Modified natural cycle allows a window of 7 days for frozen embryo transfer planning.

RESEARCH QUESTION: Should ovulation be triggered in a modified natural cycle (mNC) with recombinant human chorionic gonadotrophin (rHCG) as soon as a mean follicle diameter of 17 mm is visible, or is more flexible planning possible? DESIGN: This multicentre, retrospective, observational study of 3087 single frozen blastocyst transfers in mNC was carried out between January 2020 and September 2022. The inclusion criteria included endometrial thickness ≥7 mm and serum progesterone <1.5 ng/ml. The main outcome was ongoing pregnancy rate. Secondary end-points were pregnancy rate, implantation rate, clinical pregnancy rate and miscarriage rate. The mean follicle size at triggering was stratified into three groups (13.0-15.9, 16.0-18.9 and 19.0-22 mm). RESULTS: The baseline characteristics between the groups did not vary significantly for age, body mass index and the donor's age for egg donation. No differences were found in pregnancy rate (64.5%, 60.2% and 57.4%; P = 0.19), clinical pregnancy rate (60.5%, 52.8% and 50.6%; P = 0.10), implantation rate (62.10%, 52.9% and 51.0%; P = 0.05) or miscarriage rate (15.0%, 22.2%; and 25.0%; P = 0.11). Although ongoing pregnancy rate (54.9%, 46.8% and 43.1%; P = 0.02) varied significantly in the univariable analysis, it was no longer significant after adjustment for the use of preimplantation genetic testing for aneuploidies and egg donation. CONCLUSIONS: The findings showed rHCG could be flexibly administered with a mean follicle size between 13 and 22 mm as long as adequate endometrial characteristics are met, and serum progesterone is <1.5 ng/ml. Considering the follicular growth rate of 1-1.5 mm/day, this approach could allow a flexibility for FET scheduling of 6-7 days, simplifying mNC FET planning in clinical practice.

Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial.

BACKGROUND: Patients with advanced gastric or gastro-oesophageal junction cancer that progresses on chemotherapy have poor outcomes. We compared pembrolizumab with paclitaxel in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine. METHODS: This randomised, open-label, phase 3 study was done at 148 medical centres in 30 countries. Eligible patients were randomised (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival and progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all patients, irrespective of CPS. The significance threshold for overall survival was p=0·0135 (one-sided). This trial is registered at ClinicalTrials.gov, number NCT02370498. FINDINGS: Between June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients were assigned to receive pembrolizumab and 199 patients were assigned to receive paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9·1 months (95% CI 6·2-10·7) with pembrolizumab and 8·3 months (7·6-9·0) with paclitaxel (hazard ratio [HR] 0·82, 95% CI 0·66-1·03; one-sided p=0·0421). Median progression-free survival was 1·5 months (95% CI 1·4-2·0) with pembrolizumab and 4·1 months (3·1-4·2) with paclitaxel (HR 1·27, 95% CI 1·03-1·57). In the total population, grade 3-5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel. INTERPRETATION: Pembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Additional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

Rash management and treatment persistence of cancer patients treated with epidermal growth factor receptor inhibitors in the Truven MarketScan® research database.

PURPOSE: Rash toxicity is a common, expected class effect of epidermal growth factor receptor (EGFR) inhibitors. Although rash management is practiced, it is not well characterized in the real-world setting. We describe the management of rash that developed while receiving EGFR-inhibitor therapy and how rash affects treatment duration, using Truven MarketScan® Research Database, a US medical claims database. METHODS: Adult patients who received EGFR-inhibitor treatment between 2004 and 2015 after a diagnosis of colon, head and neck, lung, breast, or thyroid cancer were identified. Descriptive analyses were conducted to describe occurrence of rash during the EGFR-inhibitor treatment period, EGFR-inhibitor treatment persistence and management of rash, including treatment and cost. RESULTS: Of 44,533 eligible patients, 4649 (10.4%) had records of rash during the EGFR-inhibitor treatment period, and of patients experiencing rash, 2891 (62.2%) received prescription drugs for rash treatment. Treatment persistence with an EGFR inhibitor was longer among patients experiencing rash compared with no rash (median 178 vs. 80 days for EGFR-TKIs, 85 vs. 57 days for EGFR-monoclonal antibodies), especially among patients with rash who were treated for rash (208 days for EGFR-tyrosine kinase inhibitors, 104 days for EGFR- monoclonal antibodies). Annualized cost during EGFR-inhibitor treatment was lowest among patients not experiencing rash (US$185,619), followed by rash patients receiving drugs for rash management (US$215,561), and highest among rash patients not treated for rash (US$267,105). CONCLUSION: Our findings suggest that management of EGFR inhibitor-associated rash could be important for EGFR-inhibitor treatment persistence.

