Polyphyly of the genus Stenurella (Coleoptera, Cerambycidae): Consensus of morphological and molecular data

Stenurella genus is represented by nine small-sized and widely distributed Palaearctic species. Representatives of the genus play a key role in the pollination of wild angiosperms, accelerate the detritus cycle and make a significant contribution to the forest food web. A number of species with heterogeneous morphological features found within the single Stenurella genus indicate the need for revision of the taxonomy this genus. The previous attempt to resolve the intrageneric composition of Stenurella was rather artificial because it did not take into an account evolutionary relationships. In this study we tested the existing model of Stenurella intrageneric subdivision using both morphological and molecular approaches. Our results showed that the genus Stenurella is polyphyletic and consists of two unrelated clades. The first clade comprises six species (S. jaegeri, S. novercalis, S. bifasciata, S. melanura, S. hybridula and S. approximans) and the second includes three species (S. septempunctata, S. vaucheri and S. nigra). Moreover, we found that the second clade is closely related to Rutpela due to both morphological and molecular phylogeny. Based on our findings, we revised the present structure of the genus Stenurella and transferred three species of the second clade to the genus Rutpela, sensu novo. The genus Rutpela was redescribed in the light of our results. Furthermore, we subdivided the genus Stenurella, sensu nov. into two subgenera, Stenurella, subgen. sensu nov. and Priscostenurella, subgen. sensu nov., respectively. Also, the genus Rutpela, sensu nov. was subdivided into four subgenera including Nigrostenurella, Rutpela, Eduardvivesia, subgen. nov. and Nigromacularia, subgen. nov. The assessment of the place of Stenurella, sensu novo and Rutpela, sensu novo within Lepturini based on molecular phylogeny, showed that Stenurella, sensu novo belongs to the Anoplodera-branch and Rutpela, sensu novo nested within the Leptura-branch. These together with morphological features confirmed our idea of the evolutionary distinctiveness of Stenurella, sensu novo and Rutpela, sensu novo. We assumed that the general external morphological similarity of Stenurella, sensu novo and Rutpela, sensu novo was the result of convergent evolution, driven by mimetic selection toward imitation of ants or wasps. Finally, our study establishes a natural phylogenetic taxonomy of Stenurella

FALCON: A phase III randomised trial of fulvestrant 500 mg vs. anastrozole for hormone receptor-positive advanced breast cancer

Background: This Phase III, randomised, double-blind, multicentre trial (FALCON; NCT01602380) compared the selective estrogen receptor (ER) degrader (SERD) fulvestrant with anastrozole in patients with ER- and/or progesterone receptor-positive locally advanced or metastatic breast cancer who had not received prior hormonal therapy. Methods: Patients were randomised 1:1 to fulvestrant (500 mg IM on Days 0, 14, 28, then each 28 days) or anastrozole (1 mg daily). The primary endpoint was progression-free survival (PFS), assessed via RECIST 1.1, surgery/radiotherapy for disease worsening, or death. Secondary endpoints were: overall survival (OS); objective response rate (ORR, complete response [CR] or partial response [PR]); duration of response (DoR); expected DoR (EDoR); clinical benefit rate (CBR; CR, PR, or stable disease ≥24 weeks); duration of clinical benefit (DoCB); expected DoCB (EDoCB); health-related quality of life (HRQoL); and safety

Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): And randomised, phase 3, open-label, multicentre study

Background: Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Methods: In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive carfilzomib with dexamethasone (carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1·3 mg/m2; intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866. Findings: Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the carfilzomib group; 465 to the bortezomib group). Median follow-up was 11·9 months (IQR 9·3-16·1) in the carfilzomib group and 11·1 months (8·2-14·3) in the bortezomib group. Median progression-free survival was 18·7 months (95% CI 15·6-not estimable) in the carfilzomib group versus 9·4 months (8·4-10·4) in the bortezomib group at a preplanned interim analysis (hazard ratio [HR] 0·53 [95% CI 0·44-0·65]; p<0·0001). On-study death due to adverse events occurred in 18 (4%) of 464 patients in the carfilzomib group and in 16 (3%) of 465 patients in the bortezomib group. Serious adverse events were reported in 224 (48%) of 463 patients in the carfilzomib group and in 162 (36%) of 456 patients in the bortezomib group. The most frequent grade 3 or higher adverse events were anaemia (67 [14%] of 463 patients in the carfilzomib group vs 45 [10%] of 456 patients in the bortezomib group), hypertension (41 [9%] vs 12 [3%]), thrombocytopenia (39 [8%] vs 43 [9%]), and pneumonia (32 [7%] vs 36 [8%]). Interpretation: For patients with relapsed or refractory multiple myeloma, carfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option. Funding: Onyx Pharmaceuticals, Inc., an Amgen subsidiary

Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE).

BACKGROUND: Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. PATIENTS AND METHODS: In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8\u2009mg/kg loading dose, then 6\u2009mg/kg every 3\u2009weeks (q3w)] and pertuzumab (840\u2009mg loading dose, then 420\u2009mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). RESULTS: Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54\u2009years; 29% had received prior trastuzumab. Median treatment duration was 16\u2009months for pertuzumab and trastuzumab and 4\u2009months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9-22.7] months overall (19.6, 23.0 and 18.1\u2009months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). CONCLUSIONS: Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. CLINICALTRIALS.GOV: NCT01572038

Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication

Background: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade 653 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design

Polyphyly of the genus Stenurella (Coleoptera, Cerambycidae): Consensus of morphological and molecular data

Stenurella genus is represented by nine small-sized and widely distributed Palaearctic species. Representatives of the genus play a key role in the pollination of wild angiosperms, accelerate the detritus cycle and make a significant contribution to the forest food web. A number of species with heterogeneous morphological features found within the single Stenurella genus indicate the need for revision of the taxonomy this genus. The previous attempt to resolve the intrageneric composition of Stenurella was rather artificial because it did not take into an account evolutionary relationships. In this study we tested the existing model of Stenurella intrageneric subdivision using both morphological and molecular approaches. Our results showed that the genus Stenurella is polyphyletic and consists of two unrelated clades. The first clade comprises six species (S. jaegeri, S. novercalis, S. bifasciata, S. melanura, S. hybridula and S. approximans) and the second includes three species (S. septempunctata, S. vaucheri and S. nigra). Moreover, we found that the second clade is closely related to Rutpela due to both morphological and molecular phylogeny. Based on our findings, we revised the present structure of the genus Stenurella and transferred three species of the second clade to the genus Rutpela, sensu novo. The genus Rutpela was redescribed in the light of our results. Furthermore, we subdivided the genus Stenurella, sensu nov. into two subgenera, Stenurella, subgen. sensu nov. and Priscostenurella, subgen. sensu nov., respectively. Also, the genus Rutpela, sensu nov. was subdivided into four subgenera including Nigrostenurella, Rutpela, Eduardvivesia, subgen. nov. and Nigromacularia, subgen. nov. The assessment of the place of Stenurella, sensu novo and Rutpela, sensu novo within Lepturini based on molecular phylogeny, showed that Stenurella, sensu novo belongs to the Anoplodera-branch and Rutpela, sensu novo nested within the Leptura-branch. These together with morphological features confirmed our idea of the evolutionary distinctiveness of Stenurella, sensu novo and Rutpela, sensu novo. We assumed that the general external morphological similarity of Stenurella, sensu novo and Rutpela, sensu novo was the result of convergent evolution, driven by mimetic selection toward imitation of ants or wasps. Finally, our study establishes a natural phylogenetic taxonomy of Stenurella