[Tumor assessment in immune checkpoint inhibitor therapy : Tumor response, progression and pseudoprogression]. / Tumorassessment bei Immun-Checkpoint-Inhibitor-Therapie : Tumoransprechen, Progression und Pseudoprogression.

In contrast to chemotherapy, treatment with immune checkpoint inhibitors occasionally results in an unconventional pattern of response. Besides an early partial or complete response or tumor progression, a so-called pseudoprogression, a "mixed response" or late responses can also be observed. Treatment beyond radiographically defined progression may therefore be appropriate in selected cases. For these treatment decisions, the clinical evaluation of the patient (performance status, symptoms, etc.), the "dynamics" of the underlying malignancy, and the availability of other treatment options are of paramount importance. However, the time to initiate another treatment should not be missed by rapid progression. In PD-1 (programmed cell death protein 1) immune checkpoint inhibition in urothelial cancer after platinum-based chemotherapy, response or progression can be observed early at week 8 in the vast majority of the cases. In contrast, in second-line treatment of renal cell carcinoma around 25% of responses are seen late, at week 24 or later (occasionally after 1 year). Therefore, immune checkpoint inhibition should be continued for stable disease. At present, it remains unclear how long to continue therapy in cases with partial or complete remission.

[Treatment with PD-1/PD-L1 and CTLA-4 immune checkpoint inhibitors : Immune-mediated side effects]. / Therapie mit PD-1/PD-L1- und CTLA-4-Immun-Checkpoint-Inhibitoren : Immunvermittelte Nebenwirkungen.

Immune checkpoint inhibitors are a new standard therapy for advanced or metastatic urothelial as well as renal cell carcinoma. Atezolizumab and Pembrolizumab have been approved for the treatment of cisplatin-ineligible patients with transitional call cancer in the 1st line setting; both antibodies and Nivolumab may also be used after platinum based prior therapy. Regarding renal cell carcinoma approval for 1st line treatment with the combination of Nivolumab and Ipilimumab for patients at intermediate or high risk (IMDC) is currently expected. Furthermore, Nivolumab is approved for renal cell carcinoma after prior therapy. With the widespread use of immune checkpoint inhibitors understanding immune related adverse events gets paramount importance. In particular, combination therapy of Nivolumab and Ipilimumab is not only characterized by improving efficacy but also by a higher rate of adverse events. Most frequently rash and pruitus, endocrine events, colitis/diarrhea, hepatitis and pneumonia are observed. However, any organ system may be affected by immune related adverse events. Differential diagnosis between immune related or other (e. g. infectious) causes of organ dysfunction may be difficult. Early diagnosis and initiation of therapy is important to avoid deleterious outcomes. The use of corticosteroids generally leads to rapid resolution of symptoms; further immunosuppressive agents (MMF, infliximab) are rarely needed. Regarding endocrine adverse events permanent hormonal replacement of hormones is frequently needed. In particular in consequence of pneumonitis fatal outcomes have been observed.

[Adverse events of immune checkpoint inhibitors]. / Nebenwirkungen der Immun-Checkpoint-Inhibitoren.

After immune checkpoint inhibitor therapy was approved for renal cell carcinoma last year, this new immune therapy has spread to urology. Further approvals (atezolizumab, nivolumab, pembrolizumab) are expected in 2017 for metastatic urothelial carcinoma that has progressed following treatment with platinum-based chemotherapy. With expanding use of immune checkpoint inhibitors, experience in diagnosing and managing immune-mediated adverse events increases. Although of low incidence, grade 3/4 toxicities play a central role. Organs most common for immune-mediated adverse events are skin, liver (hepatitis), kidneys (nephritis), gastrointestinal tract (diarrhea and colitis), lungs (pneumonitis), and endocrine organs (hyper-, hypothyroidism and hypophysitis). Diagnostic workup includes routine laboratory tests (including liver function tests) and may be supplemented with hormone values. In cases of pneumonitis or hypophysitis, imaging (high-resolution CT, MRI) can confirm diagnoses. Immune-mediated toxicities are treated with therapy interruption and administration of corticosteroids (and in individual cases additional immunosuppression). Dose modification is not intended!

[Therapy monitoring and management of adverse events in PD-1/PD-L1 immune checkpoint inhibition]. / Therapiemonitoring und Nebenwirkungsmanagement bei PD-1/PD-L1-Immuncheckpoint-Inhibition.

Nivolumab was recently approved as the first inhibitor of the programmed death 1 (PD-1) receptor and its ligand (PD-L1) for the treatment of urological cancer, namely metastasized renal cell carcinoma after prior therapy. The use of this new immunotherapy requires special therapy monitoring and management of side effects. An increase of immune cells around the tumor can initially mimic progression (so-called pseudoprogression). Treatment-associated side effects of higher grade according to the common terminology criteria for adverse events (CTCAE grades 3 or 4) are relatively rare; however, new immune-mediated side effects can occur and affect the skin, liver (hepatitis), kidneys (nephritis), gastrointestinal tract (diarrhea and colitis), lungs (pneumonitis) and endocrine organs (hyperthyroidism, hypothyroidism and hypophysitis). Treatment has to be delayed or discontinued depending on the kind and degree of side effects; furthermore, corticosteroids can be administered as immunosuppressants. When recognized in time and with correct management, immune-mediated side effects are basically reversible.

[Renaissance of immuno-oncology for urological tumors : Current status]. / Renaissance der Immunonkologie bei urologischen Tumoren : Eine Bestandsaufnahme.

With the advent of immune checkpoint inhibitors, immunotherapy has gained new importance in oncology. Current research is focused on the cytotoxic T­lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) immune checkpoints. The CTLA4 antibody ipilimumab (melanoma) as well as the PD-1 antibodies nivolumab (melanoma, non-small cell lung cancer and renal cell carcinoma) and pembrolizumab (melanoma) are approved for the treatment of metastatic disease in Europe. Immune checkpoint inhibitors (re)activate the immune system against cancer cells and appear to be more effective than current standards for many tumors. The toxicity profile is favorable but involves new so-called immune-related side effects, which need to be recognized and treated in time. Immune checkpoint inhibitors are also currently being tested in uro-oncology in phase 3 trials relevant for approval status. Based on this it is to be expected that immune checkpoint inhibitors will become a new standard (as monotherapy or as part of combination therapy) in the early lines of therapy in the near future and replace the previous standard therapies, particularly for metastasized renal cell carcinoma and urothelial cancer.

Placental Schistosoma haematobium infection in a German returnee from Malawi.

Schistosomiasis is a widespread helminthic infection which sometimes may affect travelers to endemic areas. We report on a case of urogenital and placental schistosomiasis in a 28-year-old German woman who had been exposed to schistosomiasis in Lake Malawi one year earlier. She experienced painless macrohaematuria in her 21st week of pregnancy. Cystoscopy revealed vesical lesions typical for urogenital schistosomiasis. Histopathology confirmed ova of Schistosoma (S.) haematobium. The patient was treated with praziquantel 40 mg/kg/body weight/day for 3 days. After 285 days of gestation and 18 weeks post treatment, the patient delivered a healthy girl. Histopathology of placenta revealed eggs of S. haematobium in placental stroma. The infant proved negative for anti-Schistosoma spp. antibodies at the age of 15 months. This is the first report on placental schistosomiasis since 1980 and the first case occurring in a traveler.