Peripatric speciation in an endemic Macaronesian plant after recent divergence from a widespread relative.

The Macaronesian Scrophularia lowei is hypothesized to have arisen from the widespread S. arguta on the basis of several phylogenetic studies of the genus, but sampling has been limited. Although these two annual species are morphologically distinct, the origin of S. lowei is unclear because genetic studies focused on this Macaronesian species are lacking. We studied 5 S. lowei and 25 S. arguta populations to determine the relationship of both species and to infer the geographical origin of S. lowei. The timing of S. lowei divergence and differentiation was inferred by dating analysis of the ITS region. A phylogenetic analysis of two nuclear (ITS and ETS) and two chloroplast (psbJ-petA and psbA-trnH) DNA regions was performed to study the relationship between the two species, and genetic differentiation was analysed by AMOVA. Haplotype network construction and Bayesian phylogeographic analysis were conducted using chloroplast DNA regions and a spatial clustering analysis was carried out on a combined dataset of all studied regions. Our results indicate that both species constitute a well-supported clade that diverged in the Miocene and differentiated in the Late Miocene-Pleistocene. Although S. lowei constitutes a well-supported clade according to nDNA, cpDNA revealed a close relationship between S. lowei and western Canarian S. arguta, a finding supported by the spatial clustering analysis. Both species have strong population structure, with most genetic variability explained by inter-population differences. Our study therefore supports a recent peripatric speciation of S. lowei-a taxon that differs morphologically and genetically at the nDNA level from its closest relative, S. arguta, but not according to cpDNA, from the closest Macaronesian populations of that species. In addition, a recent dispersal of S. arguta to Madeira from Canary Islands or Selvagens Islands and a rapid morphological differentiation after the colonization to generate S. lowei is the most likely hypothesis to explain the origin of the last taxon.

An Open-Label, Randomized, Controlled Phase II Study of Paclitaxel-Carboplatin Chemotherapy With Necitumumab Versus Paclitaxel-Carboplatin Alone in First-Line Treatment of Patients With Stage IV Squamous Non-Small-Cell Lung Cancer.

BACKGROUND: The combination of necitumumab with gemcitabine-cisplatin significantly improved overall survival (OS) in patients with stage IV squamous non-small-cell lung cancer (NSCLC), in the phase III SQUamous NSCLC treatment with the Inhibitor of EGF REceptor (SQUIRE) trial. Paclitaxel-carboplatin was selected as an alternative standard of care in the current phase II study. PATIENTS AND METHODS: Patients were randomized (stratified according to Eastern Cooperative Oncology Group performance status and sex) 2:1 to ≤ six 3-week cycles (Q3W) of paclitaxel and carboplatin with or without necitumumab. Chemotherapy was paclitaxel 200 mg/m2 on day 1 Q3W and carboplatin area under the curve 6 on day 1 Q3W. Necitumumab 800 mg, on days 1 and 8, was continued until disease progression or intolerable toxicity occurred. The primary end point was objective response rate (ORR) on the basis of Response Evaluation Criteria In Solid Tumors version 1.1. RESULTS: One hundred sixty-seven patients were randomized to the necitumumab-containing arm (n = 110) or the chemotherapy-only arm (n = 57). The combination of necitumumab with chemotherapy resulted in an ORR of 48.9% versus 40.0%. Median progression-free survival and OS were 5.4 versus 5.6 months (hazard ratio [HR], 1.0) and 13.2 versus 11.2 months (HR, 0.83; P = .379) in each treatment arm, respectively. Disease control rate was 87.2% versus 84.0%. Grade ≥ 3 adverse events typically associated with epidermal growth factor receptor (EGFR) monoclonal antibodies showing a > 2% increase were hypomagnesemia (5.7% vs. 0) and rash (2.8% vs. 0). Any Grade thromboembolic events occurred in < 4% of patients in either arm. CONCLUSION: The results of our study support previously reported results that the combination of necitumumab with chemotherapy improves survival in patients with advanced squamous NSCLC and shows a safety profile consistent with that of EGFR monoclonal antibodies.

