Miastenia gravis de rápida instauración Santiago Cortés, Eva de; Cortés Durán, Petra María; Bedoya, María Jesús ...
Revista clínica de medicina de familia,
2021, Letnik:
14, Številka:
1
Journal Article
Recenzirano
Odprti dostop
RESUMEN La miastenia gravis es una enfermedad que se caracteriza por fatiga y debilidad muscular de predominio proximal, como son los músculos oculares, funciones bulbares, de las extremidades y de ...los músculos respiratorios. La evolución de la enfermedad suele ser fluctuante. Es la alteración más común dentro de las enfermedades que afectan a la transmisión neuromuscular. Los síntomas derivan de la agresión inmunológica contra la membrana postsináptica de la unión neuromuscular. Presentamos el caso de un hombre de 36 años que acude a consulta por parestesias al comer, que ceden espontáneamente a los pocos minutos. Dos semanas después es ingresado por diplopía y disfagia. Tras la sospecha de miastenia gravis, se realizan las pruebas complementarias pertinentes, concluyendo en el diagnóstico de miastenia gravis generalizada seronegativa asociada a timoma.
To assess palbociclib in combination with trastuzumab with or without endocrine therapy in patients with HER2-positive advanced breast cancer.
PATRICIA is a prospective, open-label, multicenter phase ...II trial. Patients had received 2-4 prior lines of anti-HER2-based regimens. Treatment consisted of palbociclib 200 mg daily for 2 weeks and 1 week off plus trastuzumab. The study was based on a Simon two-stage design comprising three cohorts: estrogen receptor (ER)-negative (cohort A), ER-positive (cohort B1), and ER-positive with letrozole (cohort B2). ER-positive patients were randomized to cohorts B1 or B2. Primary endpoint was progression-free survival rate at 6 months (PFS6). Secondary objectives included safety and evaluation of the PAM50 intrinsic subtypes.
Seventy-one patients were recruited (
= 15 in cohort A and 28 in each cohort B). The PFS6 rate in cohorts A, B1, and B2 was 33.3% (5/15), 42.8% (12/28), and 46.4% (13/28), respectively. Regarding safety, grade 1-2 and 3-4 toxicities occurred in 97.7% and 84.4% of patients, respectively. The most common grade 3-4 toxicities were neutropenia (66.4%) and thrombocytopenia (11.3%). Regarding PAM50, 59 (83.1%) tumors were profiled. Luminal disease defined by PAM50 was found independently associated with longer PFS compared with non-luminal disease (10.6 vs. 4.2 months median PFS; adjusted hazard ratio = 0.40;
= 0.003).
Palbociclib in combination with trastuzumab is safe and exhibits promising survival outcomes in trastuzumab pretreated ER-positive/HER2-positive advanced breast cancer with a PAM50 Luminal A or B subtype. The enrollment was stopped prematurely, and a new randomized cohort was opened in this population.
Background
The WHO ordinal severity scale has been used to predict mortality and guide trials in COVID-19. However, it has its limitations.
Objective
The present study aims to compare three ...classificatory and predictive models: the WHO ordinal severity scale, the model based on inflammation grades, and the hybrid model.
Design
Retrospective cohort study with patient data collected and followed up from March 1, 2020, to May 1, 2021, from the nationwide SEMI-COVID-19 Registry. The primary study outcome was in-hospital mortality. As this was a hospital-based study, the patients included corresponded to categories 3 to 7 of the WHO ordinal scale. Categories 6 and 7 were grouped in the same category.
Key Results
A total of 17,225 patients were included in the study. Patients classified as high risk in each of the WHO categories according to the degree of inflammation were as follows: 63.8% vs. 79.9% vs. 90.2% vs. 95.1% (
p
<0.001). In-hospital mortality for WHO ordinal scale categories 3 to 6/7 was as follows: 0.8% vs. 24.3% vs. 45.3% vs. 34% (
p
<0.001). In-hospital mortality for the combined categories of ordinal scale 3a to 5b was as follows: 0.4% vs. 1.1% vs. 11.2% vs. 27.5% vs. 35.5% vs. 41.1% (
p
<0.001). The predictive regression model for in-hospital mortality with our proposed combined ordinal scale reached an AUC=0.871, superior to the two models separately.
