Representation of the population in need for pivotal clinical trials in lymphomas.

Despite the advances in cancer outcomes, significant health disparities persist. Several new agents have been recently approved for treatment of lymphomas, leading to improved outcomes. Extending the benefits of these new agents starts by adequate enrollment of all affected patient populations. This study aimed to evaluate the extent to which randomized controlled trials (RCTs) match the demographic and geographic diversity of the population affected by lymphoma. Two Food and Drug Administration databases, clinicaltrials.gov, and relevant primary manuscripts were reviewed for drug approval data and demographic representation in RCTs for classical Hodgkin lymphoma (cHL) and non-Hodgkin lymphoma. Maps showing the distribution and frequency of trial participation relative to disease burden, insurance status, and racial representation were created. Black, Hispanic, and female patients were significantly underrepresented in the RCTs for lymphoma compared with that for the disease burden (3.6% [95% confidence interval (CI), 2.8-5.4] vs 14.6% [95% CI, 13.8-15.3]; 6.7% [95% CI, 5.5-7.9] vs 16.3% [95% CI, 15.5-17.1]; and 39.1% [95% CI, 37.3-40.9] vs 42.7% [95% CI, 42.3-43.1], respectively). White and male patients were overrepresented. More counties with higher mortality rates and racial minority representation had low access to the trials, particularly for cHL in the southern region of the United States. There are significant racial misrepresentations in pivotal RCTs in the United States, and geographic distribution of these trials may not provide easy access to all patients in need. Disparities in enrollment should be corrected to make results applicable to all populations.

Efficacy of JAK1/2 inhibition in murine immune bone marrow failure.

Immune aplastic anemia (AA) is a severe blood disease characterized by T-lymphocyte- mediated stem cell destruction. Hematopoietic stem cell transplantation and immunosuppression are effective, but they entail costs and risks, and are not always successful. The Janus kinase (JAK) 1/2 inhibitor ruxolitinib (RUX) suppresses cytotoxic T-cell activation and inhibits cytokine production in models of graft-versus-host disease. We tested RUX in murine immune AA for potential therapeutic benefit. After infusion of lymph node (LN) cells mismatched at the major histocompatibility complex [C67BL/6 (B6)⇒CByB6F1], RUX, administered as a food additive (Rux-chow), attenuated bone marrow hypoplasia, ameliorated peripheral blood pancytopenia, preserved hematopoietic progenitors, and prevented mortality, when used either prophylactically or therapeutically. RUX suppressed the infiltration, proliferation, and activation of effector T cells in the bone marrow and mitigated Fas-mediated apoptotic destruction of target hematopoietic cells. Similar effects were obtained when Rux-chow was fed to C.B10 mice in a minor histocompatibility antigen mismatched (B6⇒C.B10) AA model. RUX only modestly suppressed lymphoid and erythroid hematopoiesis in normal and irradiated CByB6F1 mice. Our data support clinical trials of JAK/STAT inhibitors in human AA and other immune bone marrow failure syndromes.

Phase 2 study of epigenetic priming with decitabine followed by cytarabine for acute myeloid leukemia in older patients.

Acute myeloid leukemia (AML) in older patients has a poor prognosis, low complete remission (CR) rates, and poor overall survival (OS). Preclinical studies have shown synergistic effects of epigenetic priming with hypomethylating agents followed by cytarabine. Based on these data, we hypothesized that an induction regimen using epigenetic priming with decitabine, followed by cytarabine would be effective and safe in older patients with previously untreated AML. Here, we conducted a phase 2 trial in which older patients with previously untreated AML received an induction regimen consisting of 1 or 2 courses of decitabine 20 mg/m2 intravenously (IV) for 5 days followed by cytarabine 100 mg/m2 continuous IV infusion for 5 days. Forty-four patients (median age 76 years) were enrolled, and CR/CRi was achieved by 26 patients (59% of all patients, 66.7% of evaluable patients). Fourteen of 21 (66.7%) patients with adverse cytogenetics achieved CR including six out of seven evaluable patients with TP53 mutations. The 4- and 8-week mortality rates were 2.3% and 9.1%, respectively, with median OS of 10.7 months. These results suggest epigenetic priming with decitabine followed by cytarabine should be considered as an option for first-line therapy in older patients with AML. This trial was registered at www.clinicaltrials.gov as # NCT01829503.

