Clinical and Experimental Projects on Chemotherapy of Bladder Tumours

Our clinical and experimental experience with chemotherapy of bladder tumours is reviewed. The routes of drug administrations, drug dosages and combinations, are presented. Adjuvant radiotherapy and chemoprophylaxis of certain tumours are discussed.S. Afr. Med. J., 48, 631 (1974

An update of the Worldwide Integrated Assessment (WIA) on systemic insecticides. Part 2: impacts on organisms and ecosystems

New information on the lethal and sublethal effects of neonicotinoids and fipronil on organisms is presented in this review, complementing the previous WIA in 2015. The high toxicity of these systemic insecticides to invertebrates has been confirmed and expanded to include more species and compounds. Most of the recent research has focused on bees and the sublethal and ecological impacts these insecticides have on pollinators. Toxic effects on other invertebrate taxa also covered predatory and parasitoid natural enemies and aquatic arthropods. Little, while not much new information has been gathered on soil organisms. The impact on marine coastal ecosystems is still largely uncharted. The chronic lethality of neonicotinoids to insects and crustaceans, and the strengthened evidence that these chemicals also impair the immune system and reproduction, highlights the dangers of this particular insecticidal classneonicotinoids and fipronil. , withContinued large scale – mostly prophylactic – use of these persistent organochlorine pesticides has the potential to greatly decreasecompletely eliminate populations of arthropods in both terrestrial and aquatic environments. Sublethal effects on fish, reptiles, frogs, birds and mammals are also reported, showing a better understanding of the mechanisms of toxicity of these insecticides in vertebrates, and their deleterious impacts on growth, reproduction and neurobehaviour of most of the species tested. This review concludes with a summary of impacts on the ecosystem services and functioning, particularly on pollination, soil biota and aquatic invertebrate communities, thus reinforcing the previous WIA conclusions (van der Sluijs et al. 2015)

CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer

Background: A phase I/II study and subsequent phase III study (MPACT) reported significant correlations between CA19-9 decreases and prolonged overall survival (OS) with nab-paclitaxel plus gemcitabine (nab-P + Gem) treatment for metastatic pancreatic cancer (MPC). CA19-9 changes at week 8 and potential associations with efficacy were investigated as part of an exploratory analysis in the MPACT trial. Patients and methods: Untreated patients with MPC (N = 861) received nab-P + Gem or Gem alone. CA19-9 was evaluated at baseline and every 8 weeks. Results: Patients with baseline and week-8 CA19-9 measurements were analyzed (nab-P + Gem: 252; Gem: 202). In an analysis pooling the treatments, patients with any CA19-9 decline (80%) versus those without (20%) had improved OS (median 11.1 versus 8.0 months; P = 0.005). In the nab-P + Gem arm, patients with (n = 206) versus without (n = 46) any CA19-9 decrease at week 8 had a confirmed overall response rate (ORR) of 40% versus 13%, and a median OS of 13.2 versus 8.3 months (P = 0.001), respectively. In the Gem-alone arm, patients with (n = 159) versus without (n = 43) CA19- 9 decrease at week 8 had a confirmed ORR of 15% versus 5%, and a median OS of 9.4 versus 7.1 months (P = 0.404), respectively. In the nab-P + Gem and Gem-alone arms, by week 8, 16% (40/252) and 6% (13/202) of patients, respectively, had an unconfirmed radiologic response (median OS 13.7 and 14.7 months, respectively), and 79% and 84% of patients, respectively, had stable disease (SD) (median OS 11.1 and 9 months, respectively). Patients with SD and any CA19-9 decrease (158/199 and 133/170) had a median OS of 13.2 and 9.4 months, respectively. Conclusion: This analysis demonstrated that, in patients with MPC, any CA19-9 decrease at week 8 can be an early marker for chemotherapy efficacy, including in those patients with SD. CA19-9 decrease identified more patients with survival benefit than radiologic response by week 8

Abstract P6-10-01: A randomized phase 2 study of the antibody-drug conjugate CDX-011 in advanced GPNMB-overexpressing breast cancer: The EMERGE study

Abstract Background: GPNMB is an internalizable transmembrane glycoprotein overexpressed in multiple tumor types, including breast cancer (BC). GPNMB promotes BC metastases in a murine model and is a poor prognostic marker in patients (pts) (Rose 2010). CDX-011 (glembatumumab vedotin) is a fully human GPNMB-specific monoclonal antibody conjugated to the potent cellular toxin MMAE via a protease-sensitive peptide linker, designed to cleave upon cellular internalization. In Phase I/II studies of CDX-011 in BC (n = 42), an objective response rate (ORR) (including confirmed and unconfirmed response) of 12% overall and 20% for “triple-negative” (ER/PR/HER2−; TN) pts was observed (Saleh, ASCO 2010). Methods: The Phase II EMERGE study examined the efficacy of CDX-011 by level of GPNMB expression. Refractory BC (2–7 prior cytotoxic regimens in metastatic setting), GPNMB expression in ≥ 5% of tumor or stroma cells (as centrally determined on archival tumor), and no persistent treatment-related toxicity (including neuropathy) of ≥ Grade 2 severity were required for enrollment. Pts were stratified by GPNMB expression pattern (any tumor, low stromal or high stromal) and randomized 2:1 to CDX-011 (1.88 mg/kg IV q 21 days) or “investigator's choice” (IC) single-agent chemotherapy, and treated until progression (PD) or intolerance with IC pt crossover permitted to CDX-011 at PD. Endpoints: ORR (primary), progression-free survival (PFS), safety, pharmacokinetics, pharmacodynamics. Results: 99% of screened tumor samples expressed GPNMB. 122 treated pts (81 CDX-011 vs. 41 IC) had median age = 56 vs. 56 years; median # prior anticancer regimens = 6 vs. 5; visceral disease (liver/lung) = 83% vs. 80%; TN = 33% vs 27%, respectively. To date, 15 IC pts have crossed over to CDX-011, and 14 pts (8 CDX-011, 6 IC) continue on treatment. CDX-011 was well tolerated with less hematologic toxicity than IC; CDX-011-related toxicity included rash (overall = 38%; Grade 1 = 20%; Grade 2 = 15%; Grade 3 = 3%) and neuropathy (overall = 18%; Grade 1 = 8%; Grade 2 = 7%; Grade 3 = 2%). Conclusions: CDX-011 was a well-tolerated and active agent in this heavily pre-treated BC pt population. Preliminary analysis of the EMERGE study demonstrates enhanced activity of CDX-011 in TN as well as high GPNMB expressing BC tumors, confirming that CDX-011 is a targeted agent. This noted promising activity in advanced TN and hGPNMB enriched pt populations warrants further evaluation. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-10-01.</jats:p

Mass spectroscopic investigation of bis-1,3-urea calix[4]arenes and their ability to complex N-protected α-amino acids

We report the ability of urea's appended onto the upper-rim of conformationally locked 'cone' calix[4]arenes to show a preference for binding specific N-protected α-amino acids. Superior complexation (as judged by mass spectroscopy) between N-protected α-amino results and bis-1,3-N-benzylureas calix[4]arenes was observed when methylene bridges were present between the calix[4]arene 'host' and the urea motif. Interestingly we also demonstrate that subjecting mixtures of structurally diverse N-Fmoc-α-amino acids to a single bis-1,3-N-benzylurea derived calix[4]arene allows, in some cases, the calix[4]arene 'host' to selectively 'pick out' and complex a specific N-Fmoc amino acid from the mixture. © Springer Science+Business Media B.V. 2009

Infections and organ transplantation: new challenges for prevention and treatment--a colloquium

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