Conclusions
The present study proposes a new severity grading scale for COVID-19 hospitalized patients. In our opinion, it is the most informative, representative, and predictive scale in COVID-19 patients to date.
We undertook this study to understand how the transcription factor Sox2 contributes to the malignant phenotype of glioblastoma multiforme (GBM), the most aggressive primary brain tumor. We initially ...looked for unbalanced genomic rearrangements in the Sox2 locus in 42 GBM samples and found that Sox2 was amplified in 11.5% and overexpressed in all the samples. These results prompted us to further investigate the mechanisms involved in Sox2 overexpression in GBM. We analyzed the methylation status of the Sox2 promoter because high CpG density promoters are associated with key developmental genes. The Sox2 promoter presented a CpG island that was hypomethylated in all the patient samples when compared to normal cell lines. Treatment of Sox2-negative glioma cell lines with 5-azacitidine resulted in the re-expression of Sox2 and in a change in the methylation status of the Sox2 promoter. We further confirmed these results by analyzing data from GBM cases generated by The Cancer Genome Atlas project. We observed Sox2 overexpression (86%; N = 414), Sox2 gene amplification (8.5%; N = 492), and Sox 2 promoter hypomethylation (100%; N = 258), suggesting the relevance of this factor in the malignant phenotype of GBMs. To further explore the role of Sox2, we performed in vitro analysis with brain tumor stem cells (BTSCs) and established glioma cell lines. Downmodulation of Sox2 in BTSCs resulted in the loss of their self-renewal properties. Surprisingly, ectopic expression of Sox2 in established glioma cells was not sufficient to support self-renewal, suggesting that additional factors are required. Furthermore, we observed that ectopic Sox2 expression was sufficient to induce invasion and migration of glioma cells, and knockdown experiments demonstrated that Sox2 was essential for maintaining these properties. Altogether, our data underscore the importance of a pleiotropic role of Sox2 and suggest that it could be used as a therapeutic target in GBM.
Patients with coronavirus disaese 2019 (COVID-19) can develop a cytokine release syndrome that eventually leads to acute respiratory distress syndrome requiring invasive mechanical ventilation (IMV). ...Because IL-6 is a relevant cytokine in acute respiratory distress syndrome, the blockade of its receptor with tocilizumab (TCZ) could reduce mortality and/or morbidity in severe COVID-19.
We sought to determine whether baseline IL-6 serum levels can predict the need for IMV and the response to TCZ.
A retrospective observational study was performed in hospitalized patients diagnosed with COVID-19. Clinical information and laboratory findings, including IL-6 levels, were collected approximately 3 and 9 days after admission to be matched with preadministration and postadministration of TCZ. Multivariable logistic and linear regressions and survival analysis were performed depending on outcomes: need for IMV, evolution of arterial oxygen tension/fraction of inspired oxygen ratio, or mortality.
One hundred forty-six patients were studied, predominantly males (66%); median age was 63 years. Forty-four patients (30%) required IMV, and 58 patients (40%) received treatment with TCZ. IL-6 levels greater than 30 pg/mL was the best predictor for IMV (odds ratio, 7.1; P < .001). Early administration of TCZ was associated with improvement in oxygenation (arterial oxygen tension/fraction of inspired oxygen ratio) in patients with high IL-6 (P = .048). Patients with high IL-6 not treated with TCZ showed high mortality (hazard ratio, 4.6; P = .003), as well as those with low IL-6 treated with TCZ (hazard ratio, 3.6; P = .016). No relevant serious adverse events were observed in TCZ-treated patients.
Baseline IL-6 greater than 30 pg/mL predicts IMV requirement in patients with COVID-19 and contributes to establish an adequate indication for TCZ administration.
