HDAC6 inhibition upregulates CD20 levels and increases the efficacy of anti-CD20 monoclonal antibodies.

Downregulation of CD20, a molecular target for monoclonal antibodies (mAbs), is a clinical problem leading to decreased efficacy of anti-CD20-based therapeutic regimens. The epigenetic modulation of CD20 coding gene (MS4A1) has been proposed as a mechanism for the reduced therapeutic efficacy of anti-CD20 antibodies and confirmed with nonselective histone deacetylase inhibitors (HDACis). Because the use of pan-HDACis is associated with substantial adverse effects, the identification of particular HDAC isoforms involved in CD20 regulation seems to be of paramount importance. In this study, we demonstrate for the first time the role of HDAC6 in the regulation of CD20 levels. We show that inhibition of HDAC6 activity significantly increases CD20 levels in established B-cell tumor cell lines and primary malignant cells. Using pharmacologic and genetic approaches, we confirm that HDAC6 inhibition augments in vitro efficacy of anti-CD20 mAbs and improves survival of mice treated with rituximab. Mechanistically, we demonstrate that HDAC6 influences synthesis of CD20 protein independently of the regulation of MS4A1 transcription. We further demonstrate that translation of CD20 mRNA is significantly enhanced after HDAC6 inhibition, as shown by the increase of CD20 mRNA within the polysomal fraction, indicating a new role of HDAC6 in the posttranscriptional mechanism of CD20 regulation. Collectively, our findings suggest HDAC6 inhibition is a rational therapeutic strategy to be implemented in combination therapies with anti-CD20 monoclonal antibodies and open up novel avenues for the clinical use of HDAC6 inhibitors.

Open partial nephrectomy for entirely intraparenchymal tumors: a matched case-control study of oncologic outcome and complication rate.

PURPOSE: To compare the oncologic and clinical outcomes for open partial nephrectomy (OPN) performed in patients with entirely intraparenchymal tumors versus casematched controls, with exophytic lesions. MATERIAL AND METHODS: Patients having undergone OPN between 2007 and 2012 were investigated. Exclusion criteria included patients with a benign tumor, advanced malignancy, malignancies other than renal cell carcinoma, end-stage renal failure, or 3 or more co-existing chronic diseases. Individuals with tumors that were invisible at the renal surface were identified, and then matched with 2 controls chosen for tumor size, pathology, age, follow-up period, and presence of a solitary kidney. Oncological status, perioperative, and postoperative data were collected and compared between groups. RESULTS: 17 individuals with entirely endophytic RCC tumors and available oncologic status were identified. For five patients, only one suitable control could be identified, bringing the control group number to 29. All tumors were clear cell carcinomas staged at pT1a. Median tumor size was 25mm for endophytic lesions, and 27mm for exophytic masses (P=0.32). The operative period was extended by 20 minutes for intrarenal tumors (P=0.03), with one case of a positive surgical margin in each group (P=0.7). There were no significant differences in perioperative or postoperative complications. Median follow-up was 47 and 43 months for patients with endophytic and exophytic tumors respectively. Disease recurrence was recorded in one patient after endophytic tumor resection, and in four controls (P=0.4). CONCLUSIONS: OPN shows equivalent safety and efficacy for both intrarenal RCC tumors and exophytic tumors of the same size and type.

B-cell receptor signaling in the pathogenesis of lymphoid malignancies.

B-cell receptor (BCR) signaling pathway plays a central role in B-lymphocyte development and initiation of humoral immunity. Recently, BCR signaling pathway has been shown as a major driver in the pathogenesis of B-cell malignancies. As a result, a vast array of BCR-associated kinases has emerged as rational therapeutic targets changing treatment paradigms in B cell malignancies. Based on high efficacy in early-stage clinical trials, there is rapid clinical development of inhibitors targeting BCR signaling pathway. Here, we describe the essential components of BCR signaling, their function in normal and pathogenic signaling and molecular effects of their inhibition in vitro and in vivo.

Pityriasis Alba--Common Disease, Enigmatic Entity: Up-to-Date Review of the Literature.

Pityriasis alba (PA) is a skin disorder that affects children and adolescents. Although it is common worldwide, its incidence is markedly higher in darker skin phototypes. Its characteristic features include an extended, multistage course and spontaneous remissions and recurrences. Preceded by erythematous changes, patches of hypopigmented skin of up to a few centimeters in diameter appear on the upper body. Pruritus may accompany it. Even though its etiology is unknown, possible reported triggering factors include sunlight, beauty treatments, and microorganisms, among others. Calcineurin inhibitors play the most crucial role in PA pharmacotherapy. PA often coexists with atopic dermatitis and is considered one of its milder forms.

FOXO1 promotes resistance of non-Hodgkin lymphomas to anti-CD20-based therapy.

