Somatic mutations in FAS pathway increase hemophagocytic lymphohistiocytosis risk in T- and/or NK-cell lymphoma patients.

While significant progress has been made in understanding the genetic basis of primary hemophagocytic lymphohistiocytosis (HLH), the pathogenesis of secondary HLH, the more prevalent form, remains unclear. Among the various conditions giving rise to secondary HLH, HLH in lymphoma patients (HLH-L) accounts for a substantial proportion. In this study, we investigated the role of somatic mutations in the pathogenesis of HLH-L in a cohort of patients with T- and/or NK-cell lymphoma. We identified a 3-time higher frequency of mutations in FAS pathway in patients with HLH-L. Patients harbouring these mutations had a 5-time increased HLH-L risk. These mutations were independently associated with inferior outcome. Hence, our study demonstrates the association between somatic mutations in FAS pathway and HLH-L. Further studies are warranted on the mechanistic role of these mutations in HLH-L.

Universal germline genetic testing in patients with hematologic malignancies using DNA isolated from nail clippings.

Not available.

Effects of Novel Insulin Resistance Indices on Early Renal Functions in Donors.

OBJECTIVE: To investigate the relationship between quickly calculable new insulin resistance (IR) indices used to evaluate IR in early kidney functions after donor nephrectomy. STUDY DESIGN: Descriptive design. Place and Duration of the Study: Department of Urology, Ufuk University Faculty of Medicine, Ankara, Turkiye, between January 2016 and August 2021. METHODOLOGY: The preoperative biochemical analyses of patients undergoing open donor nephrectomies and estimated glomerular filtration rates (eGFR) were recorded in the preoperative and first postoperative month. The IR indices (triglyceride glucose [TyG] index, TyG-body mass index [TyG-BMI], triglyceride/HDL cholesterol ratio [TG/HDL-C], and metabolic score for IR [METS-IR]) were computed. Additionally, the patients were separated into two categories. Group 1 had a less than 30% decrease in eGFR values in the postoperative first-month period, and group 2 had a more than 30% decrease. The relationship between variables was analysed using the Spearman correlation, and comparisons between groups were analysed using the independent t-test or Mann-Whitney U-test. RESULTS: A total of 107 patients were included in the study. The mean eGFR reduction rate was 31.81 ± 8.87 %. In the correlation analyses, an increase in the rate of decrease in postoperative GFR was associated with higher IR indices, specifically TyG (r = 0.19, p = 0.04), TG/HDL-C (r = 0.21, p = 0.02), and METS-IR (r = 0.21, p = 0.02). No statistically significant difference was found between the groups regarding all the calculated IR indices (p < 0.05). CONCLUSION: The results suggest a possible link between increased IR and postoperative renal function decline. KEY WORDS: Insulin resistance, Glomerular filtration rate, Donor nephrectomy, Triglyceride-Glucose index, METS-IR.

Mixed histiocytic neoplasms: A multicentre series revealing diverse somatic mutations and responses to targeted therapy.

Histiocytic neoplasms are diverse clonal haematopoietic disorders, and clinical disease is mediated by tumorous infiltration as well as uncontrolled systemic inflammation. Individual subtypes include Langerhans cell histiocytosis (LCH), Rosai-Dorfman-Destombes disease (RDD) and Erdheim-Chester disease (ECD), and these have been characterized with respect to clinical phenotypes, driver mutations and treatment paradigms. Less is known about patients with mixed histiocytic neoplasms (MXH), that is two or more coexisting disorders. This international collaboration examined patients with biopsy-proven MXH with respect to component disease subtypes, oncogenic driver mutations and responses to conventional (chemotherapeutic or immunosuppressive) versus targeted (BRAF or MEK inhibitor) therapies. Twenty-seven patients were studied with ECD/LCH (19/27), ECD/RDD (6/27), RDD/LCH (1/27) and ECD/RDD/LCH (1/27). Mutations previously undescribed in MXH were identified, including KRAS, MAP2K2, MAPK3, non-V600-BRAF, RAF1 and a BICD2-BRAF fusion. A repeated-measure generalized estimating equation demonstrated that targeted treatment was statistically significantly (1) more likely to result in a complete response (CR), partial response (PR) or stable disease (SD) (odds ratio [OR]: 17.34, 95% CI: 2.19-137.00, p = 0.007), and (2) less likely to result in progression (OR: 0.08, 95% CI: 0.03-0.23, p < 0.0001). Histiocytic neoplasms represent an entity with underappreciated clinical and molecular diversity, poor responsiveness to conventional therapy and exquisite sensitivity to targeted therapy.

