Thyroid cancer is the single most prevalent endocrine malignancy; differentiated thyroid cancer (DTC) accounts for more than 90 % of all malignancies and its incidence has been rising steadily. For ...more patients, surgical treatment, radioactive iodine (RAI) ablation, and thyroid-stimulating hormone (TSH) suppressive therapy achieve an overall survival (OS) rate of 97.7 % at 5 years. Nevertheless, locoregional recurrence occurs in up to 20 % and distant metastases in approximately 10 % at 10 years. Two-thirds of these patients will never be cured with radioactive iodine therapy and will become RAI-refractory, with a 3-year OS rate of less than 50 %. Over the last decade, substantial progress has been made in the management of RAI-refractory DTC. Given the controversy in some areas, the Spanish Task Force for Thyroid Cancer on behalf of Spanish Society of Endocrinology Thyroid Cancer Working Group (GTSEEN) and the Spanish Rare Cancer Working Group (GETHI) have created a national joint task force to reach a consensus addressing the most challenging aspects of management in these patients. In this way, multidisciplinary management should be mandatory and nuclear medicine targeted therapy, novel molecular targeted agents, and combinations are currently changing the natural history of RAI-refractory DTC.
This randomised, open-label, phase I/II study evaluated the efficacy and safety of nintedanib, an oral, triple angiokinase inhibitor, combined with chemotherapy, relative to bevacizumab plus ...chemotherapy as first-line therapy in patients with metastatic colorectal cancer (mCRC).
Patients with histologically confirmed mCRC (adenocarcinoma), an Eastern Cooperative Oncology Group performance status ≤2 and adequate organ function were included. Patients were randomised 2:1 to receive nintedanib 150 mg or 200 mg b.i.d. plus mFOLFOX6 (oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2 or d,l-leucovorin 400 mg/m2, 5-fluoruracil bolus 400 mg/m2 followed by 2400 mg/m2, every 2 weeks) or bevacizumab (5 mg/kg every 2 weeks) plus mFOLFOX6. During phase I, patients underwent a 3 + 3 dose-escalation schema to determine the maximum tolerated dose (MTD) of nintedanib in combination with mFOLFOX6. The primary end point was progression-free survival (PFS) rate at 9 months. Objective response (OR) was a secondary end point.
The nintedanib recommended phase II dose was 200 mg b.i.d. plus mFOLFOX6 based on safety data from phase I (n = 12). Of 128 patients randomised in the phase II part, 126 received treatment (nintedanib plus mFOLFOX6, n = 85; bevacizumab plus mFOLFOX6, n = 41). PFS at 9 months was 62.1% with nintedanib and 70.2% with bevacizumab difference: -8.1% (95% confidence interval -27.8 to 11.5). Confirmed ORs were recorded in 63.5% and 56.1% of patients in the nintedanib and bevacizumab groups, respectively. The incidence of adverse events (AEs) considered related to treatment was 98.8% with nintedanib and 97.6% with bevacizumab; the incidence of serious AEs was 37.6% with nintedanib and 53.7% with bevacizumab. The pharmacokinetics of nintedanib and the components of mFOLFOX6 were unaffected by their combination.
Nintedanib in combination with mFOLFOX6 showed efficacy as first-line therapy in patients with mCRC with a manageable safety profile and further studies in this population are warranted.
•Widely recommended symptoms identified only ∼70% COVID-19 cases.•Additional symptoms increased case finding to > 90% but tests needed doubled.•Optimal symptom combinations maximise case capture ...considering available resources.•Implications for COVID-19 vaccine efficacy trials and wider public health.
Diagnostic work-up following any COVID-19 associated symptom will lead to extensive testing, potentially overwhelming laboratory capacity whilst primarily yielding negative results. We aimed to identify optimal symptom combinations to capture most cases using fewer tests with implications for COVID-19 vaccine developers across different resource settings and public health.
UK and US users of the COVID-19 Symptom Study app who reported new-onset symptoms and an RT-PCR test within seven days of symptom onset were included. Sensitivity, specificity, and number of RT-PCR tests needed to identify one case (test per case TPC) were calculated for different symptom combinations. A multi-objective evolutionary algorithm was applied to generate combinations with optimal trade-offs between sensitivity and specificity.
UK and US cohorts included 122,305 (1,202 positives) and 3,162 (79 positive) individuals. Within three days of symptom onset, the COVID-19 specific symptom combination (cough, dyspnoea, fever, anosmia/ageusia) identified 69% of cases requiring 47 TPC. The combination with highest sensitivity (fatigue, anosmia/ageusia, cough, diarrhoea, headache, sore throat) identified 96% cases requiring 96 TPC.
