CD40-mediated lymphotoxin α expression in human B cells is tyrosine kinase dependent

The cytokine lymphotoxin (LT)α is known to play a role in B cell activation. As the engagement of the B cell antigen CD40 is known to lead to B cell proliferation and differentiation, we studied LTα expression in human B cells after CD40 ligation. We demonstrate that anti-CD40 monoclonal antibody (mAb) induces strong LTα mRNA and surface expression in human tonsil B cells. Induction of LTα mRNA and surface expression by CD40 ligation is inhibited by the protein tyrosine kinase (PTK) inhibitors herbimycin and genistein in a dose-dependent manner. The protein kinase C (PKC)-specific inhibitors sphingosine and bisindolylmaleimide caused negligible inhibition of anti-CD40-induced LTα mRNA and surface expression. No inhibition is observed with the protein kinase (PKA) inhibitors H89 and HA1004. Cross-linking of the transmembrane phosphatase CD45 to CD40 by using goat-anti-mouse F(ab')₂ fragments strongly inhibits CD40-mediated LTα expression in human B cells, confirming the role of PTK activation in CD40-mediated induction of LTα expression. Inhibitors of the serine/threonine protein phosphatases PP1 and PP2A, okadaic acid and calyculin induce LTα mRNA expression. In contrast, cyclosporin A, an inhibitor of the serine/threonine phosphatase calcineurin has no effect on anti-CD40-induced LTα expression. These results suggest that induction of LTα expression in B cells following engagement of CD40 involves activation of protein tyrosine kinases.     

Health-related quality of life with tralokinumab in moderate-to-severe atopic dermatitis: A phase 2b randomized study

BackgroundAtopic dermatitis (AD) is associated with a substantial burden on quality of life (QoL).ObjectiveTo evaluate the effects of tralokinumab on health-related QoL in patients with moderate-to-severe AD using patient-reported outcomes.MethodsThis was a phase 2b, randomized, double-blind, placebo-controlled, dose-ranging study in adults with moderate-to-severe AD. The patients received subcutaneous tralokinumab or placebo (1:1:1:1) every 2 weeks for 12 weeks and class 3 topical corticosteroid cream or ointment at least once daily from the run-in to end of follow-up. Patient-reported outcome end points were change from baseline to week 12 in the Dermatology Life Quality Index (dermatology life quality index (DLQI); prespecified secondary objective), the Short Form 36 Health Survey (SF-36) version 2, and sleep interference numeric rating scale score (prespecified exploratory objectives).ResultsA total of 204 patients were randomized to placebo (n = 51) or tralokinumab (45 mg, n = 50; 150 mg, n = 51; 300 mg, n = 52). Tralokinumab 300 mg every 2 weeks improved total Dermatology Life Quality Index vs placebo at week 12 (placebo-adjusted mean change, ?3.51 [95% confidence interval, ?6.00 to ?1.02]). At week 12, both the mental component summary (4.23 [0.98-7.47]) and the physical component summary (4.26 [1.83-6.69]) and all 8 domains of the Short Form 36 Health Survey were improved in patients treated with tralokinumab 300 mg vs placebo. Sleep interference was improved at week 12 with all tralokinumab doses vs placebo.ConclusionTralokinumab improved health-related QoL in patients with moderate-to-severe atopic dermatitis, providing further evidence of the value of targeting interleukin-13 in such patients.Trial RegistrationClinicalTrials.gov identifier: NCT02347176; https://clinicaltrials.gov/ct2/show/NCT02347176.     

Update 2016 – Immuntherapie beim Urothelkarzinom

Advanced urothelial carcinoma of the bladder is an aggressive tumor with a poor prognosis. Besides surgical therapy, classical chemotherapy with platinum compounds is the mainstay of advanced bladder cancer treatment. In recent years, immune modulating therapies have come into the focus of clinical trials. This review provides an overview of the biological mechanisms and immuno-oncological drugs that are currently being analyzed in clinical trials as well as established standard therapies.     

Comparison of bone scintigraphy and <Superscript>68</Superscript>Ga-PSMA PET for skeletal staging in prostate cancer

Purpose

The aim of our study was to compare the diagnostic performance of ⁶⁸Ga-PSMA PET and ^99mTc bone scintigraphy (BS) for the detection of bone metastases in prostate cancer (PC) patients.

Methods

One hundred twenty-six patients who received planar BS and PSMA PET within three months and without change of therapy were extracted from our database. Bone lesions were categorized into benign, metastatic, or equivocal by two experienced observers. A best valuable comparator (BVC) was defined based on BS, PET, additional imaging, and follow-up data. The cohort was further divided into clinical subgroups (primary staging, biochemical recurrence, and metastatic castration-resistant prostate cancer [mCRPC]). Additionally, subgroups of patients with less than 30 days delay between the two imaging procedures and with additional single-photon emission computed tomography (SPECT) were analyzed.

Results

A total of 75 of 126 patients were diagnosed with bone metastases. Sensitivities and specificities regarding overall bone involvement were 98.7–100 % and 88.2–100 % for PET, and 86.7–89.3 % and 60.8–96.1 % (p?<?0.001) for BS, with ranges representing results for ‘optimistic’ or ‘pessimistic’ classification of equivocal lesions. Out of 1115 examined bone regions, 410 showed metastases. Region-based analysis revealed a sensitivity and specificity of 98.8–99.0 % and 98.9–100 % for PET, and 82.4–86.6 % and 91.6–97.9 % (p?<?0.001) for BS, respectively. PSMA PET also performed better in all subgroups, except patient-based analysis in mCRPC.

Conclusion

Ga-PSMA PET outperforms planar BS for the detection of affected bone regions as well as determination of overall bone involvement in PC patients. Our results indicate that BS in patients who have received PSMA PET for staging only rarely offers additional information; however, prospective studies, including a standardized integrated x-ray computed tomography (SPECT/CT) protocol, should be performed in order to confirm the presented results.