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Within a multistate viral genomic surveillance program, we evaluated whether proportions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections attributed to the JN.1 variant and to XBB-lineage variants (including HV.1 and EG.5) differed between inpatient and outpatient care settings during periods of cocirculation. Both JN.1 and HV.1 were less likely than EG.5 to account for infections among inpatients versus outpatients (adjusted odds ratio [aOR], 0.60 [95% confidence interval (CI),.43–.84; P =.003] and 0.35 [.21–.58; P <.001], respectively). JN.1 and HV.1 variants may be associated with a lower risk of severe illness. The severity of coronavirus disease 2019 may have attenuated as predominant circulating SARS-CoV-2 lineages shifted from EG.5 to HV.1 to JN.1. [ABSTRACT FROM AUTHOR]

Several recurrent disease-initiating genetic abnormalities define biologically, clinically, and prognostically distinct subsets of disease in B-lymphoblastic leukemia (B-ALL) [[1]]. Coexistence of ETV6/RUNX1 and MLL aberrations in B-cell precursor acute lymphoblastic leukemia discloses a small subclass of BCP-ALL. (D) Metaphase nucleus illustrating derivative chromosomes 9 (black dashed arrow) and 11 (full black arrow) with a KMT2A:MLLT3 fusion and an uninvolved chromosome 11 (white arrow) with metaphase FISH. [Extracted from the article]

Glycogen storage disease type IV (GSD IV; Andersen's disease) is a rare autosomal recessive disorder that results from defects in the GBE1 gene (3p12.2) and subsequent deficiencies of glycogen branching. We report a case of GSD IV diagnosed at autopsy in a 35 4/7 weeks gestational age female neonate that died shortly after birth. Multisystem blue, ground glass inclusions initially presumed artefactual were periodic acid-Schiff positive, diastase resistant. Chromosomal microarray analysis identified a deletion of exons 2 through 16 of the GBE1 gene and whole exome sequencing identified a nonsense mutation within exon 14, confirming the diagnosis of GSD IV. A strong index of suspicion was required determine GSD IV as the ultimate cause of death, illustrating the need for critical evaluation of postmortem artifact in the setting of fetal demise of unknown etiology and highlighting the role of postmortem molecular diagnostics in a subset of cases. [ABSTRACT FROM AUTHOR]

Vitreous fluid sampling for postmortem chemistry analysis is discouraged in pediatric forensic cases involving head trauma due to the risk of introducing retinal artifacts. Aqueous fluid is physically separated from the posterior chamber of the eye, and therefore, unlikely to produce vitreal artifact when sampled. Analysis of aqueous fluid is therefore proposed as a substitute for vitreous. Vitreous and aqueous fluid was sampled concurrently from 28 pediatric and 55 adult decedents, and sodium (Na), potassium (K), chloride (Cl), urea nitrogen (UN), creatinine (Cr), and glucose (Glc) concentrations were compared. Significant correlation existed between all analytes regardless of age or postmortem interval, and linear regression equations were derived. Aqueous concentrations were generally higher than vitreous for Na, K, and Cr and were marginally lower for Cl, UN, and Glc. Assuming vitreous fluid as a standard for correlating postmortem chemistry to antemortem serum values, aqueous may be a viable substitute for vitreous when expected differences are considered. [ABSTRACT FROM AUTHOR]

The SOX10 gene plays a vital role in neural crest cell development and migration. Abnormalities in SOX10 are associated with Waardenburg syndrome Types II and IV, and these patients have recognizable clinical features. This case report highlights the first ever reported homozygous loss of function of the SOX10 gene in a human. This deletion is correlated using family history, prenatal ultrasound, microarray analysis of amniotic fluid, and ultimately, a medical autopsy examination to further elucidate phenotypic effects of this genetic variation. Incorporating the use of molecular pathology into the autopsy examination of fetuses with suspected congenital anomalies is vital for appropriate family counseling, and with the ability to use formalin-fixed and paraffin-embedded tissues, has become a practical approach in autopsy pathology. [ABSTRACT FROM AUTHOR]

Myxoid lesions of the breast can be diagnostically challenging entities. We report 4 cases of CD34+ fibromyxoid lesion that have been previously diagnosed as "benign myxoid lesion," "nodular mucinosis," or "mammary myofibroblastoma, myxoid type" on the basis of CD34-positivity. The lesions were microscopically well circumscribed and composed of a paucicellular spindle cell proliferation in a background of myxoid stroma. No epithelial component was identified. The spindle cells showed immunohistochemical reactivity for CD34 and smooth muscle actin. Based on morphologic and immunohistochemical similarities between these cases and myxoid myofibroblastoma, we compared 4 myxoid lesions with cases of typical myofibroblastoma, utilizing retinoblastoma (Rb) antibody and fluorescent in situ hybridization for 13q14 gene rearrangement (encoding the Rb gene). The myxoid lesions showed retention of Rb protein by immunohistochemistry, whereas Rb expression was lost in cases of myofibroblastoma. We identified loss of 13q14 in 3 of 4 cases of myofibroblastoma. Notably, 13q14 gene rearrangement was not observed in any of the myxoid lesions. Our data show that there is at least a subset of CD34+ fibromyxoid lesions that, despite overlapping morphologic and immunohistochemical phenotype and proposed common histogenesis with myofibroblastomas, is genetically distinct from the latter based on Rb analysis. [ABSTRACT FROM AUTHOR]