Small peptide-based nano delivery systems for cancer therapy and diagnosis.

Developing nano-biomaterials with tunable topology, size, and surface characteristics has shown tremendously favorable benefits in various biological and clinical applications. Among various nano-biomaterials, peptide-based drug delivery systems offer multiple merits over other synthetic systems due to their enhanced bio and cytocompatibility and desirable biochemical and biophysical properties. Currently, around 100 peptide-based drugs are clinically available for numerous therapeutic purposes. In conjugation with chemotherapeutic moieties, peptides demonstrate a remarkable ability to reduce nonspecific drug effects by improving drug targetability at cancer sites. This review encompasses a wide-ranging role played by different peptide-based nanostructures in cancer theranostics. Section 1 introduces the rising concern about cancer as a disease and further describes peptide-based nanomaterials as biomedical agents to tackle the ailment. The subsequent section explores the mechanistic pathways behind the self-assembly of peptides to form hierarchically distinct assemblies. The crux of our review lies in an exhaustive exploration of the applications of various types of peptide-based nanostructures in cancer therapy and diagnosis. Significance Statement Peptide-based drug delivery systems possess superior biocompatibility, biochemical, and biophysical properties compared to other synthetic alternatives. The development of these nanobiomaterials with customizable topology, size, and surface characteristics have shown promising outcomes in biomedical contexts. Peptides in conjunction with chemotherapeutic agents exhibit the ability to enhance drug targetability at cancer sites, reducing nonspecific drug effects. This comprehensive review emphasizes the pivotal role of diverse peptide-based nanostructures as cancer theranostics, elucidating their potential in revolutionizing cancer therapy and diagnosis.

Alemtuzumab in relapsed immune severe aplastic anemia: Long-term results of a phase II study.

Immune severe aplastic anemia (SAA) is characterized by pancytopenia and immune-mediated bone marrow destruction. SAA may be treated with hematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST). However, 30% of patients treated with IST relapse. We previously reported a clinical trial of alemtuzumab in which more than half of 25 relapsed SAA patients (56%) responded hematologically. Here, we present long-term results of a total of 42 patients. Participants with SAA who had previously completed antithymocyte globulin (ATG)-based IST, but had relapsed, were enrolled on this study. Alemtuzumab was administered intravenously (IV) (n = 28) or subcutaneously (SC) (n = 14). The primary endpoint was hematologic response at 6 months. Secondary endpoints included relapse, clonal evolution, and survival. This trial was registered at clinicaltrials.gov (NCT00195624). Patients were enrolled over 9 years, with median follow-up of 6 years. Median age was 32 years, with 57% being female. At 6 months, 18 patients (43%) achieved response; 15 (54%) of those who received IV compared with 3 (21%) who received SC therapy. Six patients (14%) had durable long-term response without need for subsequent AA-directed therapy or HSCT at last follow-up. Nine patients had clonal evolution, with high-risk evolution occurring in 6. Overall survival was 67% at median follow-up of 6 years. Prolonged iatrogenic immunosuppression was observed as long as 2 years after alemtuzumab administration. Alemtuzumab induces responses in relapsed SAA, some of which are durable long-term. However, immunosuppression can persist for years, requiring long-term monitoring.

Emerging molecular subtypes and therapies in acute lymphoblastic leukemia.