Abstract
Background: CDK4/6 inhibition combined with anti-HER2 therapy is currently being explored in HER2-positive (HER2+) breast cancer (BC). Here, we report the final efficacy and genomic analysis ...of cohort A and B of the PATRICIA phase II trial evaluating palbociclib in combination with trastuzumab in advanced HER2+ BC. Methods: PATRICIA is a prospective, open-label, multicenter phase II trial. Patients had received 2-4 prior lines of anti-HER2-based regimens. Treatment consisted of palbociclib 200 mg daily for 2 weeks and 1 week off plus trastuzumab. The study was based on a Simon two-stage design comprising three cohorts: estrogen receptor (ER)-negative (cohort A), ER-positive (cohort B1), and ER-positive with letrozole (cohort B2). Patients with ER-positive tumors were randomized to cohorts B1 or B2. Primary endpoint was progression-free survival (PFS) rate at 6 months (PFS6). Secondary objectives included PFS, overall survival (OS) and the association of the research-based PAM50 intrinsic subtyping with PFS and OS. PAM50 was performed from FFPE samples using the nCounter platform. For each sample we calculated the PAM50 signature scores (Basal-like, HER2-E, Luminal A and B, Normal-like), CES, ROR-Subtype, ROR-proliferation and the proliferation signature score. Multivariable Cox regression analyses evaluating PAM50 subtypes, age, performance status, treatment line, type of biopsy, and ER status. Results: Seventy-one patients were recruited (n = 15 in cohort A and 28 in each cohort B). Median follow-up was 42.3 months (IQR 34.7-54.8). The PFS6 rate in cohorts A, B1, and B2 was 33.3% (5/15), 42.8% (12/28), and 46.4% (13/28), respectively. Median PFS was 4.2 months (95% CI 0.7-6.7) in cohort A, 6.0 months (95% CI 4.0-10.6) in cohort B1 and 5.1 months (95% CI 3.7-9.1) in cohort B2. Regarding PAM50, 59 (83.1%) tumors samples (42.4% metastasis) were profiled. 49.2% of the tumor samples were identified as HER2-E, followed by Luminal B (22.0%), Luminal A (16.9%), normal-like (10.2%), and Basal-like (1.7%). Luminal disease defined by PAM50 was independently associated with longer PFS compared with non-luminal disease (10.6 vs. 4.2 months median PFS; adjusted hazard ratio HR = 0.34; P = 0.007). Median OS was 21.8 months (95% CI 13.8-32.2) in cohort A, 28.0 months (95% CI 14.2-48.8) in cohort B1 and 34.3 months (95% CI 20.6-47.6) in cohort B2. Luminal disease defined by PAM50 was not independently associated with OS compared with non-luminal disease (34.3 vs. 26.1 months; adjusted HR = 0.753; P = 0.365). Among the 9 PAM50 signatures, expression of 3 signatures were found significantly associated with OS: CES (HR = 0.50; p=0.021), Luminal A score (HR=0.33; p=0.022) and ROR-S (HR=1.018; p=0.027). Conclusion: Our analysis shows that the promising PFS previously reported in trastuzumab pretreated ER-positive/HER2+ advanced breast cancer with a PAM50 Luminal A or B subtype were maintained after a median of >3 years of follow-up. A longer OS was seen in patients with luminal tumors, but results were not statistically significant and could have been influenced by the low sample size. Cohort C of PATRICIA is currently randomizing patients with HR-positive/HER2+, PAM50 Luminal A or B tumors to palbociclib and endocrine therapy plus trastuzumab or treatment of physician’s choice (NCT02448420). Acknowledgements: This study is sponsored by SOLTI and financially supported by Pfizer
Citation Format: Eva Ciruelos, Tomás Pascual, Mafalda Oliveira, Santiago Escrivá-de-Romaní, Sonia Pernas, Laia Paré, Barbara Adamo, Eduardo Martínez, Javier Cortés, Antonia Perelló, Maria Galan, Mireia Melé, Pablo Tolosa, Blanca González-Farré, Patricia Galván, Jordi Canes, Paolo Nuciforo, Xavier Gonzalez, Patricia Villagrasa, Aleix Prat. Palbociclib and trastuzumab for HER2-positive metastatic breast cancer (SOLTI-1303 PATRICIA): Final results from cohort A and B, prospective, open-label, multicenter phase II study abstract. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD8-03.
Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with ...HR+/HER2−/PIK3CA-mutated advanced breast cancer (ABC).
Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2−/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose <100 mg/dL <5.6 mmol/L and HbA1c <5.7%), and cohort B, prediabetes (fasting plasma glucose 100–140 mg/dL 5.6–7.8 mmol/L and/or haemoglobin A1C HbA1c 5.7–6.4%). Participants were at least 18 years old, with Eastern Cooperative Oncology Group performance status of 0–1, and up to two prior lines of endocrine therapy (ET) for ABC. Alpelisib plus ET were administered in 28-day cycles after initiation of prophylactic metformin plus ET. Primary endpoint was the incidence of grade 3–4 hyperglycaemia over the first 8 weeks. Secondary endpoints included safety, progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). The primary objective for cohort A and B is met with ≤7 (14.6%) and ≤4 (20%) patients with grade 3–4 hyperglycaemia over the first 8 weeks, respectively.
233 patients were screened, and 68 (20.2%) patients were enrolled in cohorts A (n = 48) and B (n = 20). Median follow-up was 7.8 months (IQR 1.4–19.6). Over the first 8 weeks, one (2.1%) of 48 patients in cohort A (95% CI: 0.5–11.1; P < 0.0001), and three (15.0%) of 20 patients in cohort B (95% CI: 5.6–37.8; P = 0.016) had grade 3–4 hyperglycaemia. Serious treatment-related adverse events occurred in seven patients (10.3%). The most common were rash (two 2.9%), vomiting (two 2.9%), and diarrhoea (two 2.9%). Discontinuation of alpelisib caused by AEs was reported in nine patients (13.2%), none caused by hyperglycaemia. At data cutoff (15 June, 2022), no treatment-related deaths were observed. In the full analysis set, median PFS was 7.3 months (95% CI: 5.9–not reached), ORR was 20.6% (95% CI: 11.7–32.1%), and CBR was 52.9% (95% CI: 40.4–65.2).
In HR+/HER2−/PIK3CA-mutated ABC, prophylactic metformin before alpelisib plus endocrine treatment has low incidence and severity of alpelicib-induced hyperglycaemia.
Novartis Pharmaceuticals.
The Basque Colorectal Cancer Screening Programme has both high participation rate and high compliance rate of colonoscopy after a positive faecal occult blood test (FIT). Although, colorectal cancer ...(CRC) screening with biannual (FIT) has shown to reduce CRC mortality, the ultimate effectiveness of the screening programmes depends on the accuracy of FIT and post-FIT colonoscopy, and thus, harms related to false results might not be underestimated. Current CRC screening programmes use a single faecal haemoglobin concentration (f-Hb) cut-off for colonoscopy referral for both sexes and all ages. We aimed to determine optimum f-Hb cut-offs by sex and age without compromising neoplasia detection and interval cancer proportion.
Prospective cohort study using a single-sample faecal immunochemical test (FIT) on 444,582 invited average-risk subjects aged 50-69 years. A result was considered positive at ≥20 μg Hb/g faeces. Outcome measures were analysed by sex and age for a wide range of f-Hb cut-offs.
We analysed 17,387 positive participants in the programme who underwent colonoscopy. Participation rate was 66.5%. Men had a positivity rate for f-Hb of 8.3% and women 4.8% (p < 0.0001). The detection rate for advanced neoplasia (cancer plus advanced adenoma) was 44.0‰ for men and 15.9‰ for women (p < 0.0001). The number of colonoscopies required decreased in both sexes and all age groups through increasing the f-Hb cut-off. However, the loss in CRC detection increased by up to 28.1% in men and 22.9% in women. CRC missed were generally at early stages (Stage I-II: from 70.2% in men to 66.3% in women).
This study provides detailed outcomes in men and women of different ages at a range of f-Hb cut-offs. We found differences in positivity rates, neoplasia detection rate, number needed to screen, and interval cancers in men and women and in younger and older groups. However, there are factors other than sex and age to consider when consideration is given to setting the f-Hb cut-off.
