Transfusion Independence Achieved with Combination Fedratinib and Luspatercept in an Elderly Man with Heavily Pretreated Intermediate-2 Risk Primary Myelofibrosis.

Myelofibrosis (MF)-associated anemia and transfusion dependency are associated with inferior quality of life and poor prognosis. JAK2 inhibitors and TGF-ß superfamily ligand traps are being explored as treatment options for MF-associated anemia. Here, we present the case of a 66-year-old man with heavily pretreated intermediate-2 (INT-2) risk primary MF who had an exceptional response to combination fedratinib and luspatercept therapy. He achieved transfusion independence and experienced a reduction in spleen size from 20 cm to 12 cm, with remarkable improvement in performance status. Compared with other JAK inhibitors, the mechanism of action of fedratinib may explain its milder effect on anemia. It is possible that the addition of luspatercept may result in an additive or synergistic effect of one or both medications. Although the exact biological pathways have not yet been elucidated, combination fedratinib and luspatercept nevertheless is a promising therapy for anemia in patients with transfusion-dependent INT-2 risk MF.

Paraganglioma of the Spine: Review of 6 Cases in 20 Years at a Single Institution.

BACKGROUND AND OBJECTIVES: Paragangliomas are rare neuroendocrine tumors that may localize to the spine causing progressive low back pain variably accompanied by radiculopathy. Recurrence, follow-up duration, and role of adjuvant therapy remain unestablished. METHODS: We interrogated our institution's histopathology database for all confirmed cases of spinal paraganglioma between 2000 and 2021. Patient records were retrospectively reviewed to extract diagnostic features, operative treatment, and follow-up outcomes. RESULTS: 6 cases of spinal paraganglioma were surgically treated (67% female vs. 33% male, mean age = 51.3 years). Preoperative symptom duration did not correlate with tumor size (Spearman r = 0.154, P = 0.80). The mean postoperative follow-up duration lasted 3.3 years (range = 2-96 months). There were an equal number of primary and metastatic lesions. 1 tumor exhibited secretory features and was consequently embolized preoperatively. No residual or recurrent disease was evident in the primary cases; however, 2 metastatic cases recurred within 2 years of surgery and 1 patient died. CONCLUSIONS: Given nonspecific clinical and radiologic features, spinal paragangliomas are diagnosed via biopsy or after surgery. Complete surgical resection is often necessary to alleviate symptoms and prevent tumor recurrence. In cases with benign metastases, long-term surveillance is important and adjuvant medical and radiotherapeutic treatment may be beneficial.

Pembrolizumab-induced autoimmune haemolytic anemia in a patient with chronic lymphocytic leukaemia successfully treated with ibrutinib.

We present a unique case of a patient with a long-standing history of indolent chronic lymphocytic leukaemia (CLL) who suddenly developed autoimmune haemolytic anaemia after starting immune checkpoint inhibitor therapy for bladder cancer. He had no clear indication to start CLL-directed treatment based on current clinical practice guidelines; however, targeted treatment of CLL with ibrutinib proved to be effective in treating the haemolytic anaemia.

Epstein Barr Virus Infection Can be a Secondary Event in B-Cell Lymphomas: A Review of 338 Cases and a Novel Finding of Zonal EBER+ Tumor Cells Showing Features of Progression From Underlying EBV-negative Lymphoma.

Cases of B-cell lymphoma over an 8-year interval with diagnosis of EBER positivity were retrieved from archives and reviewed for classification and pattern of Epstein Barr Virus (EBV) expression. Of 46 cases that were EBV early RNA (EBER)+ by in situ hybridization staining, 7 had nonuniform staining among the neoplastic cells. Four of those cases showed a uniform admixture of EBER+ and EBER- tumor cells, compatible with the prevailing theory of episomal EBV loss with cell replication. Three cases of lymphomas showed a partial and zonal pattern and other features suggest that EBV infection occurred after the lymphoma was already established. In case 1, an EBV-negative follicular lymphoma and an EBV+ diffuse large B-cell lymphoma (DLBCL) of activated B cell type were contiguous in a lymph node. Both components showed a BCL2 translocation by fluorescence in situ hybridization. In case 2, a DLBCL of germinal center type in an human immunodeficiency virus positive patient contained clusters of EBR+ lymphoma cells with Reed-Sternberg morphology and shift to an activated B-cell immunophenotype. In case 3, an ulcerated and perforated DLBCL in the stomach showed a superficial swath of EBER+ tumor cells accompanied by a relative absence of reactive T cells. In all 3 cases the tumor cells in EBER+ areas expressed latent membrane protein-1 and showed strong CD30 positivity. All 3 patients were treated with chemotherapy are currently in remission. Heterogenous EBER positivity has been reported previously in DLBCLs, attributed to loss of the episomal viral DNA from a subset of fully transformed tumor cells. Previously reported cases did not include description of zonation of EBV or phenotypic differences correlating with the presence of EBV. The cases reported here suggest that in a subset of EBV+ DLBCLs, EBV infection may not be the "first hit."

Evidence that ternary complex (eIF2-GTP-tRNA(i)(Met))-deficient preinitiation complexes are core constituents of mammalian stress granules.

