Birds have played a central role in many biological disciplines, particularly ecology, evolution, and behavior. The chicken, as a model vertebrate, also represents an important experimental system ...for developmental biologists, immunologists, cell biologists, and geneticists. However, genomic resources for the chicken have lagged behind those for other model organisms, with only 1845 nonredundant full-length chicken cDNA sequences currently deposited in the EMBL databank. We describe a large-scale expressed-sequence-tag (EST) project aimed at gene discovery in chickens (http://www.chick.umist.ac.uk). In total, 339,314 ESTs have been sequenced from 64 cDNA libraries generated from 21 different embryonic and adult tissues. These were clustered and assembled into 85,486 contiguous sequences (contigs). We find that a minimum of 38% of the contigs have orthologs in other organisms and define an upper limit of 13,000 new chicken genes. The remaining contigs may include novel avian specific or rapidly evolving genes. Comparison of the contigs with known chicken genes and orthologs indicates that 30% include cDNAs that contain the start codon and 20% of the contigs represent full-length cDNA sequences. Using this dataset, we estimate that chickens have approximately 35,000 genes in total, suggesting that this number may be a characteristic feature of vertebrates.
Patients who have residual invasive carcinoma after the receipt of neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative breast cancer have poor prognoses. The benefit ...of adjuvant chemotherapy in these patients remains unclear.
We randomly assigned 910 patients with HER2-negative residual invasive breast cancer after neoadjuvant chemotherapy (containing anthracycline, taxane, or both) to receive standard postsurgical treatment either with capecitabine or without (control). The primary end point was disease-free survival. Secondary end points included overall survival.
The result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease-free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval CI, 0.53 to 0.92; P=0.01). Overall survival was longer in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P=0.01). Among patients with triple-negative disease, the rate of disease-free survival was 69.8% in the capecitabine group versus 56.1% in the control group (hazard ratio for recurrence, second cancer, or death, 0.58; 95% CI, 0.39 to 0.87), and the overall survival rate was 78.8% versus 70.3% (hazard ratio for death, 0.52; 95% CI, 0.30 to 0.90). The hand-foot syndrome, the most common adverse reaction to capecitabine, occurred in 73.4% of the patients in the capecitabine group.
After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease-free survival and overall survival among patients with HER2-negative breast cancer who had residual invasive disease on pathological testing. (Funded by the Advanced Clinical Research Organization and the Japan Breast Cancer Research Group; CREATE-X UMIN Clinical Trials Registry number, UMIN000000843 .).
El gen SCN2A codifica para el canal de sodio Nav1.2, carece de hotspots y presenta variantes patogénicas que se manifiestan con un amplio espectro fenotípico: convulsiones neonatales-infantiles ...familiares benignas, encefalopatías epilépticas, epilepsia severa no sindrómica, retraso mental y autismo sin epilepsia y ataxia episódica (AE). Describimos una familia: Varón de 6 años con convulsiones neonatales e infantiles, retraso del neurodesarrollo e inicio de AE a los 4 años. Su padre presentó convulsiones neonatales y posteriormente episodios de AE, y una hermana menor con convulsiones neonatales e infantiles y AE desde los 2 años. La madre y dos hermanos son asintomáticos. Con el objetivo de arribar al diagnóstico molecular se realizó en el probando secuenciación completa del genoma en la plataforma Illumina con una cobertura promedio de 50X. Se detectó una variante patogénica en He en el exón 7 de SCN2A, c.788C>T (p.A263V), previamente reportada por otros autores. Esta variante ubicada en un residuo altamente conservado de Nav1.2 origina una ganancia de función con hiperexcitabilidad neuronal, lo que plantea un potencial uso de fármacos orientados al defecto molecular en AE por SCN2A. Resta el análisis de segregación de la variante en esta familia. Las tcas de secuenciación masiva actualmente permiten incrementar la probabilidad de identificar defectos moleculares en trastornos clínica y genéticamente heterogéneos, tal es el caso del grupo de AE, dando fin a la odisea diagnóstica y en ocasiones logrando incorporar eventuales opciones terapéuticas.
The phase Ib KEYNOTE-173 study was conducted to assess the safety and preliminary antitumor activity of neoadjuvant chemotherapy plus pembrolizumab in high-risk, early-stage, non-metastatic ...triple-negative breast cancer (TNBC).
Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A–F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), then eight cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks, and then doxorubicin and cyclophosphamide for an additional 12 weeks before surgery. Primary end points were safety and recommended phase II dose (RP2D); secondary end points were pathological complete response (pCR) rate, objective response rate, and event-free and overall survival. Exploratory end points were the relationship between outcome and potential biomarkers, such as tumor programmed death ligand 1 (PD-L1) expression (combined positive score) and stromal tumor-infiltrating lymphocyte levels (sTILs).