Validation of LymphGen classification on a 400-gene clinical next-generation sequencing panel in diffuse large B-cell lymphoma: real-world experience from a cancer center.

Not available.

Cell-free DNA from nail clippings as source of normal control for genomic studies in hematologic malignancies.

Comprehensive genomic sequencing is becoming a critical component in the assessment of hematologic malignancies, with broad implications for patient management. In this context, unequivocally discriminating somatic from germline events is challenging but greatly facilitated by matched analysis of tumor:normal pairs. In contrast to solid tumors, conventional sources of normal control (peripheral blood, buccal swabs, saliva) could be highly involved by the neoplastic process, rendering them unsuitable. In this work we describe our real-world experience using cell free DNA (cfDNA) isolated from nail clippings as an alternate source of normal control, through the dedicated review of 2,610 tumor:nail pairs comprehensively sequenced by MSK-IMPACT-heme. Overall, we find nail cfDNA is a robust source of germline control for paired genomic studies. In a subset of patients, nail DNA may have tumor DNA contamination, reflecting unique attributes of the hematologic disease and transplant history. Contamination is generally low level, but significantly more common among patients with myeloid neoplasms (20.5%; 304/1482) compared to lymphoid diseases (5.4%; 61/1128) and particularly enriched in myeloproliferative neoplasms with marked myelofibrosis. When identified in patients with lymphoid and plasma-cell neoplasms, mutations commonly reflected a myeloid profile and correlated with a concurrent/evolving clonal myeloid neoplasm. For nails collected after allogeneic stem-cell transplantation, donor DNA was identified in 22% (11/50). In this cohort, an association with recent history of graft-vs-host disease was identified. These findings should be considered as a potential limitation for the use of nail as normal control but could also provide important diagnostic information regarding the disease process.

Role of flow cytometric immunophenotyping in the diagnosis of breast implant-associated anaplastic large cell lymphoma: A 6-year, single-institution experience.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon mature T-cell neoplasm occurring in patients with textured breast implants, typically after 7-10 years of exposure. Although cytopathologic or histopathologic assessment is considered the gold standard diagnostic method for BIA-ALCL, flow cytometry (FC)-based immunophenotyping is recommended as an adjunct test. However, the diagnostic efficacy of FC is not well reported. We reviewed 290 FC tests from breast implant pericapsular fluid and capsule tissue from 182 patients, including 16 patients with BIA-ALCL over a 6-year period, calculating diagnostic rates and test efficacy. FC showed an overall sensitivity of 75.9%, specificity of 100%, and negative and positive predictive values of 95.4% and 100%, respectively. Blinded expert review of false-negative cases identified diagnostic pitfalls, improving sensitivity to 96.6%. Fluid samples had better rates of adequate samples for FC testing compared with tissue samples. Paired with FC testing of operating room (OR)-acquired fluid samples, capsulectomy FC specimens added no diagnostic value in patients with concurrent fluid samples; no cases had positive capsule FC with negative fluid FC. Fluid samples are adequate for FC testing more often than tissue. Capsule tissue FC specimens do not improve FC efficacy when paired with OR-acquired fluid FC samples and are often inadequate samples. FC is 100% specific for BIA-ALCL and can serve as a confirmatory test but should not be the sole diagnostic method. Awareness of sample-specific diagnostic pitfalls greatly improves the sensitivity of BIA-ALCL testing by FC.

Radiographic Impact on the Clinical Decision Making of Achilles Tenotomy in Clubfoot: In Search of an Objective Cut-Off Value.