Environmental stress-induced phosphorylation of eIF2alpha inhibits protein translation by reducing the availability of eIF2-GTP-tRNA(i)Met, the ternary complex that joins initiator tRNA(Met) to the 43S preinitiation complex. The resulting untranslated mRNA is dynamically routed to discrete cytoplasmic foci known as stress granules (SGs), a process requiring the related RNA-binding proteins TIA-1 and TIAR. SGs appear to be in equilibrium with polysomes, but the nature of this relationship is obscure. We now show that most components of the 48S preinitiation complex (i.e., small, but not large, ribosomal subunits, eIF3, eIF4E, eIF4G) are coordinately recruited to SGs in arsenite-stressed cells. In contrast, eIF2 is not a component of newly assembled SGs. Cells expressing a phosphomimetic mutant (S51D) of eIF2alpha assemble SGs of similar composition, confirming that the recruitment of these factors is a direct consequence of blocked translational initiation and not due to other effects of arsenite. Surprisingly, phospho-eIF2alpha is recruited to SGs that are disassembling in cells recovering from arsenite-induced stress. We discuss these results in the context of a translational checkpoint model wherein TIA and eIF2 are functional antagonists of translational initiation, and in which lack of ternary complex drives SG assembly.

A case of lenalidomide-dependent myelodysplastic syndrome.

A man with cytopenias, dysplasia, excess blasts, P53 and RUNX1 mutations, and ring chromosome 7 recovered after stopping lenalidomide.

Extranodal nasal-type natural killer T-cell lymphoma in an adolescent from Bangladesh.

Natural killer (NK)-cell neoplasms are relatively uncommon tumors. Classification schemes prior to that of the World Health Organization (2001) did not account clearly for these neoplasms. Advances in immunohematology over the past 10 years have aided in the recognition and categorization of NK-cell tumors. One type of tumor that belongs to this class is extranodal, nasal-type NK/T-cell lymphoma. These lymphoma cells express a cytotoxic T-cell or NK-cell phenotype, including CD56 and TIA-1. Nasal-type NK/T-cell lymphomas arise from extranasal sites such as the skin and are often associated with Epstein-Barr virus infection. Asian adults are affected most commonly. Very few pediatric cases are reported in the literature, of which only 5 presented with cutaneous involvement. We report a case of an adolescent Bangladeshi boy with extranodal, nasal-type NK/T-cell lymphoma who had cutaneous nodules on the extremities.

Sialidase Unmasks Mucin Domain Epitopes of Lubricin.

Lubricin is a secreted, mucin-like glycoprotein and proteoglycan abundant in synovial fluid that provides boundary lubrication and prevents cell adhesion in synovial joints. The antilubricin S6.79 monoclonal antibody recognizes an O-linked glycopeptide epitope in lubricin's mucin domain. The central, long mucin domain of lubricin is extensively O-glycosylated with Gal(ß1-3)GalNAc-O-Ser/Thr, and about two thirds of the O-glycosylated sites are capped with sialic acid. Our aim was to determine whether removal of sialic acid by sialidase could improve the detection of lubricin in a number of human tissues using the S6.79 monoclonal antibody. Sialidase treatment caused a dramatic increase in antibody reactivity in human pericardium, splenic capsule and trabeculae, plasma, serum, eye sleep extract, and liver sinusoids. Sialidase had minimal effect on S6.79 antibody reactivity with lubricin in synovial fluid and synovial tissue. These observations suggest that the origin of lubricin in blood may be different from that in synovial fluid and that desialylation of lubricin is essential for unmasking epitopes within the mucin domain.

Abundant lubricin expression suggests a link between synoviocytes, synovial tumors, and myxomas.

Progenitor cell differentiation into fibroblast-like synoviocytes (FLSs) and their ensuing phenotypic changes are incompletely explored. Synovial lining is composed of intimal macrophages and FLSs. FLSs have epithelioid morphology and directionally secrete components of synovial fluid, including lubricin. We stained human tissues and tumors using two anti-lubricin antibodies. Lubricin was found in FLSs in synovium and in tenosynovial giant cell tumors (TSGCTs) and not in the associated monocyte/macrophage cells, which were identified by double immunostaining for CD163. In TSGCTs, giant cells, known to form by fusion of mononuclear cells, were negative for both lubricin and CD163. Occasional mononuclear cells with the same phenotype were also seen, suggesting that the precursors of the giant cells are derived from the minor CD163-negative monocyte subset. Lubricin was also detected in intramuscular myxomas, in early myxoid changes of ganglion cysts, and in one of five low-grade myxofibrosarcomas, but not in other fibroconnective tissues, epithelial tissues, or other tumors tested. This suggests that lubricin expression may typify adaptive and neoplastic changes along a pathway toward FLSs. Further support for this concept comes from ganglion cysts and juxta-articular myxoma tumors, which show a spectrum of myxoid, cystic and synovial differentiation, and in which moderate lubricin staining of myxoid stroma was seen.

Malignant degeneration of multilevel monostotic Paget's disease involving the thoracic spine: an unusual presentation.

Paget's disease is the second most common metabolic bone disease after osteoporosis and is characterized by abnormal bone turnover and remodeling that can lead to pain, pathological fracture, bony deformity and nerve compression syndromes. The lumbar region is the most commonly affected site within the spine followed by the thoracic and cervical spine. Even though the spine is affected very commonly in Paget's disease, malignant degeneration is exceptionally rare. Multilevel monostotic spine involvement due to Paget's disease is very uncommon. An unusual clinico-radiological manifestation of multilevel thoracic Paget's disease with sarcomatous degeneration presenting as a neurosurgical emergency is reported with a pertinent review of the literature.

A case of recurrent giant cell tumor of bone with malignant transformation and benign pulmonary metastases.

Giant cell tumor (GCT) of bone is a locally destructive tumor that occurs predominantly in long bones of post-pubertal adolescents and young adults, where it occurs in the epiphysis. The majority are treated by aggressive curettage or resection. Vascular invasion outside the boundary of the tumor can be seen. Metastasis, with identical morphology to the primary tumor, occurs in a few percent of cases, usually to the lung. On occasion GCTs of bone undergo frank malignant transformation to undifferentiated sarcomas. Here we report a case of GCT of bone that at the time of recurrence was found to have undergone malignant transformation. Concurrent metastases were found in the lung, but these were non-transformed GCT.