Incremental Innovation and Progress in Advanced Squamous Cell Lung Cancer: Current Status and Future Impact of Treatment.

Squamous cell lung cancer (sqCLC) is an aggressive form of cancer that poses many therapeutic challenges. Patients tend to be older, present at a later stage, and have a high incidence of comorbidities, which can compromise treatment delivery and exacerbate toxicity. In addition, certain agents routinely available for nonsquamous cell histologic subtypes, such as bevacizumab and pemetrexed, are contraindicated or lack efficacy in sqCLC. Therapeutic progress has been much slower for advanced sqCLC, with median survival times of approximately 9 to 11 months in most studies. Herein, we discuss the current therapeutic landscape for patients with sqCLC versus with nonsquamous NSCLC. Current evidence indicates that new targeted treatments, notably monoclonal antibodies such as ramucirumab and necitumumab, and immunotherapies such as nivolumab and pembrolizumab can provide survival prolongation, although the benefits are still relatively modest. These incremental improvements, all realized since 2012, in aggregate, will very likely have a clinically meaningful impact for patients with sqCLC. We also discuss recent genomic studies of sqCLC that have identified potentially actionable molecular targets, as well as the relevant targeted agents in clinical development. Finally, we discuss the magnitude of survival benefit and the risk-to-benefit ratio that would prove clinically meaningful in this underserved patient population with unmet needs.

Clinicopathologic Features of Advanced Squamous NSCLC.

Lung cancer remains the leading cause of cancer-related death worldwide. NSCLC accounts for more than 85% of all lung cancers, and the prognosis for advanced-stage disease is typically poor. In recent years, the importance of histologic subtypes of NSCLC has been recognized, and the distinction between squamous and other NSCLC histologic subtypes is now critical to patient management. Squamous cell lung cancer (sqCLC) represents approximately 25% to 30% of NSCLC. The prognosis for patients with advanced NSCLC is poorer for those with sqCLC than for those with adenocarcinoma. This is partly due to a number of clinical characteristics that distinguish sqCLC from other NSCLC histologic subtypes, such as smoking history, comorbid diseases, age, and molecular profile. Together, these factors make sqCLC an especially challenging disease to manage. Herein, we review some of the key clinicopathologic features of sqCLC. Understanding these features to optimally address many of the unique therapeutic challenges of this disease is likely to be central to ultimately improving outcomes for patients with squamous NSCLC.

Management of epidermal growth factor receptor inhibitor-associated rash: a systematic review.

Cancer patients treated with epidermal growth factor receptor inhibitors (EGFRIs) frequently experience skin toxicities (rash) that can compromise their quality of life and lead to dose reduction or discontinuation of treatment. Reflecting the need for effective management of EGFRI-associated rash, a number of clinical practice guidelines and management recommendations have been developed. The objective of this systematic review is to identify and summarize all available published recommendations of rash management strategies and evaluate their basis of evidence, to describe consensus in the recommendations, and where there is a lack of consensus to describe the opportunities for future clinical research to improve clinical practice in the management of EGFRI rash. Fifty-nine articles published from 2005-2011 were selected for inclusion in the systematic review. Common drug recommendations were oral and topical antibiotics, topical corticosteroids, and antihistamines; low-grade rash was generally recommended to be managed with topical antibiotics or corticosteroids, grade 2 rash with oral antibiotics or antihistamines, and severe grades of rash with oral corticosteroids or delay/dose reduction of EGFRI. The focus of clinical practice guidelines and recommendations was on reactive management. A better understanding of pre-emptive versus reactive treatment with the implementation of appropriately designed randomized controlled studies could support a more effective management of EGFRI-associated rash and improve patient outcomes. Consideration of patients' self-reported outcomes and consistent grading of rash toxicity are also recommended. Funding/sponsor: Eli Lilly & Co, Bristol-Myers Squibb.

Green chromatography determination of fatty acid methyl esters in biodiesel.

