Low-grade primary splenic CD10-positive small B-cell lymphoma/follicular lymphoma

Primary splenic lymphoma (PSL) is a rare malignancy representing about 1% of all lymphoproliferative disorders, when using a strict definition that allows only involvement of spleen and hilar lymph nodes. In contrast, secondary low-grade B-cell lymphomas in the spleen, such as follicular lymphomas (FL), lymphoplasmacytic lymphoma and chronic lymphocytic leukemia/ small lymphocytic lymphoma, particularly as part of advanced stage disease, are more common. Indolent B cell lymphomas expressing CD10 almost always represent FL, which in its primary splenic form is the focus of this review. Primary splenic follicular lymphoma (PSFL) is exceedingly infrequent. This type of lymphoproliferative disorder is understudied and, in most cases, clinically characterized by splenomegaly or cytopenias related to hypersplenism. The diagnosis requires correlation of histopathology of spleen, blood and/or bone marrow with the correct immunophenotype (determined by flow cytometry and/or immunohistochemistry) and if necessary, additional molecular profiling. Management of this incurable disease is evolving, and splenectomy remains the mainstream treatment for stage I PSFL

Platelet Count Increase Seen with Ledipasvir-Sofosbuvir Combination Treatment of Chronic Hepatitis C in Patients with Thrombocytopenia

Background: Thrombocytopenia (TCP) is commonly seen in chronic Hepatitis C (HCV). Ledipasvir-sofosbuvir (LDV/SOF) is a novel, fixed-dose anti-HCV combination that has shown high sustained virologic response (SVR) rates. However, since much remains to be learned about the natural history of TCP following LDV/SOF treatment, we set out to examine platelet (PLT) counts in thrombocytopenic patients with chronic HCV before, during, and after treatment with LDV/SOF. Methods: This is an IRB-approved, retrospective study of patients diagnosed with chronic HCV who received LDV/SOF between November 2014 and April 2016 at the Washington DC Veterans Affairs Medical Center. Patients who had PLT counts less than or equal to 150 x 109/L for at least 6 months prior to treatment and completed therapy with LDV/SOF were included. Patients diagnosed with heparin-induced TCP; disseminated intravascular coagulation; medication-induced TCP; sepsis; as well as those who received PLT transfusion or thrombopoietic agents were excluded. PLT counts were collected at baseline (within 6 months prior to the start of therapy), during treatment, and throughout the follow-up period until the last follow-up, initiation of a new HCV medication, liver transplant, or death. Patients were categorized into 3 groups: mild TCP (100-150 x 109/L), moderate (50-99 x 109/L), and severe (\u3c50 x 109/L). Paired t-test was used to compare pre-treatment, on-treatment (week 4), and the last measured PLT counts. Multivariate regression analysis was used to determine the baseline variables associated with improvement in PLT counts. All registered PLT counts from the start of therapy were included in repeated measurement analyses to assess the evolution of PLTs over time. Results: Inclusion criteria were met in 244 patients (median age 64, 98% male, 88.9% African American). HCV genotypes were 1a (77.4%) and 1b (22.6%). The median follow-up from treatment start was 13 months. Treatment duration was 8 weeks (13.9%), 12 weeks (69.7%), or 24 weeks (16.4%), all at the fixed dose of LDV 90 mg and SOF 400 mg once daily. SVR at 12 weeks (SVR12) was attained in 159 patients (65.2%) while 67 patients (27.5%) had a documented undetectable viral load earlier than 12 weeks from treatment completion with no further testing. Eight patients (3.3%) failed treatment and 10 (4.1%) were lost-to-follow-up. The mean pre-treatment PLT count was 114 x 109/L (22-150). The on-treatment and last measured PLT counts were significantly higher than the baseline PLT count (129 x 109/L, p\u3c0.001 and 144 x 109/L, p\u3c0.001 respectively). The increase from the on-treatment to the last measured PLT count was also statistically significant (p=0.008). The last measured PLT counts were on average 32.8 ± 66.7% higher than the baseline and 31.6% of patients had normal last measured PLT counts. The increase in PLT count was observed for all three TCP groups: mild (73.4%): from 129 x 109/L at baseline to 149 x 109/L during treatment (p\u3c0.001) to 160 x 109/L after (p=0.045); moderate (24.2%): from 75 x 109/L before to 89 x 109/L during (p=0.004) to 112 x 109/L after (p=0.027); severe (2.5%): from 38 x 109/L before to 64 x 109/L during (p=0.003) to 97 x 109/L after (p=0.234). Multivariate regression analysis was performed including the following variables: age; gender; HCV genotype; baseline PLT count, albumin, bilirubin, and AST/ALT; history of severe alcohol abuse; HIV coinfection; Hepatitis B coinfection; presence of splenomegaly; presence of cirrhosis; treatment duration and reaching SVR12. It showed that reaching SVR12 is associated with a faster increase in PLT count (p=0.022). Repeated measurement analyses showed a gradual and linear increase in PLT counts from the start of therapy for the entire cohort (p\u3c0.001) as well as in every TCP group: mild (p\u3c0.001), moderate (p=0.001) and severe (p=0.015). Conclusion: LDV/SOF is associated with an increase in PLT counts in chronic HCV patients with TCP. This desired effect becomes apparent even before the conclusion of therapy. It is thus tempting to correlate the increase in PLT count with LDV/SOF-associated quick eradication of HCV soon after treatment initiation. Whether that is due to elimination of HCV-associated bone marrow suppression and autoimmune TCP or other not yet known mechanisms, these results are tantalizing but would require longer follow-up. Larger prospective studies are needed to ascertain these results and uncover potential mechanisms

