Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies.

Despite progress in systemic small interfering RNA (siRNA) delivery to the liver and to solid tumors, systemic siRNA delivery to leukocytes remains challenging. The ability to silence gene expression in leukocytes has great potential for identifying drug targets and for RNAi-based therapy for leukocyte diseases. However, both normal and malignant leukocytes are among the most difficult targets for siRNA delivery as they are resistant to conventional transfection reagents and are dispersed in the body. We used mantle cell lymphoma (MCL) as a prototypic blood cancer for validating a novel siRNA delivery strategy. MCL is an aggressive B-cell lymphoma that overexpresses cyclin D1 with relatively poor prognosis. Down-regulation of cyclin D1 using RNA interference (RNAi) is a potential therapeutic approach to this malignancy. Here, we designed lipid-based nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that are specifically taken up by human MCL cells in the bone marrow of xenografted mice. When loaded with siRNAs against cyclin D1, CD38-targeted LNPs induced gene silencing in MCL cells and prolonged survival of tumor-bearing mice with no observed adverse effects. These results highlight the therapeutic potential of cyclin D1 therapy in MCL and present a novel RNAi delivery system that opens new therapeutic opportunities for treating MCL and other B-cell malignancies.

Laparoscopic Lymph Node Biopsy: Efficacy and Advantages.

BACKGROUND: Diagnosis of abdominal lymphadenopathy is challenging when not accompanied by peripheral lymphadenopathy. Computed tomography-guided core-needle biopsy has largely replaced open procedures in recent years, but this approach is limited by access to the anatomic region and the amount of tissue acquired. OBJECTIVES: To demonstrate the feasibility of the laparoscopic approach in obtaining abdominal lymph node biopsies and to evaluate the diagnostic adequacy of the technique. METHODS: We reviewed the data of patients who underwent laparoscopic lymph node biopsy between 2014 and 2014 in our department. Demographics, intra-operative parameters and postoperative course were examined, as were histological reports. Postoperative complications were categorized according to the Clavien-Dindo(CD) classification. RESULTS: Between 2004 and 2014, 57 laparoscopic biopsies were performed for intra-abdominal lymphadenopathy. One case was a repeated attempt due to limited histologic material. The mean age was 49.5 ± 19.6 years. There were two conversions to open laparotomy, one due to small bowel injury and the other due to a sizable mass. Overall, 56 cases had full clinical data: 48 cases (85.7%) had CD=0, six (10.7%) had CD=1, one postoperative severe complication (CD=3) and one mortality (CD=5), which was related to preexisting hepatic insufficiency. Mean hospital stay was 1.6 days. Overall, adequate tissue samples were acquired in 96.7% and only 3 of these cases resulted in inconclusive diagnoses. CONCLUSIONS: Laparoscopic lymph node biopsy is a viable alternative to the currently available methods of tissue retrieval. It provides an access for nodes which are inaccessible percutaneously, and may allow a superior diagnostic yield.

Extrafollicular PD1 and Intrafollicular CD3 Expression Are Associated With Survival in Follicular Lymphoma.

INTRODUCTION: Both microenvironment and tumor biomarkers impact outcome in follicular lymphoma (FL). We aimed to study the effect of Ki-67, CD3, CD68, and PD1 expression on outcome of FL. MATERIALS AND METHODS: Forty-eight patients were included. Stained slides were visually assessed and marker expression was correlated with outcome. Both intra- and extrafollicular expression of Ki-67, CD68, and PD1 were evaluated. CD3 was evaluated only in the intrafollicular area. The median values of expression served as a cutoff point for low- and high-expression groups. RESULTS: High extrafollicular PD1 expression predicted superior FFTF (freedom from treatment failure) compared with low expression (5-year 52% vs. 44%, P = .04). Five-year FFTF markedly increased from 37% to 67% (P = .057) in patients with low intrafollicular CD3 expression. CONCLUSION: Our study supports the hypothesis that survival in FL depends on the immunologic cross talk between malignant cells and microenvironment; however, the specific types of cells that influence the clinical behavior of FL are still unknown.

Fertility status among women treated for aggressive non-Hodgkin's lymphoma.

In young women treated for intermediate-high-grade non-Hodgkin's lymphoma with CHOP (cyclophosphamide, adriamycin, oncovine and prednisone), there is insufficient data concerning gonadotoxicity or the need for fertility-preserving measures. The aim of the present study was to evaluate the fertility status in the first complete remission of women who were treated for aggressive non-Hodgkin's lymphoma. A cohort of 36 women with aggressive non-Hodgkin's lymphoma in first remission, who were treated in five university-affiliated hospitals in Israel, was evaluated. All women were aged younger than 40 years at diagnosis and received frontline protocols, including cyclophosphamide and adriamycin, mostly CHOP. Menstrual cycle characteristics, as well as pregnancies before the diagnosis, during treatment and in first complete remission, were evaluated. The patients' mean age at the diagnosis was 28 +/- 7 years (range 17 - 40 years). All patients were treated with chemotherapy, although 10 patients received additional radiotherapy. Follow-up time at first complete remission was 84 +/- 48 months. Before diagnosis, all patients had menstrual cycles, which were regular in 31 (86%). Three patients received gonadtropin-releasing hormone analogs, whereas nine received contraceptive pills together with cytotoxic treatment. During treatment, 18 patients (50%) had amenorrhea, six (17%) had irregular menstrual cycles, and 12 (33%) continued their regular cycles. All but two women resumed menses in the first complete remission, and these were regular in 22 (61%) patients. In 63% of patients, the menstrual cycle recovered within 3 months of the discontinuation of chemotherapy. Eighteen patients (50%) became pregnant during the first complete remission. There was no significant difference between those patients who received fertility-preserving measures versus the remainder concerning regular menstrual cycles recovery or pregnancies. The two patients who developed amenorrhea were 40 years old at the time of diagnosis. In conclusion, the rate of gonadal dysfunction is very low among young, CHOP treated, non-Hodgkin's lymphoma female patients. Fertility-preserving techniques are not needed for women aged younger than 40 years and should probably be reserved for those who are at high risk for gonadal toxicity.

RNA inhibition highlights cyclin D1 as a potential therapeutic target for mantle cell lymphoma.

Mantle cell lymphoma is characterized by a genetic translocation results in aberrant overexpression of the CCND1 gene, which encodes cyclin D1. This protein functions as a regulator of the cell cycle progression, hence is considered to play an important role in the pathogenesis of the disease. In this study, we used RNA interference strategies to examine whether cyclin D1 might serve as a therapeutic target for mantle cell lymphoma. Knocking down cyclin D1 resulted in significant growth retardation, cell cycle arrest, and most importantly, induction of apoptosis. These results mark cyclin D1 as a target for mantle cell lymphoma and emphasize the therapeutic potential hidden in its silencing.