Background: Malignancy after transplantation is an uncommon multifactorial occurrence. Immunosuppression to prevent graft rejection is described as a major risk factor in malignancy development in the post-transplant state. Donor-derived malignancy is a rare reported complication. Herein, we review our patient history and discuss diagnostic strategies and the implications of immunosuppression for donor-derived malignancy. Case presentation: This is a 69-year-old man with post-renal-transplant urothelial carcinoma determined to be of donor origin. His course was complicated by BK virus at six years post-transplant; urothelial carcinoma was identified nine years post-transplant. Cystectomy was performed, but because of immunosuppression and underlying chronic kidney disease, the patient was considered ineligible for adjuvant chemotherapy. Two years after resection, screening MRI demonstrated retroperitoneal lymphadenopathy and a right upper pole mass in the transplanted kidney. Urine cytology confirmed the presence of malignant cells; FISH showed 2-8 copies of the X chromosome and no Y chromosome consistent with female origin of the malignant cells. CT-guided renal mass and paraaortic lymph node biopsies demonstrated that about 50 % of cells had an XY complement, while the remainder showed a XX genotype by chromosomal SNP microarray analysis. Immunosuppression was discontinued and the donor kidney removed. X/Y FISH of the urothelial carcinoma identified in the explanted kidney confirmed that the malignant cells were of female donor origin. Follow-up at 3, 6 and 12 months after discontinuation of immunosuppression and surgery demonstrated normalization of the lymphadenopathy and absence of new lesions. Conclusions: Immunosuppression is a major risk factor for development of malignancy in transplant recipients. Donor-derived malignancy can arise and current molecular studies allow an accurate diagnosis. Withdrawal of immunosuppression and surgical resection of the transplant kidney proved an effective treatment in our case. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article related to astute hypothesis which used in the diagnosis of migraine with brainstem aura, published in previous issue.

• Aggressive lymphoma (DLBCL) arising in CLL/SLL is a Richter transformation. • Clonal relationship between the DLBCL and CLL/SLL carries a poor prognosis. • CMA can help establish clonality and detect high risk aberrations. • Molecular profiling with CMA has potential prognostic and therapeutic implications. Richter transformation (RT) refers to the development of an aggressive lymphoma in patients with pre-existing chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). It carries a poor prognosis secondary to poor response to therapy or rapid disease relapse. Currently there are no randomized trials to guide treatment. Therapeutic decisions are often influenced by the presence or absence of a clonal relationship between the underlying CLL/SLL and the new lymphoma given the poor prognosis of patients with clonally related RT. Chromosomal microarray analysis (CMA) can help to establish clonality while also detecting genomic complexity and clinically relevant genetic variants such as loss of CDKN2A and/or TP53. As a result, CMA has potential prognostic and therapeutic implications. For this study, CMA results from patients with Richter transformation were evaluated in paired CLL/SLL and transformed lymphoma samples. CMA revealed that 86% of patients had common aberrations in the two samples indicating evidence of common clonality. CMA was also useful in detecting aberrations associated with a poor prognosis in 71% of patients with RT. This study highlights the potential clinical utility of CMA to investigate the clonal relationship between CLL/SLL and RT, provide prognostic information, and possibly guide therapeutic decision making for patients with Richter transformation. [ABSTRACT FROM AUTHOR]

• Integrated genomic approach to diagnose myeloid neoplasms should include microarray. • MPseq precisely identifies and characterizes complicated chromosomal rearrangements. • PCM1-JAK2 fusions with aberrant tyrosine kinases have potential for targeted therapy. The 2016 World Health Organization entity 'Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1 , or with PCM1-JAK2 ' encompasses a group of rare neoplasms that result from the formation of a fusion gene that leads to expression of an aberrant tyrosine kinase. This entity also contains variant JAK2 fusion partners, and detection of this defining event can be facilitated by various cytogenetic and molecular methods. Cryptic rearrangements of 9p24/ JAK2 can be particularly challenging to identify. We describe the use of chromosomal microarray analysis (CMA), fluorescence in situ hybridization (FISH) with a probe for JAK2 , and genomic mate pair analysis to describe a complex karyotype with a t(9;22) that produced a functional BCR-JAK2 fusion, leading to the appropriate diagnosis for the patient. This case highlights the importance of using an integrated genomic approach to fully define complex aberrations to assign proper diagnoses. [ABSTRACT FROM AUTHOR]

Primary cytogenetic abnormalities in B-lymphoblastic leukemia (B-ALL) define subgroups of disease with distinct clinical implications. These subgroups are largely mutually exclusive and only rarely observed in conjunction. We describe a three-year-old female presenting with de novo B-ALL in whom dual color, dual fusion fluorescence in situ hybridization (D-FISH) evaluation suggested concurrent ETV6::RUNX1 and KMT2A::MLLT3 rearrangements. Chromosomal microarray analysis (CMA) indicated that the breakpoint within KMT2A was located outside the typical region described in KMT2A leukemogenic translocations. Owing to the unexpected identification of concurrent ETV6::RUNX1 and KMT2A translocations by D-FISH and the suspicious findings on CMA, research-based whole genome sequencing (WGS) was performed. While this analysis confirmed the ETV6::RUNX1 fusion, WGS revealed the apparent KMT2A::MLLT3 fusion detected by D-FISH resulted from a juxtaposition of the 3′ portion of KMT2A (from intron 1) to an intergenic region on chromosome 9 located 460 Kb upstream of MLLT3. The WGS results indicate the apparent KMT2A::MLLT3 rearrangement would not result in an oncogenic chimeric fusion protein, and the characteristic KMT2A::MLLT3 dual fusion identified by D-FISH testing represented a false-positive FISH result. WGS thus more precisely resolved the genomic abnormalities in this B-ALL clone in comparison to chromosomes, FISH and chromosomal microarray and enabled accurate risk stratification. This case illustrates the importance of careful interpretation of atypical cases with aberrant genomic results, comprehensively considering expected fusion product structure, assay design and integrating results in their entirety. WGS may provide a means for resolution of atypical results by standard investigation modalities. [ABSTRACT FROM AUTHOR]