Tremendous strides have been made in the molecular and cytogenetic classification of acute lymphoblastic leukemia based on gene expression profiling data, leading to an expansion of entities in the recent International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias and 2022 WHO Classification of Tumours: Haematolymphoid Tumors, 5th edition. This increased diagnostic and therapeutic complexity can be overwhelming, and this review compares nomenclature differences between the ICC and WHO 5th edition publications, compiles key features of each entity, and provides a diagnostic algorithmic approach. In covering B-lymphoblastic leukemia (B-ALL), we divided the entities into established (those present in the revised 4th edition WHO) and novel (those added to either the ICC or WHO 5th edition) groups. The established B-ALL entities include B-ALL with BCR::ABL1 fusion, BCR::ABL1-like features, KMT2A rearrangement, ETV6::RUNX1 rearrangement, high hyperdiploidy, hypodiploidy (focusing on near haploid and low hypodiploid), IGH::IL3 rearrangement, TCF3::PBX1 rearrangement, and iAMP21. The novel B-ALL entities include B-ALL with MYC rearrangement; DUX4 rearrangement; MEF2D rearrangement; ZNF384 or ZNF362 rearrangement, NUTM1 rearrangement; HLF rearrangement; UBTF::ATXN7L3/PAN3,CDX2; mutated IKZF1 N159Y; mutated PAX5 P80R; ETV6::RUNX1-like features; PAX5 alteration; mutated ZEB2 (p.H1038R)/IGH::CEBPE; ZNF384 rearranged-like; KMT2A-rearranged-like; and CRLF2 rearrangement (non-Ph-like). Classification of T-ALL is complex with some variability in how the subtypes are defined in recent literature. It was classified as early T-precursor lymphoblastic leukemia/lymphoma and T-ALL, NOS in the WHO revised 4th edition and WHO 5th edition. The ICC added an entity into early T-cell precursor ALL, BCL11B-activated, and also added provisional entities subclassified based on transcription factor families that are aberrantly activated.

Genomics of myelodysplastic/myeloproliferative neoplasm.

Myelodysplastic/ Myeloproliferative neoplasms (MDS/MPN) demonstrate overlapping pathologic and molecular features of myelodysplastic (MDS) and myeloproliferative (MPN) neoplasms. Diagnosis is difficult based on morphology alone, requiring exclusion of various non-neoplastic causes for CBC abnormalities and morphologic findings and other myeloid neoplasms. Identifying a clonal abnormality by cytogenetics or molecular studies has vastly improved our ability to diagnose MDS/MPN and has been incorporated in the different classification schemas. Currently two separate classification systems are in use- The 5th edition WHO and international consensus classification. The two competing classifications emphasize genetic work-up and are similar on many levels; however, they do introduce diagnostic dilemma when diagnosing certain entities such as chronic myelomonocytic leukemia in the presence of NPM1 mutations. The genetic profile overlaps among different subentities; however, the combination and the incidence of mutations; together with the clinical features and morphology helps in further subclassification. In this review, we discuss the advances in molecular characterization of MDS/MPN. We attempt to summarize the differences between the various classification schemes, and highlight the changes made in the diagnostic criteria.

B-Cell Acute Lymphoblastic Leukemia with iAMP21 in a Patient with Constitutional Ring Chromosome 21.

Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is associated with various specific cytogenetic and molecular markers that significantly influence treatment and prognosis. Intrachromosomal amplification of chromosome 21 (iAMP21) defines a rare distinct cytogenetic subgroup of childhood B-ALL, which is characterized by amplification of region 21q22.12 comprising the RUNX1 gene. Constitutional structural chromosomal abnormalities involving chromosome 21 confer an increased risk for B-ALL with iAMP21. Here, we report the development of B-ALL with iAMP21 in a 9-year-old child with a constitutional ring chromosome 21, r(21)c, uncovered after B-ALL diagnosis. Cytogenetic and microarray analysis of the post-therapy sample revealed an abnormal chromosome 21 lacking a satellite and having a deletion of the terminal 22q22.3 region, consistent with a constitutional ring chromosome 21, r(21)(p11.2q22). On a retrospective analysis, this ring chromosome was observed in the normal cells in the pre-treatment diagnostic specimen. Constitutional ring chromosome 21 may remain undetected in patients with mild or no neurodevelopmental phenotype, posing an unknown lifelong risk of developing B-ALL with iAMP21. Individuals with constitutional structural chromosome 21 rearrangements such as ring 21 require a close surveillance and long-term follow-up studies to establish their risk of B-ALL relapse and possibility of developing other malignancies. Germline analysis is recommended to all pediatric patients with iAMP21-related B-ALL to rule out structural chromosome 21 rearrangements and to elucidate molecular mechanisms of iAMP21 formation.

