A phase I clinical and pharmacological study evaluating vinflunine in combination with doxorubicin as first line treatment in metastatic breast cancer

Vinfunine (VFL) is a novel bifluorinated tubulin-targeted agent of the vinca alkaloids class active in advanced stage breast cancer. We conducted a phase I study combining VFL with doxorubicin (DXR) to define the recommended dose (RD), safety, pharmacokinetic (PK) interaction and efficacy. Two schedules (day 1 every 3weeks; days 1 and 8 every 3weeks) were investigated as first line chemotherapy in metastatic breast cancer patients. Thirty-two patients received a total of 162 cycles of the VFL-DXR combination (median 6). The RDs were VFL 250mg/m2/DXR 40mg/m2 every 3weeks for schedule 1 and VFL 120mg/m2/DXR 25mg/m2 days 1 and 8 every 3weeks for schedule 2. The main dose-limiting toxicity was neutropenia. The most frequent non-hematological adverse events were nausea, fatigue, constipation, vomiting, anorexia, stomatitis and dyspnea. Objective response rate was reached in 47.1% of the patients. No PK interaction was observed. VFL-DXR combination is feasible with manageable toxicity. The antitumor activity was promising and supports further evaluatio

Treatment algorithm in patients with ovarian cancer

Most ovarian cancer patients are diagnosed only at advanced stages when survival outcomes are worse, and when therapeutic decisions might prove challenging. The fundamental treatment for women with ovarian cancer includes debulking surgery whenever possible and appropriate systemic therapy (chemotherapy, targeted and antiangiogenic agents). In the last few years, knowledge about histological and molecular characteristics of ovarian cancer subtypes and stages has increased considerably. This has enabled the development and improvement of several options for the diagnosis and treatment of ovarian cancer in a patient-tailored approach. Accordingly, therapeutic decisions are guided by the characteristics of the patient and the tumour, especially the molecular features of the cancer subtype and disease stage. Particularly relevant are the advances in early genetic testing of germline and somatic mutations involved in DNA repair, and the clinical development of targeted agents. In order to implement the best individual medical strategies, in this article, we present an algorithm of treatment options, including recently developed targeted agents, for primary and recurrent ovarian cancer patients in Belgium

Efficacy of individualised starting dose (isd) and fixed starting dose (fsd) of niraparib per investigator assessment (ia) in newly diagnosed advanced ovarian cancer (oc) patients

Niraparib is a poly(ADP-ribose) polymerase inhibitor approved for maintenance treatment of patients with newly diagnosed or recurrent OC that responded to platinumbased chemotherapy and treatment in heavily-pretreated recurrent OC. Here we report efficacy in patients receiving the FSD and ISD in the PRIMA/ENGOT-OV26/GOG-3012 trial (NCT02655016)

Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial

Despite an improved antitumor efficacy as noticed by an enhanced response rate and an improved progression-free survival, the hepatic intra-arterial fotemustine did not increase the overall survival of uveal melanoma patients with liver metastases only. We propose to consider intrahepatic treatment as an experimental approac

Tisotumab Vedotin in Combination With Carboplatin, Pembrolizumab, or Bevacizumab in Recurrent or Metastatic Cervical Cancer: Results From the innovaTV 205/GOG-3024/ENGOT-cx8 Study.

PURPOSE: Tissue factor is highly expressed in cervical carcinoma and can be targeted by tisotumab vedotin (TV), an antibody-drug conjugate. This phase Ib/II study evaluated TV in combination with bevacizumab, pembrolizumab, or carboplatin for recurrent or metastatic cervical cancer (r/mCC). METHODS: This open-label, multicenter study (ClinicalTrials.gov identifier: NCT03786081) included dose-escalation arms that assessed dose-limiting toxicities (DLTs) and identified the recommended phase II dose (RP2D) of TV in combination with bevacizumab (arm A), pembrolizumab (arm B), or carboplatin (arm C). The dose-expansion arms evaluated TV antitumor activity and safety at RP2D in combination with carboplatin as first-line (1L) treatment (arm D) or with pembrolizumab as 1L (arm E) or second-/third-line (2L/3L) treatment (arm F). The primary end point of dose expansion was objective response rate (ORR). RESULTS: A total of 142 patients were enrolled. In dose escalation (n = 41), no DLTs were observed; the RP2D was TV 2 mg/kg plus bevacizumab 15 mg/kg on day 1 once every 3 weeks, pembrolizumab 200 mg on day 1 once every 3 weeks, or carboplatin AUC 5 on day 1 once every 3 weeks. In dose expansion (n = 101), the ORR was 54.5% (n/N, 18/33; 95% CI, 36.4 to 71.9) with 1L TV + carboplatin (arm D), 40.6% (n/N, 13/32; 95% CI, 23.7 to 59.4) with 1L TV + pembrolizumab (arm E), and 35.3% (12/34; 19.7 to 53.5) with 2L/3L TV + pembrolizumab (arm F). The median duration of response was 8.6 months, not reached, and 14.1 months, in arms D, E, and F, respectively. Grade ≥3 adverse events (≥15%) were anemia, diarrhea, nausea, and thrombocytopenia in arm D and anemia in arm F (none ≥15%, arm E). CONCLUSION: TV in combination with bevacizumab, carboplatin, or pembrolizumab demonstrated manageable safety and encouraging antitumor activity in treatment-naive and previously treated r/mCC