BACKGROUND: We tried to determine whether the indication of Achilles tenotomy (AT) in clubfoot patients based on clinical evaluation could be confirmed radiographically, and to find an objective radiographic cut-off value for its indication. METHODS: Eighty-six clubfeet from 60 patients, (26 bilateral and 34 unilateral) were included. A standard Ponseti treatment regimen was applied. Group 1 comprised patients who underwent AT immediately after serial plaster casting (26 feet). Group 2 comprised patients who underwent AT during the follow-up period (48 feet). Group 3 comprised patients who were assumed to have a corrected foot and did not undergo AT (12 feet). Group 4 comprised the healthy sides of the unilateral cases (34 feet). RESULTS: Both Group 1 and Group 2 showed significant improvement after tenotomy (p = 0.002). In order to differentiate between the normal and AT groups according to the pre-tenotomy angle, we obtained an optimal cut-off value of >85° according to the Youden index, a sensitivity of 96%, a specificity of 91.2%, a positive predictive value of 95.9%, a negative predictive value of 91.2%, and an accuracy rate of 94.4% (AUC: 0.983; p < 0.001). CONCLUSIONS: Feet with a lateral tibio-calcaneal angle > 85° can be considered pathologic and accepted as candidates for AT.

Quantifying the Expanding Landscape of Clinical Actionability for Patients with Cancer.

There is a continuing debate about the proportion of cancer patients that benefit from precision oncology, attributable in part to conflicting views as to which molecular alterations are clinically actionable. To quantify the expansion of clinical actionability since 2017, we annotated 47,271 solid tumors sequenced with the MSK-IMPACT clinical assay using two temporally distinct versions of the OncoKB knowledge base deployed 5 years apart. Between 2017 and 2022, we observed an increase from 8.9% to 31.6% in the fraction of tumors harboring a standard care (level 1 or 2) predictive biomarker of therapy response and an almost halving of tumors carrying nonactionable drivers (44.2% to 22.8%). In tumors with limited or no clinical actionability, TP53 (43.2%), KRAS (19.2%), and CDKN2A (12.2%) were the most frequently altered genes. SIGNIFICANCE: Although clear progress has been made in expanding the availability of precision oncology-based treatment paradigms, our results suggest a continued unmet need for innovative therapeutic strategies, particularly for cancers with currently undruggable oncogenic drivers. See related commentary by Horak and Fröhling, p. 18. This article is featured in Selected Articles from This Issue, p. 5.

Novel identification of t(14;18)(q32;q21)/IGH::MALT1 in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is a clonal B-cell malignancy and remains a chronic disease despite improvements in clinical outcomes since the use of targeted therapies. Both clinical and biological parameters are important for determining prognosis. Unlike other mature B-cell lymphomas, translocations involving the immunoglobulin heavy chain (IGH) locus are uncommon in CLL. There have been few case reports of CLL harbouring t(14;18)/IGH::BCL2 and t(14;19)/IGH::BCL3. Here we describe the first two cases of patients with CLL with documented t(14;18)(q32;q21)/IGH::MALT1. Both cases in this report were associated with lower-risk biological parameters. Thus, FISH testing for MALT1 in cases with unknown IGH translocation partners in the setting of CLL should be implemented in clinical practice to better define such cases.

Mycetoma case series in Somalia.

Mycetoma is a suppurative chronic bacterial or fungal disease inoculated into the body by minor trauma which may penetrate from subcutaneous tissue to bone. Although the lower extremities are most commonly affected, rare forms can also be seen from time to time. The diagnostic triad of swelling in the affected area, multiple sinus formation, and purulent discharge with grains are typical. Definitive diagnosis is made by isolation of the causative pathogen, radiologic imaging, and histopathologic examination. Antifungal and antibacterial options are applied together with surgery. Our aim in this case series is to report and analyze 10 rare cases of mycetoma.

Quantification of Measurable Residual Disease Detection by Next-Generation Sequencing-Based Clonality Testing in B-Cell and Plasma Cell Neoplasms.

Next-generation sequencing (NGS)-based measurable residual disease (MRD) monitoring in post-treatment settings can be crucial for relapse risk stratification in patients with B-cell and plasma cell neoplasms. Prior studies have focused on validation of various technical aspects of the MRD assays, but more studies are warranted to establish the performance characteristics and enable standardization and broad utilization in routine clinical practice. Here, the authors describe an NGS-based IGH MRD quantification assay, incorporating a spike-in calibrator for monitoring B-cell and plasma cell neoplasms based on their unique IGH rearrangement status. Comparison of MRD status (positive or undetectable) by NGS and flow cytometry (FC) assays showed high concordance (91%, 471/519 cases) and overall good linear correlation in MRD quantitation, particularly for chronic lymphocytic leukemia and B-lymphoblastic leukemia/lymphoma (R = 0.85). Quantitative correlation was lower for plasma cell neoplasms, where underestimation by FC is a known limitation. No significant effects on sequencing efficiency by the spike-in calibrator were observed, with excellent inter- and intra-assay reproducibility within the authors' laboratory, and in comparison to an external laboratory, using the same assay and protocols. Assays performed both at internal and external laboratories showed highly concordant MRD detection (100%) and quantitation (R = 0.97). Overall, this NGS-based MRD assay showed highly reproducible results with quantitation that correlated well with FC MRD assessment, particularly for B-cell neoplasms.