Chrysin ameliorates 3 nitropropinoic acid induced neurotoxicity targeting behavioural, biochemical and histological alterations.

BACKGROUND AND PURPOSE: Huntington disease (HD) is an autosomal dominant inheritance neurodegenerative disorder. 3-Nitropropanoic acid (3-NP) is a mitochondrial toxin that induces HD-like symptoms and thus serves as a good experimental model of HD. Chrysin (5, 7-dihydroxyflavone) is a natural flavonoid that have multiple biological activities. The present work was aimed to evaluate the neuroprotective efficacy of Chrysin in rat brain, under the influence of 3-NP treatment, by studying neurobehavioral and biochemical alterations alongwith histo-architectural changes. MATERIALS AND METHODS: Male Wistar rats (220-250 g) were used in the study and were divided into three groups following randomization. Each group comprised of nine animals. Group I animals served as control group and administered with normal saline (orally) as vehicle. Animals of Group II were treated with 3-NP for four successive days, at the dose of 20 mg/kg, intraperitoneally (i.p.). Animals that received Chrysin for the period of four consecutive days with the dose of 50 mg/kg, orally twice daily (30 min pre-treatment and 6 h post-treatment) following 3-NP administration served as Group III. After the treatment regime, animals were evaluated for neurobehavioral alterations and brain homogenates were used for estimation of neurotoxicity marker activity and neurotransmitter level along with histological assessment. RESULTS: The significant alteration in neurobehavioral, biochemical and neuronal structure in striatal part of brain was observed in the 3-NP administered (Group II) animals. It was observed that co-treatment of Chrysin with 3-NP treated rats the rotarod performance, grip strength, stride length as well as monoamine oxidase activity and serotonin levels were elevated. CONCLUSION: The results of this study reveal that Chrysin treatment alleviated the neurobehavioral, biochemical and histological alterations against HD symptoms in rats.

The impact of COVID-19 on kidney transplantation and the kidney transplant recipient - One year into the pandemic.

The COVID-19 pandemic has significantly changed the landscape of kidney transplantation in the United States and worldwide. In addition to adversely impacting allograft and patient survival in postkidney transplant recipients, the current pandemic has affected all aspects of transplant care, including transplant referrals and listing, organ donation rates, organ procurement and shipping, and waitlist mortality. Critical decisions were made during this period by transplant centers and individual transplant physicians taking into consideration patient safety and resource utilization. As countries have begun administering the COVID vaccines, new and important considerations pertinent to our transplant population have arisen. This comprehensive review focuses on the impact of COVID-19 on kidney transplantation rates, mortality, policy decisions, and the clinical management of transplanted patients infected with COVID-19.

Acute myeloid leukemia with isolated del(5q) is associated with IDH1/IDH2 mutations and better prognosis when compared to acute myeloid leukemia with complex karyotype including del(5q).

