No abstract

BACKGROUND: Before hospital discharge, newborn infants should be assessed for the risk of excessive hyperbilirubinemia. We determined maternal and obstetric risk factors for hyperbilirubinemia in infants born at term (gestational age $37 weeks) to form an individualized risk assessment tool for clinical use.

In 2009, vinflunine was introduced as a second-line treatment to be used after the failure of platinum therapy in patients with metastatic urothelial carcinoma (mUC). The present study investigated the administered vinflunine to patients with mUC in standard clinical practice with the aim of evaluating treatment patterns, response, survival parameters and side-effects. Data were collected retrospectively from the first 100 mUC patients treated with vinflunine at three Nordic cancer centers associated with the Nordic Urothelial Cancer Oncology Group. The overall response rate was 23% and complete response was observed in one patient. The median progression-free survival (mPFS) and median overall survival (mOS) were 2.8 (range, 0.5–34.3) and 6.3 (range, 0.3–39.7) months, respectively. An Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 was present in 20% of the patients, and those patients exhibited significantly shorter mOS (4.1 vs. 7.0 months, P=0.001) and a significantly higher degree of grade 3/4 toxicity (P=0.026) compared with ECOG PS 0–1 patients. Furthermore, patients without visceral metastases had significantly longer mOS than patients with visceral metastases (10.6 vs. 6.0 months, P=0.008). The median number of cycles of vinflunine was 3 (range, 1–28). The current data confirms that vinflunine is an active agent for second-line treatment in an unselected clinical cohort of patients with mUC. ECOG PS and presence of visceral metastases were significant prognostic parameters. In particular, patients with ECOG PS 2 receiving vinflunine had a shorter mOS and a higher frequency of severe toxicity, and, thus, should be treated with caution. Furthermore, the present study observed large inter-individual differences in radiological response and OS, indicating the need for further development of improved patient selection tools to optimize vinflunine treatment in platinum-refractory mUC patients.

Background: Chemotherapy options in advanced urothelial carcinoma (UC) remain limited. Here we evaluated the peptide‐based alkylating agent melphalan‐flufenamide (mel‐flufen) for UC. Methods: UC cell lines J82, RT4, TCCsup and 5637 were treated with mel‐flufen, alone or combined with cisplatin, gemcitabine, dasatinib or bestatin. Cell viability (MTT assay), intracellular drug accumulation (liquid chromatography) apoptosis induction (apoptotic cell nuclei morphology, western blot analysis of PARP‐1/caspase‐9 cleavage and Bak/Bax activation) were evaluated. Kinome alterations were characterized by PathScan array and phospho‐Src validated by western blotting. Aminopeptidase N (ANPEP) expression was evaluated in UC clinical specimens in relation to patient outcome. Results: In J82, RT4, TCCsup and 5637 UC cells, mel‐flufen amplified the intracellular loading of melphalan in part via aminopeptidase N (ANPEP), resulting in increased cytotoxicity compared to melphalan alone. Mel‐flufen induced apoptosis seen as activation of Bak/Bax, cleavage of caspase‐9/PARP‐1 and induction of apoptotic cell nuclei morphology. Combining mel‐flufen with cisplatin or gemcitabine in J82 cells resulted in additive cytotoxic effects and for gemcitabine also increased apoptosis induction. Profiling of mel‐flufen‐induced kinome alterations in J82 cells revealed that mel‐flufen alone did not inhibit Src phosphorylation. Accordingly, the Src inhibitor dasatinib sensitized for mel‐flufen cytotoxicity. Immunohistochemical analysis of the putative mel‐flufen biomarker ANPEP demonstrated prominent expression levels in tumours from 82 of 83 cystectomy patients. Significantly longer median overall survival was found in patients with high ANPEP expression (P = 0.02). Conclusion: Mel‐flufen alone or in combination with cisplatin, gemcitabine or Src inhibition holds promise as a novel treatment for UC.