Acoel Flatworms Are Not Platyhelminthes: Evidence from Phylogenomics

Acoel flatworms are small marine worms traditionally considered to belong to the phylum Platyhelminthes. However, molecular phylogenetic analyses suggest that acoels are not members of Platyhelminthes, but are rather extant members of the earliest diverging Bilateria. This result has been called into question, under suspicions of a long branch attraction (LBA) artefact. Here we re-examine this problem through a phylogenomic approach using 68 different protein-coding genes from the acoel Convoluta pulchra and 51 metazoan species belonging to 15 different phyla. We employ a mixture model, named CAT, previously found to overcome LBA artefacts where classical models fail. Our results unequivocally show that acoels are not part of the classically defined Platyhelminthes, making the latter polyphyletic. Moreover, they indicate a deuterostome affinity for acoels, potentially as a sister group to all deuterostomes, to Xenoturbellida, to Ambulacraria, or even to chordates. However, the weak support found for most deuterostome nodes, together with the very fast evolutionary rate of the acoel Convoluta pulchra, call for more data from slowly evolving acoels (or from its sister-group, the Nemertodermatida) to solve this challenging phylogenetic problem

The evolution of photosynthesis in chromist algae through serial endosymbioses

Chromist algae include diverse photosynthetic organisms of great ecological and social importance. Despite vigorous research efforts, a clear understanding of how various chromists acquired photosynthetic organelles has been complicated by conflicting phylogenetic results, along with an undetermined number and pattern of endosymbioses, and the horizontal movement of genes that accompany them. We apply novel statistical approaches to assess impacts of endosymbiotic gene transfer on three principal chromist groups at the heart of long-standing controversies. Our results provide robust support for acquisitions of photosynthesis through serial endosymbioses, beginning with the adoption of a red alga by cryptophytes, then a cryptophyte by the ancestor of ochrophytes, and finally an ochrophyte by the ancestor of haptophytes. Resolution of how chromist algae are related through endosymbioses provides a framework for unravelling the further reticulate history of red algal-derived plastids, and for clarifying evolutionary processes that gave rise to eukaryotic photosynthetic diversity

Mechanisms of local immunosuppression in cutaneous melanoma

Cutaneous melanoma is highly immunogenic, yet primary melanomas and metastases develop successfully in otherwise immunocompetent patients. To investigate the local immunosuppressive microenvironment, we examined the presence of suppressor T lymphocytes and tolerising dendritic cells (DCs), the expression of immunosuppressive cytokines (IL-10, TGFβ1 and TGFβ2) and the enzyme indoleamine 2,3-dioxygenase (IDO) using qRT–PCR and immunohistochemistry in primary skin melanomas, negative and positive sentinel lymph nodes (SLN), and lymph nodes with advanced metastases. Our results indicate that tolerogenic DCs and suppressor T lymphocytes are present in melanoma at all stages of disease progression. They express transforming growth factor β receptor 1 (TGFβR1), and are therefore susceptible to TGFβ1 and TGFβ2 specifically expressed by primary melanoma. We found that expression of IDO and interleukin 10 (IL-10) increased with melanoma progression, with the highest concentration in positive SLN. We suggest that negative SLN contain immunosuppressive cells and cytokines, due to preconditioning by tolerogenic DCs migrating from the primary melanoma site to the SLN. In primary melanoma, TGFβ2 is likely to render peripheral DCs tolerogenic, while in lymph nodes IDO and TGFβ1 may have a major effect. This mechanism of tumour-associated immunosuppression may inhibit the immune response to the tumour and may explain the discrepancy between the induction of systemic immunity by anti-melanoma vaccines and their poor performance in the clinic

Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT).

A European Society for Medical Oncology (ESMO)-sponsored expert meeting was held in Paris on 8 March 2018 which comprised 11 experts from academia, 11 experts from the pharmaceutical industry and 2 clinicians who were representatives of ESMO. The focus of the meeting was exclusively on the intratumoral injection/delivery of immunostimulatory agents with the aim of harmonizing the standard terms and methodologies used in the reporting of human intratumoral immunotherapy (HIT-IT) clinical trials to ensure quality assurance and avoid a blurring of the data reported from different studies. The goal was to provide a reference document, endorsed by the panel members that could provide guidance to clinical investigators, pharmaceutical companies, ethics committees, independent review boards, patient advocates and the regulatory authorities and promote an increase in the number and quality of HIT-IT clinical trials in the future. Particular emphasis was placed not only on the development of precise definitions to facilitate a better understanding between investigators but also on the importance of systematic serial biopsies as a driver for translational research and the need for the recording and reporting of data, to facilitate a better understanding of the key processes involved