IGH/BCL2 Status Better Predicts Clinico-Pathological Behavior in Primary Splenic Follicular Lymphoma than Histological Grade and Other Molecular Markers.

Splenic lymphoma may be primary or secondary. Primary splenic lymphoma's are rare and usually of follicular cell origin representing <1% of Non-Hodgkin's Lymphoma's. Most are secondary with 35% representing Marginal Cell sub-type with the rest being Diffuse Large B-Cell Lymphoma's. Unlike the uniformly aggressive clinical course of Diffuse Large B-Cell Lymphoma's, biological behavior of Primary Splenic CD10-Positive Small B-Cell Lymphoma/Follicular Lymphoma remains less well defined. We present here a solitary splenic mass confirmed as Primary Splenic CD10-Positive Small B-Cell Lymphoma/Follicular Lymphoma after a diagnostic splenectomy. Biopsy revealed monomorphic small lymphoid cells with low grade mitotic activity. Flow cytometry showed a lambda restricted population of B-Cells displaying dim CD19 and CD10. The cells were negative for CD5, CD11c, and CD103. FISH was negative for IGH/BCL2 fusion unlike nodal Follicular Lymphoma's which are usually positive for this translocation. Evidence from this case and a review of literature support the finding that Primary Splenic CD10-Positive Small B-Cell Lymphoma/Follicular Lymphoma is less likely to have the classic IGH-BCL2 fusion and the associated chromosomal 14;18 translocation. This profile is associated with less aggressive clinical behavior even when histopathology represents a high-grade pattern. In such cases splenectomy alone is adequate for localized disease when negative for IGH/BCL2 fusion regardless of histological grade.

Increased Incidence of Thrombotic Complications With Non-small Cell Lung Cancer Necessitates Consideration of Prophylactic Anticoagulation in Young Individuals.

Venous thromboembolism (VTE) is a common complication in cancer patients and is associated with increased morbidity and mortality. Lung cancer is commonly associated with VTE including pulmonary embolism. We did a retrospective analysis from the 2013 Healthcare Cost and Utilization Project data to determine the role of age as a factor in the development of VTE in this patient group. Patients were selected using the International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes for metastatic lung cancer and VTE. The patients were stratified by age, sex, race/ethnicity, and site of VTE. There was a total of 16,577 VTE events detected out of a total of 182,863 cases of metastatic lung cancer, representing 9% of the total cases. In patients under 65 years of age, there were 356.82 more cases of pulmonary embolism per 100,000 individuals compared to those older than 65 years (p<0.0001). The same age group also showed 374.83 more upper extremity VTE, 286.94 more non-pulmonary thoracic VTE, and 263.97 more abdominal VTE events per 100,000 individuals (p<0.0001). In conclusion, we found that patients under the age of 65 years had a significantly higher incidence of VTE, pulmonary embolism, upper extremity VTE as well as abdominal and non-pulmonary VTE.

A long-term, open-label study of valbenazine for tardive dyskinesia.

BACKGROUND: Individuals with tardive dyskinesia (TD) who completed a long-term study (KINECT 3 or KINECT 4) of valbenazine (40 or 80 mg/day, once-daily for up to 48 weeks followed by 4-week washout) were enrolled in a subsequent study (NCT02736955) that was primarily designed to further evaluate the long-term safety of valbenazine. METHODS: Participants were initiated at 40 mg/day (following prior valbenazine washout). At week 4, dosing was escalated to 80 mg/day based on tolerability and clinical assessment of TD; reduction to 40 mg/day was allowed for tolerability. The study was planned for 72 weeks or until termination due to commercial availability of valbenazine. Assessments included the Clinical Global Impression of Severity-TD (CGIS-TD), Patient Satisfaction Questionnaire (PSQ), and treatment-emergent adverse events (TEAEs). RESULTS: At study termination, 85.7% (138/161) of participants were still active. Four participants had reached week 60, and none reached week 72. The percentage of participants with a CGIS-TD score ≤2 (normal/not ill or borderline ill) increased from study baseline (14.5% [23/159]) to week 48 (64.3% [36/56]). At baseline, 98.8% (158/160) of participants rated their prior valbenazine experience with a PSQ score ≤2 (very satisfied or somewhat satisfied). At week 48, 98.2% (55/56) remained satisfied. Before week 4 (dose escalation), 9.4% of participants had ≥1 TEAE. After week 4, the TEAE incidence was 49.0%. No TEAE occurred in ≥5% of participants during treatment (before or after week 4). CONCLUSIONS: Valbenazine was well-tolerated and persistent improvements in TD were found in adults who received once-daily treatment for >1 year.

A Phase 3, 1-Year, Open-Label Trial of Valbenazine in Adults With Tardive Dyskinesia.