Myelodysplastic syndrome with isolated del(5q) is a well-recognized entity with a relatively favorable prognosis. Isolated del(5q) in acute myeloid leukemia is rare and acute myeloid leukemia cases with isolated del(5q) are not well characterized. Del(5q) has been shown to be a poor prognostic marker in acute myeloid leukemia based on multivariable analysis in large cohort studies, which contained mostly cases with del(5q) in the context of multiple chromosomal abnormalities. To further characterize acute myeloid leukemia with isolated del(5q), clinicopathologic characterization including mutation analysis was performed. During a 10-year period, we identified 12 cases of acute myeloid leukemia with isolated del(5q), 7 cases of acute myeloid leukemia with del(5q) plus one additional chromosome abnormality not involving chromosome 7, as well as two control groups composed of 124 cases of acute myeloid leukemia with complex karyotype including del(5q), and 40 cases of myelodysplastic syndrome with isolated del(5q). At diagnosis, cases of acute myeloid leukemia with isolated del(5q) had higher platelet counts (p = 0.044), hemoglobin (p = 0.011), and mean corpuscular volume (p = 0.017) compared with cases of acute myeloid leukemia with complex karyotype including del(5q). Acute myeloid leukemia with isolated del(5q) was less likely therapy-related (p = 0.037), more likely to have IDH1/IDH2 mutations (p = 0.009), and less likely to have TP53 mutations (p = 0.005) when compared to acute myeloid leukemia with complex karyotype including del(5q). Acute myeloid leukemia with isolated del(5q) also showed longer overall survival than acute myeloid leukemia with complex karyotype cases including del(5q) (p = 0.004). In summary, acute myeloid leukemia with isolated del(5q) appeared to show some distinct clinicopathologic and genomic features as compared to cases of acute myeloid leukemia with complex karyotype including del(5q).

Genetic and phenotypic characterization of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract.

Indolent T-cell lymphoproliferative disorders of the gastrointestinal tract are rare clonal T-cell diseases that more commonly occur in the intestines and have a protracted clinical course. Different immunophenotypic subsets have been described, but the molecular pathogenesis and cell of origin of these lymphocytic proliferations is poorly understood. Hence, we performed targeted next-generation sequencing and comprehensive immunophenotypic analysis of ten indolent T-cell lymphoproliferative disorders of the gastrointestinal tract, which comprised CD4+ (n=4), CD8+ (n=4), CD4+/CD8+ (n=1) and CD4-/CD8- (n=1) cases. Genetic alterations, including recurrent mutations and novel rearrangements, were identified in 8/10 (80%) of these lymphoproliferative disorders. The CD4+, CD4+/CD8+, and CD4-/CD8- cases harbored frequent alterations of JAK-STAT pathway genes (5/6, 82%); STAT3 mutations (n=3), SOCS1 deletion (n=1) and STAT3-JAK2 rearrangement (n=1), and 4/6 (67%) had concomitant mutations in epigenetic modifier genes (TET2, DNMT3A, KMT2D). Conversely, 2/4 (50%) of the CD8+ cases exhibited structural alterations involving the 3' untranslated region of the IL2 gene. Longitudinal genetic analysis revealed stable mutational profiles in 4/5 (80%) cases and acquisition of mutations in one case was a harbinger of disease transformation. The CD4+ and CD4+/CD8+ lymphoproliferative disorders displayed heterogeneous Th1 (T-bet+), Th2 (GATA3+) or hybrid Th1/Th2 (T-bet+/GATA3+) profiles, while the majority of CD8+ disorders and the CD4-/CD8- disease showed a type-2 polarized (GATA3+) effector T-cell (Tc2) phenotype. Additionally, CD103 expression was noted in 2/4 CD8+ cases. Our findings provide insights into the pathogenetic bases of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract and confirm the heterogeneous nature of these diseases. Detection of shared and distinct genetic alterations of the JAK-STAT pathway in certain immunophenotypic subsets warrants further mechanistic studies to determine whether therapeutic targeting of this signaling cascade is efficacious for a proportion of patients with these recalcitrant diseases.

Safety and Efficacy of Adjunctive Θ Burst Repetitive Transcranial Magnetic Stimulation to Right Inferior Parietal Lobule in Schizophrenia Patients With First-Rank Symptoms: A Pilot, Exploratory Study.

