cancers, the adjusted prevalence ratios were higher in older than in younger women. There was no significant difference in the adjusted prevalence ratios for all cancer types combined in the race/ethnicity-stratified analyses of the women living with HIV cohort. However, in cancer type-specific sub-analyses, differences in adjusted prevalence ratios between Hispanic versus non-Hispanic women were observed. For example, the adjusted prevalence ratio for Hispanic women for non-Hodgkin's lymphoma was 2.00 (1.30-3.07) and 0.73 (0.58-0.92), respectively, for breast cancer. CONCLUSION: Compared to their counterparts without HIV, women living with HIV on Medicaid have excess prevalence of cervical and anal cancers, both of which are human papillomavirus related, as well as Kaposi's sarcoma and lymphoma. Older age is also associated with increased burden of non-AIDS-defining cancers in women living with HIV. Our findings emphasize the need for not only cancer screening among women living with HIV but also for efforts to increase human papillomavirus vaccination among all eligible individuals.

Patterns of Diagnostic Evaluation and Determinants of Treatment in Older Patients With Non-transfusion Dependent Myelodysplastic Syndromes.

BACKGROUND: Older patients with myelodysplastic syndromes (MDS), particularly those with no or one cytopenia and no transfusion dependence, typically have an indolent course. Approximately, half of these receive the recommended diagnostic evaluation (DE) for MDS. We explored factors determining DE in these patients and its impact on subsequent treatment and outcomes. PATIENTS AND METHODS: We used 2011-2014 Medicare data to identify patients ≥66 years of age diagnosed with MDS. We used Classification and Regression Tree (CART) analysis to identify combinations of factors associated with DE and its impact on subsequent treatment. Variables examined included demographics, comorbidities, nursing home status, and investigative procedures performed. We conducted a logistic regression analysis to identify correlates associated with receipt of DE and treatment. RESULTS: Of 16 851 patients with MDS, 51% underwent DE. patients with MDS with no cytopenia (n = 3908) had the lowest uptake of DE (34.7%). Compared to patients with no cytopenia, those with any cytopenia had nearly 3 times higher odds of receiving DE [adjusted odds ratio (AOR), 2.81: 95% CI, 2.60-3.04] and the odds were higher for men than for women [AOR, 1.39: 95%CI, 1.30-1.48] and for Non-Hispanic Whites [vs. everyone else (AOR, 1.17: 95% CI, 1.06-1.29)]. The CART showed DE as the principal discriminating node, followed by the presence of any cytopenia for receiving MDS treatment. The lowest percentage of treatment was observed in patients without DE, at 14.6%. CONCLUSION: In this select older patients with MDS, we identified disparities in accurate diagnosis by demographic and clinical factors. Receipt of DE influenced subsequent treatment but not survival.

Lower Extremity Response to Blast Loading: A Computational Study.

This study has investigated the response of the Total Human Model for Safety (THUMS) lower extremity finite element model under blast loading. Response of the model was estimated in simulated underbody blast (UBB) loading using floorplate impact velocities of increasing severity. Correlation and analysis (CORA) ratings suggested a good match between numerical response and available experimental data. The model response was then investigated in an antipersonnel landmine explosion. The model was found stable in the nearfield blast and sensitive to the threat definition. The lower extremity injury was predicted when detonation occurred below the heel. The model predicted major injuries localized to the hindfoot and midfoot with minimal damage to the forefoot, consistent with the findings in the literature. The damage to the individual bones of the foot was measured in terms of percentage change in mass and element eroded.

Prognosis of older patients with newly diagnosed AML undergoing antileukemic therapy: A systematic review.

BACKGROUND AND OBJECTIVE: The prognostic value of age and other non-hematological factors in predicting outcomes in older patients with newly diagnosed acute myeloid leukemia (AML) undergoing antileukemic therapy is not well understood. We performed a systematic review to determine the association between these factors and mortality and health-related quality of life or fatigue among these patients. METHODS: We searched Medline and Embase through October 2021 for studies in which researchers quantified the relationship between age, comorbidities, frailty, performance status, or functional status; and mortality and health-related quality of life or fatigue in older patients with AML receiving antileukemic therapy. We assessed the risk of bias of the included studies using the Quality in Prognostic Studies tool, conducted random-effects meta-analyses, and assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation approach. RESULTS: We included 90 studies. Meta-analysis showed that age (per 5-year increase, HR 1.16 95% CI 1.11-1.21, high-quality evidence), comorbidities (Hematopoietic Cell Transplantation-specific Comorbidity Index: 3+ VS less than 3, HR 1.60 95% CI 1.31-1.95, high-quality evidence), and performance status (Eastern Cooperative Oncology Group/ World Health Organization (ECOG/WHO): 2+ VS less than 2, HR 1.63 95% CI 1.43-1.86, high-quality evidence; ECOG/WHO: 3+ VS less than 3, HR 2.00 95% CI 1.52-2.63, moderate-quality evidence) were associated with long-term mortality. These studies provided inconsistent and non-informative results on short-term mortality (within 90 days) and quality of life. CONCLUSION: High-quality or moderate-quality evidence support that age, comorbidities, performance status predicts the long-term prognosis of older patients with AML undergoing antileukemic treatment.