This work proposes a green, simple and rapid chromatographic methodology for separation and determination of a group of 13 fatty acids methyl esters (FAMEs) by using a capillary gas chromatography with a flame ionization detector. The method was successfully applied for the determination of FAMEs in biodiesel samples from commercial and waste cooking oils, synthesized by homogeneous catalysis. Detection and quantification limits were in the µg L(-1) level. Direct injection of sample solution was compared with solid-phase extraction and solid-phase microextraction procedures, giving similar results. The lower analysis time represent considerable improvement compared with other papers. The described methodology is especially suitable for process control applications. The samples analysed showed total contents of FAMEs higher than 96.5%, which verifies the European regulations.

A phase II study of capecitabine plus docetaxel in gemcitabine-pretreated metastatic pancreatic cancer patients: CapTere.

PURPOSE: Docetaxel and capecitabine combination is synergistic in preclinical models. We investigated the efficacy and toxicity of this combination as second-line chemotherapy in patients with metastatic pancreatic adenocarcinoma (mPC), pretreated with gemcitabine-based chemotherapy. METHODS: Eligible patients were treated with capecitabine 800 mg/m(2) orally PO bid on days 1-14 in combination with intravenous docetaxel 30 mg/m(2) on days 1 and 8 of each 21-day cycle. The primary end point was overall response rate. Using a three-stage sequential design, two interim analyses for early stopping due to lack of efficacy were planned and conducted after 13 and 26 patients were accrued. Secondary end points included time to treatment failure, progression-free survival (PFS), overall survival (OS) and 50 % drop in CA19-9 levels. RESULTS: Forty-three patients were evaluable for toxicity and 42 evaluable for response, at a median age of 64 years. The majority of patients (74 %) had ECOG PS 0-1. Six patients (14 %) achieved a partial tumor response, and stable disease for ≥2 cycles was observed in 59 % of patients (n = 25). Thirty-five percent (n = 11/31) of patients had a ≥50 % decrease in CA19-9 levels. The median PFS was 3.7 months (95 % CI 2.1-4.3 months), and the median OS was 5.3 months (95 % CI 4.3-8.6 months). Treatment was generally well tolerated. Grade 3 toxicity and grade 4 toxicity were seen in 45 and 5 % of patients, respectively. One patient had a potential treatment-related mortality. CONCLUSIONS: The combination of capecitabine and docetaxel is active and well tolerated in mPC patients pretreated with gemcitabine-based therapy.

Insects, birds and lizards as pollinators of the largest-flowered Scrophularia of Europe and Macaronesia.

BACKGROUND AND AIMS: It has traditionally been considered that the flowers of Scrophularia are mainly pollinated by wasps. We studied the pollination system of four species which stand out for their large and showy flowers: S. sambucifolia and S. grandiflora (endemics of the western Mediterranean region), S. trifoliata (an endemic of the Tyrrhenian islands) and S. calliantha (an endemic of the Canary Islands). Our principal aim was to test whether these species were pollinated by birds or showed a mixed pollination system between insects and birds. METHODS: Censuses and captures of insects and birds were performed to obtain pollen load transported and deposited on the stigmas. Also, a qualitative and quantitative analysis of the flowers and inflorescences was carried out. KEY RESULTS: Flowers were visited by Hymenoptera and by passerine birds. The Canarian species was the most visited by birds, especially by Phylloscopus canariensis, and its flowers were also accessed by juveniles of the lizard Gallotia stehlini. The most important birds in the other three species were Sylvia melanocephala and S. atricapilla. The most important insect-functional groups in the mixed pollination system were: honey-bees and wasps in S. sambucifolia; bumble-bees and wasps in S. grandiflora; wasps in S. trifoliata; and a small bee in S. calliantha. CONCLUSIONS: The species studied show a mixed pollination system between insects and passerine birds. In S. calliantha there is, in addition, a third agent (juveniles of Gallotia stehlini). The participation of birds in this mixed pollination system presents varying degrees of importance because, while in S. calliantha they are the main pollinators, in the other species they interact to complement the insects which are the main pollinators. A review of different florae showed that the large showy floral morphotypes of Scrophularia are concentrated in the western and central Mediterranean region, Macaronesia and USA (New Mexico).