Biology and genetics of extranodal mature T-cell and NKcell lymphomas and lymphoproliferative disorders.

The extranodal mature T-cell and NK-cell lymphomas and lymphoproliferative disorders represent a unique group of rare neoplasms with both overlapping and distinct clinicopathological, biological, and genomic features. Their predilection for specific sites, such as the gastrointestinal tract, aerodigestive tract, liver, spleen, and skin/soft tissues, underlies their classification. Recent genomic advances have furthered our understanding of the biology and pathogenesis of these diseases, which is critical for accurate diagnosis, prognostic assessment, and therapeutic decision-making. Here we review clinical, pathological, genomic, and biological features of the following extranodal mature T-cell and NK-cell lymphomas and lymphoproliferative disorders: primary intestinal T-cell and NK-cell neoplasms, hepatosplenic T-cell lymphoma, extranodal NK/T-cell lymphoma, nasal type, and subcutaneous panniculitis-like T-cell lymphoma.

Needlestick and Sharps Injuries Among Healthcare Workers at a Tertiary Care Hospital: A Retrospective Single-Center Study.

Background: Healthcare workers are still at risk from needlesticks and sharps injuries, which can expose them to blood-borne diseases like hepatitis B, hepatitis C, and HIV. We aimed to investigate the proportion of needlesticks and sharps injuries among healthcare workers in a tertiary care hospital in Somalia and also evaluate associated risk factors. Materials and Methods: This retrospective study was conducted at the Mogadishu Somalia Turkey Recep Tayyip Erdogan Training and Research Hospital. The data was retrieved from the hospital record of the infection prevention and control department over a six-year period between 2017 and 2022. Results: There were a total of 233 needlestick and sharps injury incidents. The highest number of needlestick and sharps injury cases were reported among nurses (52.4%), followed by cleaners (22.3%), physicians (18.5%), and technicians (6.9%) during the six-year period. Operation theaters were the most frequent place (21.9%) where injuries happened, followed by inpatient care (17.6%) and emergency rooms (16.7%). The most commonly reported instrument that resulted in injuries was a hypodermic needle (81.1%). About 24.9% of the needles or sharps devices that caused needlestick and sharps injury cases were contaminated with hepatitis B. There was a significant difference between gender and place of injury for needlestick and sharps injuries (P=0.001). Conclusion: Healthcare professionals around the world continue to face major health risks from needle stick and sharps injuries. The present study found that 8.6%of healthcare workers sustained a needle stick and sharps injuries incident in the past year. According to our findings, healthcare institutions need to regularly teach healthcare professionals, especially nurses and cleaners about the significance of needle stick and sharps injuries.

Acute myeloid leukemia with mixed phenotype is characterized by stemness transcriptomic signatures and limited lineage plasticity.

Mixed phenotype (MP) in acute leukemias poses unique classification and management dilemmas and can be seen in entities other than de novo mixed phenotype acute leukemia (MPAL). Although WHO classification empirically recommends excluding AML with myelodysplasia related changes (AML-MRC) and therapy related AML (t-AML) with mixed phenotype (AML-MP) from MPAL, there is lack of studies investigating the clinical, genetic, and biologic features of AML-MP. We report the first cohort of AML-MRC and t-AML with MP integrating their clinical, immunophenotypic, genomic and transcriptomic features with comparison to MPAL and AML-MRC/t-AML without MP. Both AML cohorts with and without MP shared similar clinical features including adverse outcomes but were different from MPAL. The genomic landscape of AML-MP overlaps with AML without MP but differs from MPAL. AML-MP harbors more frequent RUNX1 mutations than AML without MP and MPAL. RUNX1 mutations did not impact the survival of patients with MPAL. Unsupervised hierarchal clustering based on immunophenotype identified biologically distinct clusters with phenotype/genotype correlation and outcome differences. Furthermore, transcriptomic analysis showed an enrichment for stemness signature in AML-MP and AML without MP as compared to MPAL. Lastly, MPAL but not AML-MP often switched to lymphoid only immunophenotype after treatment. Expression of transcription factors critical for lymphoid differentiation were upregulated only in MPAL, but not in AML-MP. Our study for the first time demonstrates that AML-MP clinically and biologically resembles its AML counterpart without MP and differs from MPAL, supporting the recommendation to exclude these patients from the diagnosis of MPAL. Future studies are needed to elucidate the molecular mechanism of mixed phenotype in AML. Key points: AML-MP clinically and biologically resembles AML but differs from MPAL. AML-MP shows RUNX1 mutations, stemness signatures and limited lymphoid lineage plasticity.

Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens.

Despite improving outcomes, 40% of patients with newly diagnosed multiple myeloma treated with regimens containing daratumumab, a CD38-targeted monoclonal antibody, progress prematurely. By integrating tumor whole-genome and microenvironment single-cell RNA sequencing from upfront phase 2 trials using carfilzomib, lenalidomide and dexamethasone with daratumumab ( NCT03290950 ), we show how distinct genomic drivers including high APOBEC mutational activity, IKZF3 and RPL5 deletions and 8q gain affect clinical outcomes. Furthermore, evaluation of paired bone marrow profiles, taken before and after eight cycles of carfilzomib, lenalidomide and dexamethasone with daratumumab, shows that numbers of natural killer cells before treatment, high T cell receptor diversity before treatment, the disappearance of sustained immune activation (that is, B cells and T cells) and monocyte expansion over time are all predictive of sustained minimal residual disease negativity. Overall, this study provides strong evidence of a complex interplay between tumor cells and the immune microenvironment that is predictive of clinical outcome and depth of treatment response in patients with newly diagnosed multiple myeloma treated with highly effective combinations containing anti-CD38 antibodies.

Lupus Erythematosus Panniculitis: A Rare Case Report.

An uncommon variation of lupus erythematosus is lupus panniculitis. It can exist on its own or in conjunction with discoid or systemic lupus erythematosus. Persistent, sensitive, and hard nodules that are localized on the face, arms, shoulders, breast, and buttocks are its defining features. Scarring, lipoatrophy, and ulceration are occasionally associated with the healing of lesions. We are reporting the first case of lupus erythematosus panniculitis from Somalia. A 60-year-old male patient visited our polyclinic with an upper back nodule and a left upper ulcerated lesion that had been present for four months.

Enhanced clinical assessment of hematologic malignancies through routine paired tumor and normal sequencing.

Genomic profiling of hematologic malignancies has augmented our understanding of variants that contribute to disease pathogenesis and supported development of prognostic models that inform disease management in the clinic. Tumor only sequencing assays are limited in their ability to identify definitive somatic variants, which can lead to ambiguity in clinical reporting and patient management. Here, we describe the MSK-IMPACT Heme cohort, a comprehensive data set of somatic alterations from paired tumor and normal DNA using a hybridization capture-based next generation sequencing platform. We highlight patterns of mutations, copy number alterations, and mutation signatures in a broad set of myeloid and lymphoid neoplasms. We also demonstrate the power of appropriate matching to make definitive somatic calls, including in patients who have undergone allogeneic stem cell transplant. We expect that this resource will further spur research into the pathobiology and clinical utility of clinical sequencing for patients with hematologic neoplasms.

A Rare Case of Primary Cutaneous Gamma-Delta T-cell Lymphoma with Aberrant B-cell Marker Expression.

ABSTRACT: Primary cutaneous gamma-delta T-cell lymphoma (PCGDTL) is a rare and diagnostically challenging primary skin lymphoma. We present a case of a 78-year-old otherwise healthy man who developed nonhealing nodules on his right posterior calf. Initial biopsy showed a dense, atypical, lymphoid infiltrate with gamma-delta and cytotoxic T-cell immunophenotypes. The diagnosis of PCGDTL was rendered; however, concurrent flow cytometry revealed expression of aberrant B-cell markers, including CD19 and cytoplasmic CD79a. Subsequent immunohistochemical studies corroborated this result. We report the extremely rare phenomenon of aberrant B-cell marker expression in PCGDTL, the first formally reported case to our knowledge.