Combined treatment with crizotinib and temsirolimus is an effective strategy in mantle cell lymphoma and can overcome acquired resistance to temsirolimus.

Constitutive activation of the PI3K/AKT/mTOR-pathway plays an important role in the pathogenesis of mantle cell lymphoma (MCL), leading to approval of the mTOR inhibitor temsirolimus for relapsed or refractory MCL. Yet, despite favorable initial response rates, early relapses under treatment have been observed. Therefore, understanding the underlying mechanisms of temsirolimus resistance and developing strategies to overcome it is highly warranted. Here, we established a new temsirolimus-resistant MCL cell line to evaluate the molecular background of resistance to this drug. Transcriptome profiling and gene set enrichment analysis comparing temsirolimus-sensitive and -resistant cell lines showed significant upregulation of PI3K/AKT/mTor-, RAS signaling- and the RTK-dependent PDGFR-, FGFR-, Met- and ALK-signaling-pathways in the resistant cells. Furthermore, MET, known as important proto-oncogene and mediator of drug resistance, was among the most upregulated genes in the resistant cells. Importantly, Met protein was overexpressed in both, MCL cells with acquired as well as intrinsic temsirolimus resistance, but could not be detected in any of the temsirolimus sensitive ones. Combined pharmacological inhibition of mTOR and Met signaling with temsirolimus and the RTK inhibitor crizotinib significantly restored sensitivity to temsirolimus. Furthermore, this combined treatment proved to be synergistic in all MCL cell lines investigated and was also active in primary MCL cells. In summary, we showed for the first time that overexpression of MET plays an important role for mediating temsirolimus resistance in MCL and combined treatment with temsirolimus and crizotinib is a very promising therapeutic approach for MCL and an effective strategy to overcome temsirolimus resistance.

PARP14 is a novel target in STAT6 mutant follicular lymphoma.

The variable clinical course of follicular lymphoma (FL) is determined by the molecular heterogeneity of tumor cells and complex interactions within the tumor microenvironment (TME). IL-4 producing follicular helper T cells (TFH) are critical components of the FL TME. Binding of IL-4 to IL-4R on FL cells activates JAK/STAT signaling. We identified STAT6 mutations (STAT6MUT) in 13% of FL (N = 33/258), all clustered within the DNA binding domain. Gene expression data and immunohistochemistry showed upregulation of IL-4/STAT6 target genes in STAT6MUT FL, including CCL17, CCL22, and FCER2 (CD23). Functionally, STAT6MUT was gain-of-function by serial replating phenotype in pre-B CFU assays. Expression of STAT6MUT enhanced IL-4 induced FCER2/CD23, CCL17 and CCL22 expression and was associated with nuclear accumulation of pSTAT6. RNA sequencing identified PARP14 -a transcriptional switch and co-activator of STAT6- among the top differentially upregulated genes in IL-4 stimulated STAT6MUT lymphoma cells and in STAT6MUT primary FL cells. Quantitative chromatin immunoprecipitation (qChIP) demonstrated binding of STAT6MUT but not STAT6WT to the PARP14 promotor. Reporter assays showed increased IL-4 induced transactivation activity of STAT6MUT at the PARP14 promotor, suggesting a self-reinforcing regulatory circuit. Knock-down of PARP14 or PARP-inhibition abrogated the STAT6MUT gain-of-function phenotype. Thus, our results identify PARP14 as a novel therapeutic target in STAT6MUT FL.

Clinical clues to identify patients with ocular rosacea - a Germany-wide epidemiologic analysis.

BACKGROUND AND OBJECTIVES: Ocular rosacea is a special manifestation of rosacea with unknown etiology. Eye involvement in rosacea patients is surprisingly common; however, it is often underdiagnosed, resulting in inappropriate treatment. We aimed to provide an updated epidemiologic perspective on ocular rosacea in Germany to improve patient care. PATIENTS AND METHODS: Data of 777 rosacea patients were assessed using a detailed online questionnaire regarding ocular and skin symptoms, previous dermatological and ophthalmological consults, presence of type 1 hypersensitivities, and Demodex testing. All data were statistically analyzed. RESULTS: Most patients reported ocular symptoms (399/777, 51.4%), including red eyes (179/399, 44.9%), itching (187/399, 46.9%), sty or chalazion (309/399, 77.4%), and dryness (108/399, 27.1%). Ocular rosacea was confirmed in 149/309 cases who consulted an ophthalmologist (45.3%). A total of 159/399 (39.8%) had no pre-existing allergies. Eye involvement was significantly associated with the presence of skin symptoms (P < 0.05), impacting patients' general well-being and overall treatment satisfaction. About half of Demodex-positive patients (21/45, 46.7%) showed ocular symptoms. CONCLUSIONS: Eye involvement in rosacea patients was common, often presenting with unspecific symptoms.