Esofagectomia taanshiatal: informe historico de un csso / Transhyatal esophagectomy: Historical case

Se presenta un hombre de 57 años de edad con cáncer de esófago, localizado en tercio medio al que se realizó esofagectomía transhiatal sin toracotomía con esogastroplastia tubular ascendiendo la sustitución por el mediastino posterior, cuyo objetivo fue realizar la descripción del primer caso operado en el país por este método (1983), su evolución y resultados. Se presentó un paciente con disfagia de 3 meses de evolución y pérdida de 25 libras de peso; en su evolución postoperatoria se presentan complicaciones como neumotórax, derrame pleural y fístula esofágica las dos primeras tratadas con procedimientos quirúrgicos sencillos y la última con alimentación parenteral; cerró espontáneamente y egresó a los 31 días de operado. En conclusión, se presenta un caso histórico y anecdótico de un procedimiento aceptado internacionalmente y desarrollado en varios centros hospitalarios del país.

We present a 57 years old male patient with middle third esophagus carcinoma to whom we perform a transhiatal esopagectomy without toracothomy, utilizing a tubular ascending esophagogastroplasty substituting it with the posterior mediastinum. Main: To describe the first case operated in our country by this technique (1983), its evolution and results. Presentation: Patient with a three month lasting dysphagia, which has lost 12 Kg of weight, in his post surgical he had has had pneumothorax, pleural effusion and esophageal fistulae the first two treated with simple procedures and being discharged after 31 days post surgical. Conclusions: We make known a historical and anecdotic case treated with a procedure internationally accepted; already developed in various health care centers in our country.

Esofagectomía transhiatal: informe histórico de un caso / Transhyatal esophagectomy: historical case

Se presenta un hombre de 57 años de edad con cáncer de esófago, localizado en tercio medio al que se realizó esofagectomía transhiatal sin toracotomía con esogastroplastia tubular ascendiendo la sustitución por el mediastino posterior, cuyo objetivo fue realizar la descripción del primer caso operado en el país por este método (1983), su evolución y resultados. Se presentó un paciente con disfagia de 3 meses de evolución y pérdida de 25 libras de peso; en su evolución postoperatoria se presentan complicaciones como neumotórax, derrame pleural y fístula esofágica las dos primeras tratadas con procedimientos quirúrgicos sencillos y la última con alimentación parenteral; cerró espontáneamente y egresó a los 31 días de operado. En conclusión, se presenta un caso histórico y anecdótico de un procedimiento aceptado internacionalmente y desarrollado en varios centros hospitalarios del país(AU)

We present a 57 years old male patient with middle third esophagus carcinoma to whom we perform a transhiatal esopagectomy without toracothomy, utilizing a tubular ascending esophagogastroplasty substituting it with the posterior mediastinum. Main: To describe the first case operated in our country by this technique (1983), its evolution and results. Presentation: Patient with a three month lasting dysphagia, which has lost 12 Kg of weight, in his post surgical he had has had pneumothorax, pleural effusion and esophageal fistulae the first two treated with simple procedures and being discharged after 31 days post surgical. Conclusions: We make known a historical and anecdotic case treated with a procedure internationally accepted; already developed in various health care centers in our country(AU)

Determination of pesticides in wine using micellar electrokinetic chromatography with UV detection and sample stacking.

In this work, the analysis of a group of four fungicides (pyrimethanil, nuarimol, procymidone and cyprodinil) and one insecticide (pirimicarb) by micellar electrokinetic chromatography (MEKC) with UV detection using the on-line preconcentration strategy called reversed electrode polarity stacking mode (REPSM) is proposed. After optimisation, an adequate separation electrolyte for the separation and stacking of these pesticides was obtained which consisted of 100 mM borate, 60 mM sodium dodecyl sulphate (SDS), at pH 9.0 and 2% 2-propanol. The use of this running buffer together with the REPSM preconcentration method provided limits of detection (LODs) between 38.3 and 241 microg/L. In order to apply the developed methodology for the analysis of these pesticides in wine samples, several off-line preconcentration strategies (mainly, solid-phase extraction, SPE, and solid-phase microextraction, SPME) were tested. Although the use of a SPE procedure, optimized in this work for water samples, using Oasis HLB cartridges, provided mean recovery values between 79 and 100% for spiked water samples, it could not be applied to the extraction of these pesticides from wine samples due to high interference from the sample matrix. However, the use of a SPME procedure using polydimethylsiloxane/divynilbenzene (PDMS/DVB) fibers allowed the selective extraction of four of the five pesticides which could be perfectly determined. The final combination of the off-line SPME and on-line REPSM preconcentration strategies allowed obtaining LODs between 17.6 and 32.3 microg/L.