Pharmacologic aspects of new classes of anti-cancer agents: inhibitors of topoisomerase I or tubulin

Many processes involved in unregulated proliferation of cells are subject to antitumor therapy, inhibition of the nucleair enzyme topoisomerase I and protein tubulin being two of them. Important (pre-)clinical observations, such as synergism with other cytotoxic agents, the benefices of oral therapy as a means of prolonged exposure and the crucial role of the solubilization agent Cremophor EL, are involved in their further clinical development and in refinement of existing therapies. Given the narrow therapeutic window, means to improve the individual dosing precision need to be studied. Clinical pharmacological studies, as described in this thesis, are intended to serve as a guide to better chemotherapy schedules for the individual cancer patient

The fate of camptothecin glycoconjugate: report of a clinical hold during a phase II study of BAY 56-3722 (formerly BAY 38-3441), in patients with recurrent or metastatic colorectal cancer resistant/refractory to irinotecan

Introduction BAY 56-3722 (formerly BAY 38-3441) is a glycoconjugated campthotecin, which was considered an attractive drug to assess in colorectal cancer (CRC). Patient and methods Phase II study design evaluating the antitumor activity of BAY 56-3722 IV 320 mg/m2 daily for 3 days every 3 weeks in patients with recurrent or metastatic inoperable CRC resistant to irinotecan. Results Twenty-four patients received the study treatment. Triggered by adverse events in two other studies with this compound the study was put on a clinical hold while the safety data were reviewed for the entire program. After the review Bayer decided to withdraw BAY 56-3722 from all clinical investigations. Discussion We felt it was our obligation to share this interrupted phase II study for two reasons: to report the fate of camptothecin glycoconjugate and to report the unique situation of a clinical hold during a phase II study

Isolation and Molecular Characterization of a Novel Cytopathogenic Paramyxovirus from Tree Shrews

AbstractA cytopathic infectious agent was isolated from the kidneys of an apparently healthy tree shrew (Tupaia belangeri) that had been captured in the area around Bangkok. The infectivity was propagated in Tupaia fibroblast and kidney cell cultures. Paramyxovirus-like pleomorphic enveloped particles and helical nucleocapsids were observed by electron microscopy and accordingly the infectious agent was termed Tupaia paramyxovirus (TPMV). However, no serological cross-reactions were detected between TPMV and known paramyxoviruses. For the molecular characterization of TPMV an experimental strategy that allows the random-primed synthesis of relatively large cDNA molecules from viral genomic RNA was applied. Nucleotide sequence analysis of a TPMV-specific cDNA fragment (1544 bp) revealed two nonoverlapping partial open reading frames corresponding to paramyxoviral N and P transcription units. Using modified rapid amplification of cDNA ends techniques, a substantial contiguous portion of the viral genome (4065 nt) was elucidated including the complete N and P/V/C genes. The coding strategy of TPMV as well as significant amino acid sequence homologies clearly indicates an evolutionary relationship between TPMV and members of the genus Morbillivirus. Highest homologies were detected between TPMV and Hendra virus (equine morbillivirus), which recently emerged in Australia, causing outbreaks of fatal respiratory and neurological disease in horses and humans

Paratesticular desmoplastic small round cell tumour: an unusual tumour with an unusual fusion; cytogenetic and molecular genetic analysis combining RT-PCR and COBRA-FISH

Desmoplastic small round cell tumour is a rare malignant tumour with a male to female ratio of 4:1. It manifests mostly at serosal sites. Here we present a case of a 28-year-old male patient, who presented with a fast growing paratesticular mass. On biopsy nests and cords of small round cells, without a clear morphological lineage of differentiation were seen. Occasionally desmoplatic small round cell tumour shows different lines of differentiation. An unequivocal histological diagnosis might be difficult in such cases. Here we demonstrate by a combination of methods the characteristic immunohistochemical profile and - albeit unusual - molecular background and discuss the eventual link with Ewing sarcoma

Translation and validation of EORTC QLQ-C30 into Indonesian version for cancer patients in Indonesia.

The Indonesian version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 can be used as a questionnaire to assess quality of life in Indonesian cancer patients with high-emetogenic treatments

Impact of chemotherapy-induced nausea and vomiting on quality of life in indonesian patients with gynecologic cancer.