BACKGROUND: First-rank symptoms (FRS) in schizophrenia have been found to be associated with various cognitive and biological markers. Repetitive transcranial magnetic stimulation (rTMS) has been shown to modulate such factors. We hypothesized that rTMS adjunctive to antipsychotics will be safe and effective in treatment of FRS in schizophrenia. METHODS: Schizophrenia patients with FRS randomly received either active or sham-magnetic resonance imaging navigated continuous Θ burst stimulation (cTBS)-rTMS to right inferior parietal lobule for 2 weeks; assessments were repeated. While primary outcome variables were safety profile, FRS and overall psychopathology; secondary outcomes were γ oscillatory activity, brain-derived neurotrophic factor levels, and self-monitoring function. RESULTS: No significant adverse events were reported in either group. None of the outcome measures showed sufficient power on the time by group analysis. CONCLUSIONS: This study fails to demonstrate whether or not adjunctive cTBS to right inferior parietal lobule could significantly alleviate FRS. We also fail to provide evidence for whether this protocol has any effect on brain-derived neurotrophic factor levels, self-monitoring function, and right hemispheric γ oscillations.

Catalytic efficiencies of directly evolved phosphotriesterase variants with structurally different organophosphorus compounds in vitro.

The nearly 200,000 fatalities following exposure to organophosphorus (OP) pesticides each year and the omnipresent danger of a terroristic attack with OP nerve agents emphasize the demand for the development of effective OP antidotes. Standard treatments for intoxicated patients with a combination of atropine and an oxime are limited in their efficacy. Thus, research focuses on developing catalytic bioscavengers as an alternative approach using OP-hydrolyzing enzymes such as Brevundimonas diminuta phosphotriesterase (PTE). Recently, a PTE mutant dubbed C23 was engineered, exhibiting reversed stereoselectivity and high catalytic efficiency (k cat/K M) for the hydrolysis of the toxic enantiomers of VX, CVX, and VR. Additionally, C23's ability to prevent systemic toxicity of VX using a low protein dose has been shown in vivo. In this study, the catalytic efficiencies of V-agent hydrolysis by two newly selected PTE variants were determined. Moreover, in order to establish trends in sequence-activity relationships along the pathway of PTE's laboratory evolution, we examined k cat/K M values of several variants with a number of V-type and G-type nerve agents as well as with different OP pesticides. Although none of the new PTE variants exhibited k cat/K M values >107 M-1 min-1 with V-type nerve agents, which is required for effective prophylaxis, they were improved with VR relative to previously evolved variants. The new variants detoxify a broad spectrum of OPs and provide insight into OP hydrolysis and sequence-activity relationships.

Cutaneous Small/Medium CD4+ Pleomorphic T-Cell Lymphoma-Like Nodule in a Patient With Erythema Chronicum Migrans.

CD4+ small/medium pleomorphic T-cell lymphoma is a relatively rare subtype of cutaneous lymphoproliferative disorder with an indolent clinical behavior. The place of this condition among lymphomas is debatable. The authors describe a rare case of the direct association of CD4 small/medium pleomorphic T-cell lymphoma-like solitary nodule with Borrelia burgdorferi infection in a 5-year-old boy, discuss the reactive nature of this condition, and emphasize the importance of clinicopathological correlation.

Neuroglia targeting nano-therapeutic approaches to rescue aging and neurodegenerating brain.

Despite intense efforts at the bench, the development of successful brain-targeting therapeutics to relieve malicious neural diseases remains primitive. The brain, being a beautifully intricate organ, consists of heterogeneous arrays of neuronal and glial cells. Primarily acting as the support system for neuronal functioning and maturation, glial cells have been observed to be engaged more apparently in the progression and worsening of various neural pathologies. The diseased state is often related to metabolic alterations in glial cells, thereby modulating their physiological homeostasis in conjunction with neuronal dysfunction. A plethora of data indicates the effect of oxidative stress, protein aggregation, and DNA damage in neuroglia impairments. Still, a deeper insight is needed to gain a conflict-free understanding in this arena. As a consequence, glial cells hold the potential to be identified as promising targets for novel therapeutic approaches aimed at brain protection. In this review, we describe the recent strides taken in the direction of understanding the impact of oxidative stress, protein aggregation, and DNA damage on neuroglia impairment and neuroglia-directed nanotherapeutic approaches to mitigate the burden of various neural disorders.