Purpose Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. Patients and Methods Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). Results Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). Conclusion To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients.

A tight junction (TJ) protein, claudin-1 (CLDN1), was identified recently as a key factor for hepatitis C virus (HCV) entry. Here, we show that another TJ protein, occludin, is also required for HCV entry. Mutational study of CLDN1 revealed that its tight junctional distribution plays an important role in mediating viral entry. Together, these data support the model in which HCV enters liver cells from the TJ. Interestingly, HCV infection of Huh-7 hepatoma cells downregulated the expression of CLDN1 and occludin, preventing superinfection. The altered TJ protein expression may contribute to the morphological and functional changes observed in HCV-infected hepatocytes.Recently, considerable progress has been made in elucidating the molecular mechanisms by which hepatitis C virus (HCV) infects human liver cells. The current accepted model of HCV infection is that virus particles associated with lipoproteins, found circulating in the bloodstream, use glycosaminoglycans and/or the LDL receptor on host cells as initial attachment factors. After binding, the HCV particle interacts with SR-BI and CD81 and is subsequently relocalized to the tight junction (TJ) protein claudin-1 (CLDN1) (6). Next, the HCV particle becomes internalized via clathrin-mediated endocytosis, followed by viral fusion, which likely occurs in early endosomes. Some critical information, however, is missing in such a model with regard to the role of CLDN1. (i) The interaction between CLDN1 and incoming HCV virions has yet to be verified experimentally; (ii) the precise site of viral entry needs to be determined given that CLDN1 predominantly localizes to TJs in polarized cells; and (iii) the potential involvement of other TJ proteins in HCV entry remains untested. We have shown previously that the TJ-like CLDN1 distribution correlates with cellular permissiveness to HCV infection (19). In the current study, we intend to define the importance of junctional CLDN1 and other TJ proteins in HCV entry.TJ protein OCLN is required for HCV entry. As hepatocytes are highly polarized in vivo, we first sought to investigate whether HCV entry mimics the major group B coxsackievirus (CVB) entry, in which CVB enters polarized epithelial cells through TJs by a complex mechanism requiring attachment to occludin (OCLN) and the induction of caveolar endocytosis (3). To this end, we utilized synthetic interference RNA (siRNA) or packaged retroviruses to deliver short-hairpinbased RNA (shRNA) to knock down the expression of TJ proteins CLDN1, OCLN, ZO-1, JAM-1, and CAR (CVB receptor) to examine the roles of each of the proteins during HCV infection. Targeted sequences of the siRNAs and shRNAs are presented in the supplemental material. As shown in Fig. 1A and B, depletion of OCLN affected neither the expression level nor the localization of CLDN1; however, depletion of ZO-1 by siRNA modestly reduced the CLDN1 level (Fig. 1A). We then performed the infection assay according to a previously established procedure (19). Reduction of CLDN1, OCLN, and ZO-1 expression inhibi...

Purpose In contrast to Hodgkin lymphoma and systemic anaplastic large-cell lymphoma, CD30 expression of malignant lymphocytes in mycosis fungoides (MF) and Sézary syndrome (SS) is quite variable. Clinical activity and safety of brentuximab vedotin, a CD30 targeting antibody-drug conjugate, was evaluated in MF and SS. Tissue and blood biomarkers of clinical response were explored. Patients and Methods In this phase II study, patients with MF or SS with negligible to 100% CD30 expression levels were treated with brentuximab vedotin (1.8 mg/kg) every 3 weeks for a maximum of sixteen doses. The primary end point was overall global response rate. Secondary end points included correlation of tissue CD30 expression level with clinical response, time to response, duration of response, progression-free and event-free survivals, and safety. Results Of the 32 patients enrolled and treated, 30 patients had available efficacy evaluations. Objective global response was observed in 21 (70%) of 30 patients (90% CI, 53% to 83%). CD30 expression assessed by immunohistochemistry was highly variable, with a median CD30max of 13% (range, 0% to 100%). Those with <5% CD30 expression had a lower likelihood of global response than did those with 5% or greater CD30 expression (P < .005). CD163 positive tumor-associated macrophages, many of which coexpress CD30, were abundant in tissue. Peripheral neuropathy was the most common adverse event. Conclusion Brentuximab vedotin demonstrated significant clinical activity in treatment-refractory or advanced MF or SS with a wide range of CD30 expression levels. Additional biomarker studies may help optimize rational design of combination therapies with brentuximab vedotin.