How to Diagnose and Treat CD5-Positive Lymphomas Involving the Spleen

Patients with CD5-expressing lymphomas presenting with splenomegaly are frequently diagnosed with chronic lymphocytic leukemia. The most important differential diagnosis is mantle cell lymphoma, both in its classical and leukemic, non-nodal forms, given its prognostic and therapeutic implications. Other small B-cell neoplasms that frequently involve the spleen and occasionally express CD5 include the splenic marginal zone lymphoma, hairy cell leukemia and, rarely, lymphoplasmacytic lymphoma. The frequency of CD5 positivity depends in part on the sensitivity of the detection methods employed. Usually, a combination of morphological, immunophenotypic and molecular findings allows for a precise sub-classification of CD5-positive, low-grade B-cell lymphomas of the spleen. Some of these tumors may display a mixture of small and larger B cells, raising the possibility of more aggressive lymphomas, such as diffuse large B-cell lymphomas (DLBCL). Approximately 5–10% of DLBCL are CD5-positive and some may manifest as primary splenic lesions. When available, the morphology of DLBCL in the splenic tissue is distinctive and a leukemic picture is very rare. In conclusion, the appropriate morphological and clinical context assisted by flow cytometry panels and/or immunohistochemistry allows the differential diagnosis of CD5-positive, non-Hodgkin, B-cell lymphomas involving the spleen

Non-monotonic Response to Monotonic Stimulus: Regulation of Glyoxylate Shunt Gene-Expression Dynamics in <i>Mycobacterium tuberculosis</i>

<div><p>Understanding how dynamical responses of biological networks are constrained by underlying network topology is one of the fundamental goals of systems biology. Here we employ monotone systems theory to formulate a theorem stating necessary conditions for non-monotonic time-response of a biochemical network to a monotonic stimulus. We apply this theorem to analyze the non-monotonic dynamics of the σ^B-regulated glyoxylate shunt gene expression in <i>Mycobacterium tuberculosis</i> cells exposed to hypoxia. We first demonstrate that the known network structure is inconsistent with observed dynamics. To resolve this inconsistency we employ the formulated theorem, modeling simulations and optimization along with follow-up dynamic experimental measurements. We show a requirement for post-translational modulation of σ^B activity in order to reconcile the network dynamics with its topology. The results of this analysis make testable experimental predictions and demonstrate wider applicability of the developed methodology to a wide class of biological systems.</p></div

Gene expression measurements for <i>ideR</i>.

<p>In a well-characterized interaction, σ^B acts as the sole transcriptional regulator of <i>ideR</i>. mRNA of <i>ideR</i> exhibits a non-monotonic response similar to that of <i>lrpI</i>, suggesting that the non-monotonic dynamics are a result of a post-translational regulation of σ^B activity. (*p≤0.05).</p

Gene expression measurements reveal a negative regulation of <i>icl1</i> through <i>clgR</i>.

<p>(A,B) Expression measurements for <i>icl1</i>, <i>lrpI</i> and the accessory sigma factor <i>sigB</i> mRNA for wild-type (A) and <i>clgR</i> knockout strain (B). (C,D) To simplify the model, the dynamics of <i>sigB</i> and <i>clgR</i> under hypoxia were interpolated for wild-type (C) and for <i>clgR</i> knockout strain (D) with a generalized pulse function and served as inputs into the model (See <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004741#sec010" target="_blank">Methods</a> for details). (*p≤0.05).</p