[Bacillus Calmette-Guérin (BCG) and alternatives : Drug treatment of high-risk non-muscle invasive bladder cancer]. / Bacillus Calmette-Guérin (BCG) und Alternativen : Medikamentöse Therapie des "high-risk" nicht-muskelinvasiven Blasenkarzinoms.

BACKGROUND: Intravesical instillation of bacillus Calmette-Guérin (BCG) is an accepted strategy to reduce the risk of recurrence and possibly progression of high-risk non-muscle invasive bladder cancer (NMIBC). However, side effects are not uncommon. In addition, the tumors may be BCG refractory or unresponsive. These tumors have a very high risk of recurrence and progression, so cystectomy must be weighed against conservative treatment options. OBJECTIVES: We describe the current recommendations regarding treatment of NMIBC with BCG and alternatives for BCG failure. METHODS: Literature search on current treatment options and their alternatives with the help of mainly primary literature and guideline recommendations. RESULTS AND CONCLUSION: For high-risk NMIBC, instillation therapy with BCG remains standard-of-care, applied according to a standard regimen in terms of dose and dosing intervals (induction: weekly instillation for 6 weeks, maintenance: weekly instillation for 3 weeks, 3, 6 and 12 months after initiation of BCG therapy plus, for high-risk NMIBC, 18, 24, 30 and 36 months after initiation of BCG therapy). Potential future treatment options for BCG failure are systemic (i.v.) pembrolizumab (FDA approved) and, possibly, intravesical nadofaragene firadenovec. Ongoing randomized clinical trials are furthermore evaluating the role of PD-(L)1 immune checkpoint inhibitors in combination with BCG.

[Risk-adapted therapy for metastatic renal cell carcinoma]. / Risikoadaptierte Therapie des metastasierten Nierenzellkarzinoms.

Current pivotal phase 3 studies have permanently changed the first-line treatment landscape in metastatic renal cell carcinoma. These studies showed that immune checkpoint combinations were more efficacious than sunitinib, a previous standard of care. Nivolumab plus ipilimumab is characterized by a survival advantage, a high rate of complete response and durable remission in patients with intermediate and unfavorable prognosis. Despite frequent immune-mediated side effects, fewer symptoms and a better quality of life were observed compared to sunitinib. Pembrolizumab or avelumab plus axitinib were characterized by an improved PFS and a high response rate with a low rate of intrinsic resistance. In addition, a significant survival benefit was achieved with pembrolizumab plus axitinib. The side effect profile is driven by the "chronic" toxicity of axitinib, but there is additional risk of immune-mediated side effects of the PD-1/PD-L1 immune checkpoint inhibitors. The quality-of-life data published so far do not suggest any improvement compared to the previous standard sunitinib. The PD-1/PD-L1 immune-check-point inhibitors thus form the "backbone" of the first-line therapy of metastatic renal cell carcinoma. Monotherapy with VEGFR-TKI remains an option in cases with contraindications and possibly for subgroups with favorable prognosis.

Burrowing is a sensitive behavioural assay for monitoring general wellbeing during dextran sulfate sodium colitis in laboratory mice.

An impaired intestinal epithelial barrier is thought to be a major factor in the pathogenesis of human inflammatory bowel disease (IBD). IBD is frequently investigated by inducing a damaged barrier in murine models of colitis. This can be done by feeding mice with dextran sulfate sodium (DSS) polymers in their drinking water. Refinement measures should focus on alleviating unnecessary suffering during this probably painful condition. Appropriate parameters are needed to decide when to terminate the experiments. Our aim was to investigate whether a change in burrowing behaviour is a sensitive measure of animal welfare in murine models of colitis. Acute colitis was induced in C57BL/6 mice with 2.0% DSS over nine days. The burrowing test is based on the species-typical behaviour of mice to spontaneously displace items from tubes within their home cage. As a burrowing apparatus, a water bottle (250 mL, 150 mm length, 55 mm diameter) filled with 138-142 g of pellets of the animal's diet was used. The presence of intestinal inflammation as a result of acute DSS-induced colitis was confirmed by a decrease in body weight, colon length and an increase of murine endoscopic index of colitis severity, histological score and spleen weight in the group receiving DSS as compared with the control group. An onset of intestinal inflammation correlated with a significant decrease in burrowing behaviour (P < 0.05). Altered adrenal gland histology indicated stress as a result of acute colitis. Our findings provide evidence that changes of spontaneous burrowing behaviour correlate with the onset of inflammation in acute DSS-induced colitis.

Impaired removal of Vß8(+) lymphocytes aggravates colitis in mice deficient for B cell lymphoma-2-interacting mediator of cell death (Bim).

We investigated the role of B cell lymphoma (BCL)-2-interacting mediator of cell death (Bim) for lymphocyte homeostasis in intestinal mucosa. Lymphocytes lacking Bim are refractory to apoptosis. Chronic colitis was induced in Bim-deficient mice (Bim(-/-) ) with dextran sulphate sodium (DSS). Weight loss and colonoscopic score were increased significantly in Bim(-/-) mice compared to wild-type mice. As Bim is induced for the killing of autoreactive cells we determined the role of Bim in the regulation of lymphocyte survival at mucosal sites. Upon chronic dextran sulphate sodium (DSS)-induced colitis, Bim(-/-) animals exhibited an increased infiltrate of lymphocytes into the mucosa compared to wild-type mice. The number of autoreactive T cell receptor (TCR) Vß8(+) lymphocytes was significantly higher in Bim(-/-) mice compared to wild-type controls. Impaired removal of autoreactive lymphocytes in Bim(-/-) mice upon chronic DSS-induced colitis may therefore contribute to aggravated mucosal inflammation.