Efficacy and safety of regimens used for the treatment of multicentric Castleman disease: A systematic review.

OBJECTIVES: Treatment options for multicentric Castleman disease (MCD) remain limited. The only FDA-approved drug is siltuximab for idiopathic MCD (iMCD), but the response rate with siltuximab is less than 50%. We performed a systematic review to examine the efficacy and safety of various regimens used for the treatment of MCD. METHODS: A database search on PubMed, Embase, Cochrane, Web of Science, and Clinicaltrials.gov using the terms "Castleman disease," "treatment outcome," and "patient safety" was done. RESULTS AND CONCLUSIONS: Results from a randomized controlled trial and an extension study highlighted the efficacy and long-term safety of siltuximab for iMCD; other trials showed tocilizumab to be a suitable alternative. A recent trial reported high response rates with thalidomide in iMCD patients. Promising results were reported for bortezomib in relapsed/ refractory MCD. For human herpesvirus-8 (HHV8)-associated MCD, rituximab along with doxorubicin therapy followed by maintenance with zidovudine and valganciclovir is the most effective therapy. A single-arm trial has highlighted the potential role of tocilizumab in HHV8-MCD. Data for these regimens are limited and mostly comprise nonrandomized trials. Further research on emerging agents could have a major impact on the treatment of this rare disease.

Excess cancer prevalence in men with HIV: A nationwide analysis of Medicaid data.

BACKGROUND: Cancer is one of the most common comorbidities in men living with HIV (MLWH). However, little is known about the MLWH subgroups with the highest cancer burden to which cancer prevention efforts should be targeted. Because Medicaid is the most important source of insurance for MLWH, we evaluated the excess cancer prevalence in MLWH on Medicaid relative to their non-HIV counterparts. METHODS: In this cross-sectional study using 2012 Medicaid Analytic eXtract data nationwide, we flagged the presence of HIV, 13 types of cancer, symptomatic HIV, and viral coinfections using codes from the International Classification of Diseases, Ninth Revision, Clinical Modification. The study population included individuals administratively noted to be of male sex (men), aged 18 to 64 years, with (n = 82,495) or without (n = 7,302,523) HIV. We developed log-binomial models with cancer as the outcome stratified by symptomatic status, age, and race/ethnicity. RESULTS: Cancer prevalence was higher in MLWH than in men without HIV (adjusted prevalence ratio [APR], 1.84; 95% confidence interval [CI], 1.78-1.90) and was higher among those with symptomatic HIV (APR, 2.74; 95% CI, 2.52-2.97) than among those with asymptomatic HIV (APR, 1.73; 95% CI, 1.67-1.79). The highest APRs were observed for anal cancer in younger men, both in the symptomatic and asymptomatic groups: APR, 312.97; 95% CI, 210.27-465.84, and APR, 482.26; 95% CI, 390.67-595.32, respectively. In race/ethnicity strata, the highest APRs were among Hispanic men for anal cancer (APR, 198.53; 95% CI, 144.54-272.68) and for lymphoma (APR, 9.10; 95% CI, 7.80-10.63). CONCLUSIONS: Given the Medicaid program's role in insuring MLWH, the current findings highlight the importance of the program's efforts to promote healthy behaviors and vaccination against human papillomavirus in all children and adolescents and to provide individualized cancer screening for MLWH.

Incidence, Clinical Features, and Outcomes of Langerhans Cell Histiocytosis in the United States.

Langerhans cell histiocytosis (LCH) is a disorder with highly diverse clinical manifestations. We explored if age, sex, race, organ system involved, and therapy approaches determine patient survival in the era of modern treatments. LCH patient data reported to the Surveillance, Epidemiology, and End Results (SEER) program in 2010-2016 (n=1282; age: 0 to 100 y) was analyzed. Age-specific LCH incidence flattening to a low level suggests an age cutoff for pediatric patients of 20 years. The overall survival probability is lower for patients 21 to 100 years old ( P <0.0001), irrespective of sex and race. The commonest sites involved in the 0- to 20-year age group were bone, skin, and bone marrow; this shifted to lung, bone, and skin as the commonest disease sites in patients 21 to 100 years of age. The treatments applied differed between age groups, as younger versus older patients were more likely to receive chemotherapy-based treatment (48.4% vs. 17%; P <0.0001). There also was a trend toward nonwhite versus white patients being less likely to receive chemotherapy-based treatment (31.7% vs. 38.2%; P =0.067). Whereas there are treatment disparities related to LCH patient age and perhaps race, patient age is the strongest predictor of survival, with patients 21 to 100 years of age with lung, lymph node, skin, and bone marrow disease having the worst outcomes ( P <0.0001).

