Large granular lymphocyte (LGL) leukemia comprises a group of rare lymphoproliferative disorders whose molecular landscape is incompletely defined. We leveraged paired whole exome and transcriptome sequencing in the largest LGL leukemia cohort to date, which included 105 patients (93 TCRab T-LGL and 12 TCRγδ T-LGL). 76 mutations were observed in three or more patients in the cohort, and out of those, STAT3, KMT2D, PIK3R1, TTN, EYS, and SULF1 mutations were shared between both subtypes. We identified ARHGAP25, ABCC9, PCDHA11, SULF1, SLC6A15, DDX59, DNMT3A, FAS, KDM6A, KMT2D, PIK3R1, STAT3, STAT5B, TET2, and TNFAIP3 as recurrently mutated putative drivers using an unbiased driver analysis approach leveraging our whole exome cohort. Hotspot mutations in STAT3, PIK3R1, and FAS were detected, whereas truncating mutations in epigenetic modifying enzymes such as KMT2D and TET2 were observed. Moreover, STAT3 mutations co-occurred with mutations in chromatin and epigenetic modifying genes, especially KMT2D and SETD1B (p < 0.01, p < 0.05 respectively). STAT3 was mutated in 50.5% of the patients. Most common Y640F STAT3 mutation was associated with lower ANC values, and N647I mutation was associated with lower hemoglobin values. Somatic activating mutations (Q160P, D170Y, L287F) in the STAT3 coiled-coil domain were characterized. STAT3 mutant patients exhibited increased mutational burden and enrichment of a mutational signature associated with increased spontaneous deamination of 5-methylcytosine. Finally, gene expression analysis revealed enrichment of interferon gamma signaling and decreased PI3K-Akt signaling for STAT3 mutant patients. These findings highlight the clinical and molecular heterogeneity of this rare disorder.
Background Rhegmatogenous retinal detachment (RRD) is a common, potentially blinding ocular pathology that is considered a surgical emergency. Macular involvement has been identified as a major negative prognostic indicator for visual recovery after RRD correction. It is not currently clear whether early intervention improves visual outcomes, and in practice, there are potential disadvantages to performing early surgery for fovea-involving RRD. Such disadvantages include inadequate assessment of coexisting comorbidities, increased rate of complications related to poorly trained staff or tired surgeons, and anesthetic risk. Methods A single-center, retrospective, cohort study of patients who underwent repair of macula-involving rhegmatogenous retinal detachment at the University of Virginia was performed. Variables collected included patient demographics, ocular history, clinical characteristics, and post-operative complications. Patients were excluded if they had a history of congenital or acquired pathology with an effect on visual function, bilateral or repeat rhegmatogenous detachment, age less than 18 years, follow up duration less than 6 months, or if they were repaired using scleral buckle, pneumatic retinopexy, 25- or 27-gauge pars plana vitrectomy, or any combination of these techniques. A multivariate regression model was used to compare overall outcomes such as post-operative visual acuity, intra-ocular pressure, retina attachment status, and complications among patients of differing timing of surgical repair. These analyses were adjusted for clinical factors known or considered to be associated with worse prognosis in rhegmatogenous retinal detachment. Results A total of 104 patients undergoing 23-gauge vitrectomy for repair of macula involving rhegmatogenous retinal detachments were included in this study with mean follow up period 17.9 ± 14.1 months. Early surgical repair (< 48 h) was pursued in 26 patients, moderately delayed surgical repair (3–7 days), was performed in 29 patients and late surgical repair (> 7 days) in 49 patients. Our analysis showed no difference in post-operative visual acuity between patients with detachments undergoing early versus moderately delayed repair of RRD. However, mean visual acuity differed between patients undergoing early versus late repair at 3, 6, and 12 months. No significant difference was observed in post-operative complications between the three surgical timepoints including cataract formation, development of glaucoma and re-detachment rate. Use of 360 laser was found to be protective against re-detachment overall (OR 6.70 95% CI 1.93–23.2). Conclusions These findings indicate that a moderate delay of 3–7 days from symptom onset for repair of macula-involving retinal detachment may be a safe approach as there are no differences in terms of visual acuity or post-operative complications compared to early repair within 48 h. Delaying surgery for > 7 days however is not recommended due to the loss of recovery of visual acuity observed in this study. Use of 360 laser may prevent risk of re-detachment after primary repair.
Atypical chronic myeloid leukemia (aCML) is a rare myeloproliferative disorder that shares clinical features with chronic myeloid leukemia but lacks the classic t(9;22) BCR-ABL1 translocation and features prominent dysgranulopoiesis and granulocytic dysplasia. Challenges of this diagnosis include clinical and biologic heterogeneity, the high risk of transformation to acute myeloid leukemia, and the lack of standard treatment options. Allogeneic hematopoietic stem cell transplant is likely the preferred treatment, but this can be limited by patient psychosocial support, age, concomitant medical conditions, and availability of an appropriate donor. We report the case of a 61-year-old male with no significant past medical history diagnosed with aCML with a rare t(2;13)(q33;q12). He presented with weight loss, night sweats, splenomegaly, hyperleukocytosis, a leukoerythroblastic differential with a predominant neutrophilia, anemia, and thrombocytopenia. Subsequent peripheral blood and bone marrow studies lead to the diagnosis of aCML. He was recommended to undergo an allogeneic stem cell transplant evaluation and declined. He was initially treated with hydroxyurea and imatinib to which he responded for approximately three years. After clinical progression, he was treated with sorafenib, a multiprotein kinase inhibitor more commonly used in the treatment of hepatocellular and renal cell carcinoma due to its off target FLT3 inhibition. The patient achieved complete hematologic response which has been sustained for 7 years with tolerable side effects.
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