Diminished overall survival rate of non-Hodgkin lymphoma (NHL) patients treated with a combination regimen of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) has been recently linked to recurrent somatic mutations activating FOXO1. Despite of the clinical relevance of this finding, the molecular mechanism driving resistance to R-CHOP therapy remains largely unknown. Herein, we investigated the potential role of FOXO1 in the therapeutic efficacy of rituximab, the only targeted therapy included in the R-CHOP regimen. We found CD20 transcription is negatively regulated by FOXO1 in NHL cell lines and in human lymphoma specimens carrying activating mutations of FOXO1. Furthermore, both the expression of exogenous mutants of FOXO1 and the inhibition of AKT led to FOXO1 activation in lymphoma cells, increased binding to MS4A1 promoter and diminished CD20 expression levels. In contrast, a disruption of FOXO1 with CRISPR/Cas9 genome-editing (sgFOXO1) resulted in CD20 upregulation, improved the cytotoxicity induced by rituximab and the survival of mice with sgFOXO1 tumors. Accordingly, pharmacological inhibition of FOXO1 activity in primary samples upregulated surface CD20 levels. Importantly, FOXO1 was required for the downregulation of CD20 levels by the clinically tested inhibitors of BTK, SYK, PI3K and AKT. Taken together, these results indicate for the first time that the AKT-unresponsive mutants of FOXO1 are important determinant of cell response to rituximab-induced cytotoxicity, and suggest that the genetic status of FOXO1 together with its transcriptional activity need further attention while designing anti-CD20 antibodies based regimens for the therapy of pre-selected lymphomas.

Influence of left atrial size on the outcome of pulmonary vein isolation in patients with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most frequent sustained supraventricular tachyarrhythmia. Radiofrequency (RF) ablation is one of the options used to prevent the recurrence of AF. Despite thorough studies, the relation between left atrial (LA) size and the results of RF ablation remains controversial. AIM: To estimate the relation between LA size assessed by echocardiography and the AF recurrence rate after pulmonary vein isolation (PVI). METHODS: Our analysis comprised 175 AF patients subjected to PVI between June 2011 and March 2012. Inclusion criteria comprised: symptomatic AF with no reversible cause, and age < 70, LA < 5.5 cm (anteroposterior). PVI was performed with a 4-mm non-irrigated catheter or irrigated catheter and circular mapping catheter (electroanatomic mapping with LocaLisa or CARTO systems). Recurrence was defined as any atrial tachyarrhythmia episode that lasted more than 30 s after three months of blanking period. Standard echocardiographic post-ablation anteroposterior LA measurements were performed with additional parameters such as systolic and diastolic LA area and volume (on sinus rhythm). RESULTS: The analysis included 198 procedures performed in 175 patients. Median follow-up time was 17 months. Median age was 56 years. After the first procedure, AF recurred in 88 (52.4%) patients. Efficacy after the last procedure was 55.2% (43.5% for persistent AF and 59.7% for paroxysmal AF). No significant relation between any of the LA parameters and the recurrence rate was found. Cox univariate and multivariate analysis revealed only very early AF recurrence as a prognostic factor for AF recurrence in the long term. CONCLUSIONS: In patients with AF, no relation could be observed between the recurrence rate after PVI and the echocardiographic LA measurement parameters.

Inhibitors of SRC kinases impair antitumor activity of anti-CD20 monoclonal antibodies.

Clinical trials with SRC family kinases (SFKs) inhibitors used alone or in a combination with anti-CD20 monoclonal antibodies (mAbs) are currently underway in the treatment of B-cell tumors. However, molecular interactions between these therapeutics have not been studied so far. A transcriptional profiling of tumor cells incubated with SFKs inhibitors revealed strong downregulation of MS4A1 gene encoding CD20 antigen. In a panel of primary and established B-cell tumors we observed that SFKs inhibitors strongly affect CD20 expression at the transcriptional level, leading to inhibition of anti-CD20 mAbs binding and increased resistance of tumor cells to complement-dependent cytotoxicity. Activation of the AKT signaling pathway significantly protected cells from dasatinib-triggered CD20 downregulation. Additionally, SFKs inhibitors suppressed antibody-dependent cell-mediated cytotoxicity by direct inhibition of natural killer cells. Abrogation of antitumor activity of rituximab was also observed in vivo in a mouse model. Noteworthy, the effects of SFKs inhibitors on NK cell function are largely reversible. The results of our studies indicate that development of optimal combinations of novel treatment modalities with anti-CD20 mAbs should be preceded by detailed preclinical evaluation of their effects on target cells.

Open partial nephrectomy for entirely intraparenchymal tumors: a matched case-control study of oncologic outcome and complication rate

ABSTRACT Purpose To compare the oncologic and clinical outcomes for open partial nephrectomy (OPN) performed in patients with entirely intraparenchymal tumors versus case-matched controls, with exophytic lesions. Material and methods Patients having undergone OPN between 2007 and 2012 were investigated. Exclusion criteria included patients with a benign tumor, advanced malignancy, malignancies other than renal cell carcinoma, end-stage renal failure, or 3 or more co-existing chronic diseases. Individuals with tumors that were invisible at the renal surface were identified, and then matched with 2 controls chosen for tumor size, pathology, age, follow-up period, and presence of a solitary kidney. Oncological status, perioperative, and postoperative data were collected and compared between groups. Results 17 individuals with entirely endophytic RCC tumors and available oncologic status were identified. For five patients, only one suitable control could be identified, bringing the control group number to 29. All tumors were clear cell carcinomas staged at pT1a. Median tumor size was 25mm for endophytic lesions, and 27mm for exophytic masses (P=0.32). The operative period was extended by 20 minutes for intrarenal tumors (P=0.03), with one case of a positive surgical margin in each group (P=0.7). There were no significant differences in perioperative or postoperative complications. Median follow-up was 47 and 43 months for patients with endophytic and exophytic tumors respectively. Disease recurrence was recorded in one patient after endophytic tumor resection, and in four controls (P=0.4). Conclusions OPN shows equivalent safety and efficacy for both intrarenal RCC tumors and exophytic tumors of the same size and type.