A comprehensive epidemiological study of rosacea in Germany.

BACKGROUND: Rosacea is one of the most common skin diseases causing great distress in affected patients. For optimal patient care, epidemiological studies on disease distribution and clinical aspects are essential. OBJECTIVES: The goal of this study was to provide an updated perspective on the current state of rosacea epidemiology in Germany. MATERIALS & METHODS: A cohort of 777 rosacea patients was assessed based on a detailed online questionnaire. Information regarding patients' demographics, course and clinical presentation of rosacea, trigger factors, dermatological consultations, treatment adherence and satisfaction as well as quality of life were obtained. RESULTS: There was a very high self-reported prevalence of primary and secondary rosacea features (flushing: n = 726, 93.4%; papules/pustules: n = 613, 79.0%; telangiectasia: n = 590, 75.9%; sub jective symptoms: n = 691, 88.9%). However, these clinical findings were often underdiagnosed by the treating physicians, while changes in temperature and ultraviolet radiation were potent triggers across all patients (86.3%, 77.7%, respectively). Disease-related quality of life decreased with the number of drugs prescribed as well as with uncontrolled symptom activity, and was reduced in female patients. CONCLUSION: This study is the largest German-based assessment exclusively focusing on rosacea patients covering a variety of clinical aspects to optimize patient care.

Cathepsin S Alterations Induce a Tumor-Promoting Immune Microenvironment in Follicular Lymphoma.

Tumor cells orchestrate their microenvironment. Here, we provide biochemical, structural, functional, and clinical evidence that Cathepsin S (CTSS) alterations induce a tumor-promoting immune microenvironment in follicular lymphoma (FL). We found CTSS mutations at Y132 in 6% of FL (19/305). Another 13% (37/286) had CTSS amplification, which was associated with higher CTSS expression. CTSS Y132 mutations lead to accelerated autocatalytic conversion from an enzymatically inactive profrom to active CTSS and increased substrate cleavage, including CD74, which regulates major histocompatibility complex class II (MHC class II)-restricted antigen presentation. Lymphoma cells with hyperactive CTSS more efficiently activated antigen-specific CD4+ T cells in vitro. Tumors with hyperactive CTSS showed increased CD4+ T cell infiltration and proinflammatory cytokine perturbation in a mouse model and in human FLs. In mice, this CTSS-induced immune microenvironment promoted tumor growth. Clinically, patients with CTSS-hyperactive FL had better treatment outcomes with standard immunochemotherapies, indicating that these immunosuppressive regimens target both the lymphoma cells and the tumor-promoting immune microenvironment.

Diode lasers for the treatment of genital warts.

Human papillomavirus (HPV) infections are the most common sexually transmitted diseases leading to genital warts. Developing lesions start off as small papules, which then grow larger and protrude, eventually coalescing into plaque-like formations. The aim of this study was to evaluate the efficacy of diode laser coagulation as a treatment for genital warts relative to their number, size, localisation, and recurrence rate. Altogether, 45 patients were evaluated in this study. Patients were initially assigned to one of two groups, depending on the size and number of their genital warts, and received a maximum of two laser treatments. Patients were assessed up to three months after intervention. A cure was defined as the complete removal of condylomata. In Group I, 84% of the patients (21/25) were free of recurrence after three months (last follow-up visit). In Group II, 60% of the patients were free of recurrence after three months (12/20 patients); 25% after the first and 35% after the second treatment. Overall, a cure rate of 73% was achieved (33/45 patients). By splitting the laser treatment for multiple, extensive, and/or coalescing genital warts into two sessions, thereby being less destructive to the surrounding tissue, it was possible to achieve comparable cure rates between the two groups. This study indicates that laser treatment is an effective therapy option. Further studies including larger patient cohorts are necessary to ultimately confirm the advantages of laser treatment.