Longitudinal study of 2 patients with cyclic thrombocytopenia, STAT3 and MPL mutations.

Cyclic thrombocytopenia (CTP) is a rare disease of periodic platelet count oscillations. The pathogenesis of CTP remains elusive. To study the underlying pathophysiology and genetic and cellular associations with CTP, we applied systems biology approaches to 2 patients with stable platelet cycling and reciprocal thrombopoietin (TPO) cycling at multiple time points through 2 cycles. Blood transcriptome analysis revealed cycling of platelet-specific genes, which are in parallel with and precede platelet count oscillation, indicating that cyclical platelet production leads platelet count cycling in both patients. Additionally, neutrophil and erythrocyte-specific genes also showed fluctuations correlating with platelet count changes, consistent with TPO effects on hematopoietic progenitors. Moreover, we found novel genetic associations with CTP. One patient had a novel germline heterozygous loss-of-function (LOF) thrombopoietin receptor (MPL) c.1210G>A mutation, and both had pathogenic somatic gain-of-function (GOF) variants in signal transducer and activator of transcription 3 (STAT3). In addition, both patients had clonal T-cell populations that remained stable throughout platelet count cycles. These mutations and clonal T cells may potentially involve in the pathogenic baseline in these patients, rendering exaggerated persistent thrombopoiesis oscillations of their intrinsic rhythm upon homeostatic perturbations. This work provides new insights into the pathophysiology of CTP and possible therapies.

Machine Learning Predictability of Clinical Next Generation Sequencing for Hematologic Malignancies to Guide High-Value Precision Medicine.

Advancing diagnostic testing capabilities such as clinical next generation sequencing methods offer the potential to diagnose, risk stratify, and guide specialized treatment, but must be balanced against the escalating costs of healthcare to identify patient cases most likely to benefit from them. Heme-STAMP (Stanford Actionable Mutation Panel for Hematopoietic and Lymphoid Malignancies) is one such next generation sequencing test. Our objective is to assess how well Heme-STAMP pathological variants can be predicted given electronic health records data available at the time of test ordering. The model demonstrated AUROC 0.74 (95% CI: [0.72, 0.76]) with 99% negative predictive value at 6% specificity. A benchmark for comparison is the prevalence of positive results in the dataset at 58.7%. Identifying patients with very low or very high predicted probabilities of finding actionable mutations (positive result) could guide more precise high-value selection of patient cases to test.

Splenectomy for benign and malignant hematologic pathology: Modern morbidity, mortality, and long-term outcomes.

BACKGROUND: The role of splenectomy to diagnose and treat hematologic disease continues to evolve. In this single-center retrospective review, we describe modern morbidity, mortality, and long-term outcomes associated with splenectomy for benign and malignant hematologic disorders. METHODS: We analyzed all nontrauma splenectomies performed for benign or malignant hematologic disorders from January 2009 to September 2018. Variables collected included demographics, preexisting comorbidities, laboratory results, intra- and postoperative features, and long-term follow-up. Outcomes of interest included postoperative complications, 30-day mortality, and overall mortality. RESULTS: We identified 161 patients who underwent splenectomy for hematologic disorders. Median age was 54 years (range 19-94), and 83 (52%) were female. Splenectomy was performed for 95 (59%) patients with benign hematologic disorders and for 66 (41%) with malignant conditions. Most splenectomies were laparoscopic (76%), followed by laparoscopic hand assisted (11%), open (8%), and laparoscopic converted to open (6%). Median follow-up was 761 days (interquartile range: 179-2025 days). Major complications occurred in 21 (13%) patients. Three (2%) patients died within 30 days; 16 (9%) died more than 30 days after operation, none from surgical complications, with median time to death of 438 days (interquartile range: 231-1497 days). Among malignant cases, only preoperative thrombocytopenia predicted death (odds ratio = 5.8, 95% confidence interval = 1.1-31.8, P = .04). For benign cases, increasing age was associated with inferior survival (odds ratio = 2.3, 95% confidence interval = 1.0-5.1, P = .05). CONCLUSION: Splenectomy remains an important diagnostic and therapeutic option for patients with benign and malignant hematologic disorders and can be performed with a low complication rate. Despite considerable burden of comorbid disease in these patients, early postoperative mortality was uncommon.

A Kindred with a ß-Globin Base Substitution [ß89(F5)Ser→Arg (AGT>AGG); HBB: c.270T>G] Resulting in Hemoglobin Vanderbilt.