Sixty patients were enrolled between 18 February 2016, and 28 February 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n = 10 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold; two cohorts did (A, E). The most common grade ≥3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%) and were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range 49%–71%). Twelve-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 combined positive score, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively).
Combination neoadjuvant chemotherapy and pembrolizumab for high-risk, early-stage TNBC showed manageable toxicity and promising antitumor activity. In an exploratory analysis, the pCR rate showed a positive correlation with tumor PD-L1 expression and sTIL levels.
ClinicalTrials.gov identifier: NCT02622074.
•Neoadjuvant pembrolizumab + chemotherapy showed no unexpected safety findings in patients with high-risk, early-stage TNBC.•Two chemotherapy regimens met the RP2D threshold: nab-paclitaxel 125 mg/m2 qw; paclitaxel 80 mg/m2 qw + carboplatin AUC5 q3w.•pCR rate (ypT0/Tis ypN0) across all cohorts was 60% and 12-month EFS and OS rates ranged from 80% to 100% across cohorts.•pCR rate showed positive correlation with tumor PD-L1 expression and stromal tumor-infiltrating lymphocyte levels.
The phase III CLEOPATRA study demonstrated that combining pertuzumab with trastuzumab plus docetaxel significantly improves progression-free and overall survival in previously untreated HER2-positive ...metastatic breast cancer. Here, we report health-related quality-of-life (HRQoL) results from CLEOPATRA.
Participants were randomly assigned to pertuzumab or placebo, each given with trastuzumab plus docetaxel every 3 weeks. Pertuzumab and trastuzumab were administered until progression and six or more docetaxel cycles were recommended. Time from randomization to a ≥5-point decrease in Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) of the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire was analyzed as a prespecified secondary end point. A post hoc exploratory analysis investigated time to ≥2-point deterioration in Breast Cancer Subscale (BCS) score.
Time to ≥5-point decline in TOI-PFB did not differ significantly between the pertuzumab and placebo arms hazard ratio (HR), 0.97; P = 0.7161. The median times to TOI-PFB deterioration were 18.4 and 18.3 weeks, respectively (approximately six cycles). The mean TOI-PFB declined slightly until week 18 and recovered thereafter. Pertuzumab increased time until BCS deterioration versus placebo (median 26.7 versus 18.3 weeks; HR, 0.77; P = 0.0061).
Combining pertuzumab with trastuzumab and docetaxel had no adverse impact on HRQoL and may prolong time to worsening of breast cancer-specific symptoms.
•This ESMO Clinical Practice Guideline provides key recommendations and algorithms for managing metastatic breast cancer.•It covers diagnosis, staging, risk assessment, treatment, disease monitoring, ...palliative care and the patient perspective.•ESMO-MCBS and ESCAT scores are given to describe the levels of evidence for treatment choices.•The authors comprise an international expert group, with recommendations based on available evidence and expert opinion.•In clinical practice, all recommendations provided need to be discussed with patients in a shared decision-making approach.
In the OlympiAD study, olaparib was shown to improve progression-free survival compared with chemotherapy treatment of physician’s choice (TPC) in patients with a germline BRCA1 and/or BRCA2 mutation ...(BRCAm) and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC). We now report the planned final overall survival (OS) results, and describe the most common adverse events (AEs) to better understand olaparib tolerability in this population.
OlympiAD, a Phase III, randomized, controlled, open-label study (NCT02000622), enrolled patients with a germline BRCAm and HER2-negative mBC who had received ≤2 lines of chemotherapy for mBC. Patients were randomized to olaparib tablets (300mg bid) or predeclared TPC (capecitabine, vinorelbine, or eribulin). OS and safety were secondary end points.
A total of 205 patients were randomized to olaparib and 97 to TPC. At 64% data maturity, median OS was 19.3months with olaparib versus 17.1months with TPC (HR 0.90, 95% CI 0.66–1.23; P = 0.513); median follow-up was 25.3 and 26.3months, respectively. HR for OS with olaparib versus TPC in prespecified subgroups were: prior chemotherapy for mBC no (first-line setting): 0.51, 95% CI 0.29–0.90; yes (second/third-line): 1.13, 0.79–1.64; receptor status (triple negative: 0.93, 0.62–1.43; hormone receptor positive: 0.86, 0.55–1.36); prior platinum (yes: 0.83, 0.49–1.45; no: 0.91, 0.64–1.33). Adverse events during olaparib treatment were generally low grade and manageable by supportive treatment or dose modification. There was a low rate of treatment discontinuation (4.9%), and the risk of developing anemia did not increase with extended olaparib exposure.
While there was no statistically significant improvement in OS with olaparib compared to TPC, there was the possibility of meaningful OS benefit among patients who had not received chemotherapy for metastatic disease. Olaparib was generally well-tolerated, with no evidence of cumulative toxicity during extended exposure.
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