PURPOSE/BACKGROUND: Valbenazine is approved to treat tardive dyskinesia (TD) in adults. KINECT 4 (NCT02405091) was conducted to explore the long-term effects of once-daily valbenazine in patients with TD. METHODS/PROCEDURES: The study included a 48-week, open-label treatment period and 4-week washout. Dosing was initiated at 40 mg/d, with escalation to 80 mg/d at week 4 based on efficacy and tolerability. Standard safety methods were applied, including treatment-emergent adverse event (TEAE) reporting. Valbenazine effects on TD were assessed using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD, and Patient Global Impression of Change. FINDINGS/RESULTS: After week 4, <15% of all participants had a serious TEAE (13.7%) or TEAE leading to discontinuation (11.8%). Participants experienced TD improvements during long-term treatment as indicated by mean change from baseline to week 48 in AIMS total score (sum of items 1-7, evaluated by site raters) with valbenazine 40 mg/d (-10.2 [n = 45]) or 80 mg/d (-11.0 [n = 107]). At week 48, most participants had ≥50% improvement from baseline in AIMS total score (40 mg/d, 90.0%; 80 mg/d, 89.2%), Clinical Global Impression of Change-TD rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 95.9%), and Patient Global Impression of Change rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 89.2%). No dose effects were apparent by week 36. Week 52 results indicated some loss of effect after washout. IMPLICATIONS/CONCLUSIONS: Valbenazine was generally well tolerated, and no new safety concerns were detected. Substantial clinician- and patient-reported improvements were observed in adults with TD who received once-daily valbenazine for up to 48 weeks.

Chimeric Antigen Receptor T-Cell Therapy: Reach to Solid Tumor Experience.

Chimeric antigen receptor (CAR) modified T-cell therapy, a unique platform technology highlighting precision medicine through utilization of molecular biology and cell-based therapeutics has shown unprecedented rates in patients with hematological malignancies such as acute lymphocyte leukemia, non-Hodgkin's lymphoma and multiple myeloma (MM). With the approval of CD19-targeted CAR T-cells by the Food and Drug Administration in acute lymphoblastic leukemia (ALL) and NHL, this technology is positioned for aggressive expansion to combination therapeutic opportunities and proof of principle towards utility in other malignant disorders. However, despite the impressive results seen with hematological malignancies, CAR T-cells have shown limited efficacy in solid tumors with several unsuccessful preclinical studies. Regardless, these attempts have provided us with a better understanding of the imminent challenges specific to solid tumors even if they have not so far led to expanded clinical treatment opportunities outside ALL/NHL/MM. This review summarizes our current understanding of CAR T-cell mechanism of action, while presenting the major limitations of CAR T-cell derived treatments in solid tumors. We further discuss recent findings and present new potential strategies to overcome the challenges facing solid tumor targeting by CAR T-cell platforms.

Interleukin 10-Mediated Response and Correlated Anemia in a Patient with Advanced Non-Small Cell Lung Carcinoma.

Anemia in cancer patients is associated with poor quality of life, reduced response to therapy, and decreased overall survival. We describe a case of a 56-year old woman with advanced metastatic non-small cell lung carcinoma who demonstrated marked response to a novel combinational immunotherapy approach involving a long-acting PEGylated construct of recombinant human Interleukin-10 with Nivolumab, an anti-PD-L1 checkpoint inhibitor. While on treatment, the patient developed severe anemia and hyper-ferritinemia requiring RBC transfusion support. Here we discuss a possible novel immune mechanism of IL10-mediated anemia in correlation with tumor response.

Ischemic Stroke After Plasmapheresis.

Plasmapheresis involves the separation of all cellular elements of blood with the help of an extracorporeal semipermeable membrane. Even though plasmapheresis is generally considered safe, there have been anecdotal reports of thrombosis related to this exchange. We present 2 cases of healthy young males developing ischemic strokes within 24 hours of plasmapheresis. Patient A was a 24-year-old man with a family history of Factor V Leiden mutation presented with right-sided weakness 1 hour after donating plasma. A hypercoagulable work-up revealed elevations in Factor II. Patient B was a 42-year-old man who presented with a right facial droop, expressive aphasia and right arm weakness. He had donated plasma 18 hours before his presentation. A hypercoagulable work-up revealed elevated levels of von Willebrand factor antigen and high sensitivity C-reactive protein. A procoagulant state induced by plasmapheresis likely increases the risk for symptomatic thrombosis when an underlying thrombophilic state is present in the donor.

Primary Evan Syndrome With Disseminated Intravascular Coagulation Suggests Progressive Immune Dysregulation and Early Immunosuppressive Intervention is Key to Improving Outcomes.

Evan syndrome (ES) is a rare hematological disorder that involves 2 or more immune cytopenias. It usually includes autoimmune hemolytic anemia and autoimmune thrombocytopenia. Although occasionally associated with immune neutropenia, its association with disseminated intravascular coagulation (DIC) is rare. And, early diagnosis with appropriate intervention is important because mortality from ES is known to be greater than that of isolated immune hemolytic anemia and probably worse in the presence of DIC. Considering that the presence of DIC can make the diagnosis of ES challenging, a strong clinical suspicion is important as early initiation of therapy is critical to reducing the morbidity and mortality associated with this syndrome. We report a case of ES complicated by DIC.