1008 Background: The PATRICIA trial (cohorts A-B) demonstrated that palbociclib plus trastuzumab (T) is safe and active in patients (pts) with T-pretreated HER2-positive Hormone Receptor-positive ...(HR+/HER2+) PAM50 Luminal advanced breast cancer (ABC). Here, we present the primary efficacy analysis of the randomized cohort C from the PATRICIA trial that compares the efficacy of palbociclib + T + endocrine therapy (ET) with treatment of physicians’ choice (TPC). Methods: PATRICIA (cohort C) is a randomized, open-label, phase II study conducted at 34 sites in Spain recruiting from August 2019 to August 2023. Pts with HER2+/HR+ and centrally tested PAM50 Luminal A or B intrinsic subtype ABC who had received at least one prior line of anti-HER2 based regimens were eligible. Pts were randomized 1:1 to Cohort C1 (Palbociclib 125 mg/day orally 3 weeks/1 week off + T + ET) or Cohort C2 (TPC, including T + any ET or chemotherapy (CT) + T, or T-DM1). The stratification factors were number of previous regimens for ABC and presence of visceral disease. The primary endpoint was progression-free survival (PFS). The trial was designed to recruit a total of 102 pts, having an 80% power with one-sided alpha=0.1 to detect a HR of 0.62 in favor of the palbociclib cohort. The study was closed after 73 pts were randomized due to slow recruitment. Results: At data cut-off, 264 pts were pre-screened, and 73 pts were randomized. Baseline pts characteristics are summarized in Table 1. In cohort C1, 50% of the pts received fulvestrant and 50% aromatase inhibitor as ET. In cohort C2, 37.1% of pts were treated with TDM-1, 45.7% with CT+ T, 11.4 % with ET + T and two pts withdrew their consent before starting the treatment. Palbociclib + T + ET was associated with longer PFS compared to TPC (median 9.1 vs 7.5 months, stratified HR=0.52 95%CI 0.29-0.94; two-sided p=0.031); 12-months PFS rates were 43.7% and 21.4%, respectively. The overall response rate was 18.9% (95% CI 8.6-35.7) in cohort C1 and 8.3% (95% CI 1.4-28.5) in cohort C2. Grade ≥3 adverse events occurred in 63.2% of pts in C1 and 45.5% in C2 cohort. The most frequent grade ≥3 adverse event in the experimental arm was neutropenia (55.3%). Conclusions: The combination of palbociclib, T and ET showed a statistically significant improvement in PFS in patients with previously treated PAM50 luminal A or B HER2+ advanced breast cancer, as compared to TPC. Clinical trial information: NCT02448420 . Table: see text
Background: Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in ...patients with HR+/HER2−/PIK3CA-mutated advanced breast cancer (ABC). Methods: Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2−/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose <100 mg/dL <5.6 mmol/L and HbA1c <5.7%), and cohort B, prediabetes (fasting plasma glucose 100–140 mg/dL 5.6–7.8 mmol/L and/or haemoglobin A1C HbA1c 5.7–6.4%). Participants were at least 18 years old, with Eastern Cooperative Oncology Group performance status of 0–1, and up to two prior lines of endocrine therapy (ET) for ABC. Alpelisib plus ET were administered in 28-day cycles after initiation of prophylactic metformin plus ET. Primary endpoint was the incidence of grade 3–4 hyperglycaemia over the first 8 weeks. Secondary endpoints included safety, progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). The primary objective for cohort A and B is met with ≤7 (14.6%) and ≤4 (20%) patients with grade 3–4 hyperglycaemia over the first 8 weeks, respectively. Findings: 233 patients were screened, and 68 (20.2%) patients were enrolled in cohorts A (n = 48) and B (n = 20). Median follow-up was 7.8 months (IQR 1.4–19.6). Over the first 8 weeks, one (2.1%) of 48 patients in cohort A (95% CI: 0.5–11.1; P < 0.0001), and three (15.0%) of 20 patients in cohort B (95% CI: 5.6–37.8; P = 0.016) had grade 3–4 hyperglycaemia. Serious treatment-related adverse events occurred in seven patients (10.3%). The most common were rash (two 2.9%), vomiting (two 2.9%), and diarrhoea (two 2.9%). Discontinuation of alpelisib caused by AEs was reported in nine patients (13.2%), none caused by hyperglycaemia. At data cutoff (15 June, 2022), no treatment-related deaths were observed. In the full analysis set, median PFS was 7.3 months (95% CI: 5.9–not reached), ORR was 20.6% (95% CI: 11.7–32.1%), and CBR was 52.9% (95% CI: 40.4–65.2). Interpretation: In HR+/HER2−/PIK3CA-mutated ABC, prophylactic metformin before alpelisib plus endocrine treatment has low incidence and severity of alpelicib-induced hyperglycaemia. Funding: Novartis Pharmaceuticals.
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