High oxygen affinity hemoglobins (Hbs), characterized by a decreased ability to release oxygen to the tissues and a left-shifted oxygen dissociation curve, are a rare cause of secondary erythrocytosis. Here, we report a base substitution in the ß-globin gene at codon 89 (AGT>AGG) in a kindred with familial erythrocytosis resulting in Hb Vanderbilt, a high oxygen affinity variant.

Nelarabine neurotoxicity with concurrent intrathecal chemotherapy: Case report and review of literature.

Severe nelarabine neurotoxicity in a patient who received concurrent intrathecal (IT) chemotherapy is reported. A 37-year-old Caucasian woman with a history of T-cell lymphoblastic lymphoma was admitted for relapsed disease. She was originally treated with induction chemotherapy followed by an autologous transplant. She developed relapsed disease 10 months later with leukemic involvement. She was re-induced with nelarabine 1500 mg/m(2) on days 1, 3, and 5 with 1 dose of IT cytarabine 100 mg on day 2 as central nervous system (CNS) prophylaxis. At the time of treatment, she was on continuous renal replacement therapy due to sequelae of tumor lysis syndrome (TLS). She tolerated therapy well, entered a complete remission, and recovered her renal function. She received a second cycle of nelarabine without additional IT prophylaxis one month later. A week after this second cycle, she noted numbness in her lower extremities. Predominantly sensory, though also motor and autonomic, peripheral neuropathy started in her feet, ascended proximally to the mid-thoracic region, and eventually included her distal upper extremities. A magnetic resonance imaging (MRI) of her spine demonstrated changes from C2 to C6 consistent with subacute combined degeneration. Nelarabine was felt to be the cause of her symptoms. Her neuropathy stabilized and showed slight improvement and ultimately received an unrelated, reduced-intensity allogeneic transplant while in complete remission, but relapsed disease 10 weeks later. She is currently being treated with best supportive care. To our knowledge, this is the first published case report of severe neurotoxicity caused by nelarabine in a patient who received concurrent IT chemotherapy.

Breast Angiosarcoma: Case Series and Expression of Vascular Endothelial Growth Factor.

PURPOSE: Angiosarcoma of the breast is a rare, malignant tumor for which little is known regarding prognostic indicators and optimal therapeutic regimens. To address this issue, we performed a retrospective analysis of breast angiosarcoma cases seen at Stanford University along with immunohistochemical analysis for markers of angiogenesis. METHODS: Breast angiosarcoma cases seen between 1980 and 2008 were examined. Viable tissue blocks were analyzed for expression of vascular endothelial growth factor and its receptors. RESULTS: A total of 16 cases were identified. Data was collected regarding epidemiology, treatment, response rates, disease-free survival, and the use of various imaging modalities. Five tissue blocks remained viable for immunohistochemical analysis. Vascular endothelial growth factor-A was positively expressed in 3 of these samples. CONCLUSION: Angiosarcoma of the breast is an aggressive malignancy with a propensity for both local recurrence and distant metastases. Angiogenesis inhibition may represent a novel therapeutic modality in this rare, vascular malignancy.

Changes in quality of life among low-income men treated for prostate cancer.

OBJECTIVES: To investigate as the primary objective changes over time in general and disease-specific health-related quality of life (HRQOL) among low-income men treated for prostate cancer in a longitudinal prospective study. METHODS: Study participants were recruited from a state-funded program providing free prostate cancer treatment to impoverished men. We included men who completed telephone interviews and self-administered questionnaires at study enrollment and 6 months of follow-up. Covariates univariately associated with HRQOL change scores were included in multivariate linear regression models. All HRQOL models were controlled for age at enrollment, race, baseline HRQOL, and treatment effects at baseline and follow-up. RESULTS: Subjects with greater baseline Gleason scores experienced more negative changes in their physical health than did men with lower Gleason scores. Men with less than a high school education experienced greater improvement in their mental well-being than did men with more than a high school education. Those experiencing treatment effects at baseline displayed greater positive changes in their urinary function than did those without treatment effects at baseline. Finally, men experiencing treatment effects at follow-up were characterized by profound reductions in sexual function compared with those free of treatment effects at follow-up. CONCLUSIONS: This work provides new insights into HRQOL over time in a low-income, multiethnic group of patients with prostate cancer.