Epidemiology and treatment patterns of idiopathic multicentric Castleman disease in the era of IL-6-directed therapy.

The epidemiology of human herpesvirus-8-negative/idiopathic multicentric Castleman disease (iMCD) remains incompletely understood. Prior epidemiologic studies of CD and iMCD have been hampered by difficulties in accurate case ascertainment resulting from a lack of uniform diagnostic criteria and a disease-specific International Classification of Diseases (ICD) code. In this study, we provide reliable estimates of CD and iMCD in the United States using a novel claims-based algorithm that includes a CD-specific ICD (10th revision) diagnosis code (D47.Z2) supported by the presence of ≥2 claims codes corresponding to the minor criteria from the international evidence-based diagnostic criteria for iMCD. We additionally analyzed the treatment classes and patterns in the clinical course of patients with iMCD. Using an administrative claims database of 30.7 million individuals enrolled between 1 January 2017 and 31 December 2018, we identified 254 patients with iMCD, with an estimated annual incidence and prevalence of 3.4 (95% confidence interval [CI], 1.4-9.2) and 6.9 (95% CI, 3.7-13.3) cases per million, respectively. Among patients with iMCD, 39% received corticosteroid monotherapy, 33.1% received no iMCD-directed treatment, and 9.8% received interleukin-6 (IL-6)-targeted therapy with tocilizumab or siltuximab. Siltuximab, which is the only US Food and Drug Administration-approved treatment and established first-line treatment recommendation, was used in only 8.7% of patients with iMCD. This study provides the most up-to-date understanding of the iMCD disease burden in the United States and identifies a major unmet treatment need for IL-6-directed therapy in this vulnerable cohort.

A geno-clinical decision model for the diagnosis of myelodysplastic syndromes.

The differential diagnosis of myeloid malignancies is challenging and subject to interobserver variability. We used clinical and next-generation sequencing (NGS) data to develop a machine learning model for the diagnosis of myeloid malignancies independent of bone marrow biopsy data based on a 3-institution, international cohort of patients. The model achieves high performance, with model interpretations indicating that it relies on factors similar to those used by clinicians. In addition, we describe associations between NGS findings and clinically important phenotypes and introduce the use of machine learning algorithms to elucidate clinicogenomic relationships.

Influence of Killer Immunoglobulin-Like Receptors and Somatic Mutations on Transplant Outcomes in Acute Myeloid Leukemia.

Natural killer (NK) cells are regulated by killer immunoglobulin-like receptor (KIR) interactions with human leukocyte antigen class I ligands. Various models of NK cell alloreactivity have been associated with outcomes after allogeneic hematopoietic cell transplant (alloHCT), but results have varied widely. We hypothesized that somatic mutations in acute myeloid leukemia (AML) in the context of KIR profiles may further refine their association with transplant outcomes. In this single-center, retrospective, observational study, 81 AML patients who underwent matched-related donor alloHCT were included. Post-HCT outcomes were assessed based on mutational status and KIR profiles with the Kaplan-Meier method and log-rank test. On multivariable analysis those with any somatic mutations and C1/C2 heterozygosity had less acute graft-versus-host disease (GvHD) (hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.14-0.75; P = .009), more relapse (HR, 3.02; 95% CI, 1.30-7.01; P = .010), inferior relapse-free survival (RFS; HR, 2.22; 95% CI, 1.17-4.20; P = .014), and overall survival (OS; HR, 2.21; 95% CI, 1.17-4.20; P = .015), whereas those with a missing KIR ligand had superior RFS (HR, 0.53; 95% CI, 0.30-0.94; P = .031). The presence of a somatic mutation and donor haplotype A was also associated with less acute GvHD (HR, 0.38; 95% CI, 0.16-0.92; P = .032), more relapse (HR, 2.72; 95% CI, 1.13-6.52; P = .025), inferior RFS (HR, 2.11; 95% CI, 1.07-4.14; P = .030), and OS (HR, 2.20; 95% CI, 1.11-4.38; P = .024). Enhanced NK cell alloreactivity from more KIR activating signals (donor B haplotype) and fewer inhibitory signals (recipient missing KIR ligand or C1 or C2 homozygosity) may help mitigate the adverse prognosis associated with some AML somatic mutations. These results may have implications for improving patient risk stratification prior to transplant and optimizing donor selection.

Multisite 11-year experience of less-intensive vs intensive therapies in acute myeloid leukemia.

Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.gov as #NCT01929408.