We confirmed the significance of COVID-19 specific symptoms for triggering RT-PCR and identified additional symptom combinations with optimal trade-offs between sensitivity and specificity that maximize case capture given different resource settings.
Vertebrate limb buds are embryonic structures for which much molecular and
cellular data are known regarding the mechanisms that control pattern formation
during development. Specialized regions of ...the developing limb bud, such as the
zone of polarizing activity (ZPA), the apical ectodermal ridge (AER), and the
non-ridge ectoderm, direct and coordinate the development of the limb bud along
the anterior-posterior (AP), dorsal-ventral (DV), and proximal-distal (PD)
axes, giving rise to a stereotyped pattern of elements well conserved among
tetrapods. In recent years, specific gene functions have been shown to mediate
the organizing and patterning activities of the ZPA, the AER, and the non-ridge
ectoderm. The analysis of these gene functions has revealed the existence of
complex interactions between signaling pathways operated by secreted factors of
the HH, TGF-β/BMP, WNT, and FGF superfamilies, which interact with many
other genetic networks to control limb positioning, outgrowth, and patterning.
The study of limb development has helped to establish paradigms for the
analysis of pattern formation in many other embryonic structures and
organs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
BACKGROUND: Although acute exacerbations are key events in the progression of chronic obstructive pulmonary disease (COPD), their frequency and the factors associated with acute exacerbation are not ...fully known.OBJECTIVE: To determine the incidence and risk factors of very frequent exacerbations in COPD (3 per year).PATIENTS AND METHODS: In a cohort study to analyse acute exacerbation and associated factors in 512 primary care patients during a 2-year follow-up, variables of interest were collected for each patient. Acute exacerbation was defined as an event that required antibiotics and/or systemic steroids (moderate) or hospital admission (severe). Odds ratios (OR) were used to determine factors associated with exacerbation.RESULTS: Incidence of exacerbation was 61.7% in the first year of follow-up and 63.9% in the second year. During the first year, the factors associated with very frequent exacerbation were previous hospital admission (OR 1.69), dyspnoea (moderate OR 2.86 and severe-very severe OR 5.83) and the Charlson Index (OR 1.19); during the second year, associated factors were female sex (OR 4.17), history of previous hospital admissions (OR 2.90), smoking (smoker/ex-smoker) (OR 2.00) and forced vital capacity (OR 0.98).CONCLUSIONS: Incidence of exacerbation is high in COPD patients. Previous admission for exacerbation is a strong predictor and can identify patients at risk.
In the wing imaginal disc, the decapentaplegic (dpp) gene is expressed in a stripe of anterior cells near the anterior-posterior compartment boundary, and it is required solely in these cells for the ...entire disc to develop. In some viable segment polarity mutants. alterations in dpp expression have been demonstrated that correlate with changes in wing morphology. To test the hypothesis that the abnormal patterns of dpp expression are responsible directly for the mutant phenotypes, we have expressed dpp in ectopic places in wing imaginal discs, and we have found that dpp is able to cause overgrowth and pattern duplications in both anterior and posterior compartments of the wing disc. The alterations of the anterior compartment are strikingly similar to those observed in some viable segment polarity mutants. Thus, ectopic dpp alone can account for the phenotype of these mutants. We also show that ectopic expression of the segment polarity gene hedgehog (hh) gives similar morphological changes and activates dpp expression in the anterior compartment. This strongly suggests that the organizing activity of hh is mediated by dpp. We propose that the expression of dpp near the anterior - posterior compartment boundary is directed by the interaction between patched and hh, and that dpp itself could act as a general organizer of the patterning in the wing imaginal disc.
NENs are a heterogeneous family of tumors of challenging diagnosis and clinical management. Their incidence and prevalence continue to rise across all sites, stages and grades. Although improved ...diagnostic techniques have led to earlier detection and stage migration, the improved prognosis documented over time for advanced gastrointestinal and pancreatic neuroendocrine tumors also reflect improvements in therapy. The aim of this guideline is to update practical recommendations for the diagnosis and treatment of gastroenteropancreatic and lung NENs. Diagnostic procedures, histological classification and therapeutic options are briefly discussed, including surgery, liver-directed therapy, peptide receptor radionuclide therapy, and systemic hormonal, cytotoxic or targeted therapy, and treatment algorithms are provided.
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