Recurrent myocardial infarctions in a young football player secondary to thrombophilia, associated with elevated factor VIII activity.

Myocardial infarction (MI) due to coronary atherosclerosis in young adults is uncommon; rare causes such as cocaine abuse, arterial dissection, and thromboembolism should be considered. A 21-year-old football player, and otherwise healthy African American man, developed chest pain during exercise while bench-pressing 400 lbs. Acute MI was diagnosed based on physical examination, electrocardiography findings, and elevated cardiac enzymes. Coronary arteriography showed a thrombus occluding the proximal left anterior descending artery (LAD). Aggressive antiplatelet therapy with aspirin, clopidogrel, and eptifibatide was pursued, in addition to standard post-MI care. This led to the successful resolution of symptoms and dissolution of the thrombus, demonstrated by repeat coronary arteriography. Five months later, he presented with similar symptoms during exercise after lifting heavy weights, and was found to have another acute MI. Coronary arteriography again showed a thrombus occluding the LAD. No evidence of coronary artery dissection or vasospasm was found. Only mild atherosclerotic plaque burden was observed on both occasions by intravascular ultrasound. A bare metal stent was placed at the site as it was thought this site had acted as a nidus for small plaque rupture and thrombus formation. Elevated serum factor VIII activity at 205% (reference range 60%-140%) was found, a rare cause of hypercoagulability. Further workup revealed a patent foramen ovale during a Valsalva maneuver by transesophageal echocardiography. Both events occurred during weight lifting, which can transiently increase right heart pressure in a similar way to the Valsalva maneuver. In light of all the findings, we concluded that an exercise-related increase in factor VIII activity led to coronary arterial thrombosis in the presence of a small ruptured plaque. Alternatively, venous clots may have traversed the patent foramen ovale and occluded the LAD. In addition to continuing aggressive risk factor modification, anticoagulation therapy with warfarin was initiated with close follow-up.

Left bundle branch block in type 2 diabetes mellitus: a sign of advanced cardiovascular involvement.

OBJECTIVE: To evaluate left bundle branch block (LBBB) as an indicator of advanced cardiovascular involvement in diabetic (DM) patients by examining left ventricular systolic function and proteinurea. METHODS: Data of 26 diabetic patients with left bundle branch block (DM with LBBB) were compared with data of 31 diabetic patients without left bundle branch block (DM without LBBB) and 18 nondiabetic patients with left bundle branch block (non-DM with LBBB). The inclusion criteria were age >45 years, and diabetes mellitus type 2 of >5 years. RESULTS: Mean ages of patients in DM with LBBB, DM without LBBB, and non-DM with LBBB groups were 67 +/- 8, 68 +/- 10, and 65 +/- 10 years, respectively (P = NS). Females were 65%, 61%, and 61%, respectively (P = NS). Left ventricular ejection fraction in DM with LBBB was significantly lower than in DM without LBBB and non-DM with LBBB (30 +/- 10% vs 49 +/- 12% and 47 +/- 8%, P < 0.01). Left ventricular end-diastolic volume was significantly higher in DM with LBBB than in DM without LBBB and non-DM with LBBB (188.6 +/- 16.4 mL vs 147.5 +/- 22.3 mL and 165.3 +/- 15.2 mL, P < 0.03). Similarly, left ventricular end-systolic volume was significantly higher in DM with LBBB than in DM without LBBB and non-DM with LBBB (135.4 +/- 14.7 mL vs 83.7 +/- 9.5 mL and 96.6 +/- 18.4 mL, P < 0.02). No statistically significant difference was seen in left atrial size. Proteinurea in DM with LBBB (79.4 +/- 18.9 mg/dL) was significantly higher than in DM without LBBB (35.6 +/- 8.5 mg/dL, P < 0.05) and non-DM with LBBB (12 +/- 3.5 mg/dL, P < 0.05); however, there was no significant difference in Hb A1c levels in DM with LBBB and DM without LBBB (9.01% vs 7.81%, P = NS). CONCLUSIONS: Left bundle branch block in diabetic patients indicates advanced cardiovascular involvement manifesting with more severe left ventricular systolic dysfunction and proteinurea compared to both diabetic patients without left bundle branch block and nondiabetic patients with left bundle branch block.

Acute reversible heart failure with highly active antiretroviral therapy.

Highly active antiretroviral therapy is effective in the management of AIDS. It has improved the prognosis of human immunodeficiency virus (HIV) infection. However, with increased survival, adverse effects from medications used in HIV treatment have become more apparent. Cardiac complications from HIV infection include arrhythmias, heart failure, and coronary artery disease. Heart failure in HIV disease may be related to the virus itself or to noninfectious reasons. The association of HIV medications with heart failure is controversial as patients with HIV disease often have multiple risk factors for developing heart failure. We present a case of acute onset heart failure in a patient with HIV, coronary artery disease, and hypertension who was recently started on antiretroviral therapy. There was complete resolution of heart failure after cessation of HIV medications. This case highlights the need to consider HIV medications as a cause of deterioration in cardiac function, even in the presence of other well-established risk factors for heart failure.