Patients reported a negative impact on the QoL of delayed emesis after chemotherapy. Poor prophylaxis of patients' nausea and vomiting after chemotherapy interferes with patients' QoL. Medical and behavioral interventions may help to alleviate the negative consequences of chemotherapeutic treatment in patients with gynecologic cancers treated with suboptimal antiemetics

Clinical Activity of Ripretinib in Patients with Advanced Gastrointestinal Stromal Tumor Harboring Heterogeneous KIT/PDGFRA Mutations in the Phase III INVICTUS Study

Ripretinib; Mutacions; Neoplàsies gastrointestinalsRipretinib; Mutations; Gastrointestinal neoplasmsRipretinib; Mutaciones; Neoplasias gastrointestinalesPurpose: Most patients with gastrointestinal stromal tumor (GIST) have activating mutations in KIT/PDGFRA and are initially responsive to tyrosine kinase inhibitors (TKI). The acquisition of secondary mutations leads to refractory/relapsed disease. This study reports the results of an analysis from the phase III INVICTUS study (NCT03353753) characterizing the genomic heterogeneity of tumors from patients with advanced GIST and evaluating ripretinib efficacy across KIT/PDGFRA mutation subgroups. Patients and Methods: Tumor tissue and liquid biopsy samples that captured circulating tumor DNA were collected prior to study enrollment and sequenced using next-generation sequencing. Subgroups were determined by KIT/PDGFRA mutations and correlation of clinical outcomes and KIT/PDGFRA mutational status was assessed. Results: Overall, 129 patients enrolled (ripretinib 150 mg once daily, n = 85; placebo, n = 44). The most common primary mutation subgroup detected by combined tissue and liquid biopsies were in KIT exon 11 (ripretinib, 61.2%; placebo, 77.3%) and KIT exon 9 (ripretinib, 18.8%; placebo, 15.9%). Patients receiving ripretinib demonstrated progression-free survival (PFS) benefit versus placebo regardless of mutation status (HR 0.16) and in all assessed subgroups in Kaplan–Meier PFS analysis (exon 11, P < 0.0001; exon 9, P = 0.0023; exon 13, P < 0.0001; exon 17, P < 0.0001). Among patients with wild-type KIT/PDGFRA by tumor tissue, PFS ranged from 2 to 23 months for ripretinib versus 0.9 to 10.1 months for placebo. Conclusions: Ripretinib provided clinically meaningful activity across mutation subgroups in patients with advanced GIST, demonstrating that ripretinib inhibits a broad range of KIT/PDGFRA mutations in patients with advanced GIST who were previously treated with three or more TKIs

Genetical and functional investigation of fliC genes encoding flagellar serotype H4 in wildtype strains of Escherichia coli and in a laboratory E. coli K-12 strain expressing flagellar antigen type H48

BACKGROUND: Serotyping of O-(lipopolysaccharide) and H-(flagellar) antigens is a wideley used method for identification of pathogenic strains and clones of Escherichia coli. At present, 176 O- and 53 H-antigens are described for E. coli which occur in different combinations in the strains. The flagellar antigen H4 is widely present in E. coli strains of different O-serotypes and pathotypes and we have investigated the genetic relationship between H4 encoding fliC genes by PCR, nucleotide sequencing and expression studies. RESULTS: The complete nucleotide sequence of fliC genes present in E. coli reference strains U9-41 (O2:K1:H4) and P12b (O15:H17) was determined and both were found 99.3% (1043 of 1050 nucleotides) identical in their coding sequence. A PCR/RFLP protocol was developed for typing of fliC-H4 strains and 88 E. coli strains reacting with H4 antiserum were investigated. Nucleotide sequencing of complete fliC genes of six E. coli strains which were selected based on serum agglutination titers, fliC-PCR genotyping and reference data revealed 96.6 to 100% identity on the amino acid level. The functional expression of flagellin encoded by fliC-H4 from strain U9-41 and from our strain P12b which is an H4 expressing variant type was investigated in the E. coli K-12 strain JM109 which encodes flagellar type H48. The fliC recombinant plasmid carrying JM109 strains reacted with both H4 and H48 specific antisera whereas JM109 reacted only with the H48 antiserum. By immunoelectron microscopy, we could show that the flagella made by the fliC-H4 recombinant plasmid carrying strain are constituted of H48 and H4 flagellins which are co-assembled into functional flagella. CONCLUSION: The flagellar serotype H4 is encoded by closely related fliC genes present in serologically different types of E. coli strainswhich were isolated at different time periods and geographical locations. Our expression studies show for the first time, that flagellins of different molecular weigth are functionally expressed and coassembled in the same flagellar filament in E. coli

Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial

Ripretinib; Gastrointestinal stromal tumor; BiomarkerRipretinib; Tumor del estroma gastrointestinal; BiomarcadorRipretinib; Tumor de l'estroma gastrointestinal; BiomarcadorINTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing–based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.The INTRIGUE study was funded by Deciphera Pharmaceuticals, and as the sponsor, Deciphera contributed to the conception, design and analysis of the study. We thank the patients and their families and caregivers, the investigators and the investigational site staff of the INTRIGUE study. We also thank M. Kusi for her contributions to this manuscript and Guardant Health for processing plasma samples and providing the relevant methods. M.C.H. received partial salary support from the following sources: a research grant from the Jonathan David Foundation, a VA Merit Review Grant (I01BX005358) and NCI R21 grant (R21CA263400). Medical writing support was provided by L. Hanlon and M. Chakhtoura of AlphaBioCom, a Red Nucleus company, and was funded by Deciphera Pharmaceuticals, in compliance with international good publication practice guidelines