Activity of osimeRTInib in non-small-cell lung Cancer with UNcommon epidermal growth factor receptor mutations: retrospective Observational multicenter study (ARTICUNO).

BACKGROUND: Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted. PATIENTS AND METHODS: The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method. RESULTS: Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy. CONCLUSION: The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.

Author Correction: Ancient DNA of Guinea Pigs (Cavia spp.) Indicates a Probable New Center of Domestication and Pathways of Global Distribution.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Ancient DNA of Guinea Pigs (Cavia spp.) Indicates a Probable New Center of Domestication and Pathways of Global Distribution.

Guinea pigs (Cavia spp.) have a long association with humans. From as early as 10,000 years ago they were a wild food source. Later, domesticated Cavia porcellus were dispersed well beyond their native range through pre-Columbian exchange networks and, more recently, widely across the globe. Here we present 46 complete mitogenomes of archaeological guinea pigs from sites in Peru, Bolivia, Colombia, the Caribbean, Belgium and the United States to elucidate their evolutionary history, origins and paths of dispersal. Our results indicate an independent centre of domestication of Cavia in the eastern Colombian Highlands. We identify a Peruvian origin for the initial introduction of domesticated guinea pigs (Cavia porcellus) beyond South America into the Caribbean. We also demonstrate that Peru was the probable source of the earliest known guinea pigs transported, as part of the exotic pet trade, to both Europe and the southeastern United States. Finally, we identify a modern reintroduction of guinea pigs to Puerto Rico, where local inhabitants use them for food. This research demonstrates that the natural and cultural history of guinea pigs is more complex than previously known and has implications for other studies regarding regional to global-scale studies of mammal domestication, translocation, and distribution.

[Atypical presentation of early childhood epileptic encephalopathy associated with the gene KCNT1]. / Presentación atípica de encefalopatía epiléptica infantil precoz asociada al gen KCNT1.

TITLE: Presentación atípica de encefalopatía epiléptica infantil precoz asociada al gen KCNT1.

MANAGEMENT OF ENDOCRINE DISEASE: Risk of overtreatment in patients with adrenal insufficiency: current and emerging aspects.

The effects of long-term replacement therapy of adrenal insufficiency (AI) are still a matter of controversy. In fact, the established glucocorticoid replacement regimens do not completely reproduce the endogenous hormonal production and the monitoring of AI treatment may be a challenge for the lack of reliable clinical and biochemical markers. Consequently, several AI patients are frequently exposed to relative glucocorticoid excess potentially leading to develop chronic complications, such as diabetes mellitus, dyslipidemia, hypertension and fragility fractures with consequent impaired QoL and increased mortality risk. This review deals with the pathophysiological and clinical aspects concerning the over-replacement therapy of primary and secondary AI.

Daily activity rhythms and the stress-related response in the wedge sole (Dicologoglossa cuneata Moreau, 1881).

To gain further insights on the wedge sole (Dicologoglossa cuneata Moreau, 1881) physiology and behavior, we evaluated its daily feeding and locomotor activity rhythms and compared three different feeding strategies: self-feeding (SF), diurnal feeding schedule (DS) and nocturnal feeding schedule (NS). 450 fish divided into three groups (three replicates each), were kept during 65days. SF had free access to self-feeders whereas DS and NS were fed four times a day. Physiological stress parameters as plasma cortisol, glucose, lactate, proteins and triglycerides were determined. Under the SF setting, the 91% of feeding demands occurred during the dark phase. Furthermore, locomotor activity was also higher during the scotophase (64% of the total activity). Significantly higher values for specific growth rate (SGR) and feed efficiency rate (FER) were observed in NS (0.49 and 0.48%day-1, respectively); whereas SF consumed much less food than the rest and presented a high mortality rate (46%). Plasma cortisol levels were dramatically increased in SF and DS compared to NS (21.8±6.1, 65.8±30.3 and 0.3±0.1ngmL-1, respectively). In summary, the wedge sole appears as a species with nocturnal locomotor and feeding behaviors and NS as the most appropriate feeding strategy. These new findings appear as key information for both the preservation of natural stocks of this species and its rearing.

Inyección de antitrombina en un seudoaneurisma arterial en un neonato / Thrombin injection in an arterial pseudoaneurysm in a neonate

No disponible

Malignant pleural mesothelioma: from the bench to the bedside.

Optimal management of malignant pleural mesothelioma (MPM), which is mainly based on patient characteristics and clinical stage, is not clearly defined yet, although detailed, practical guidelines for these patients have been proposed by some scientific societies. Translational research, in the field of this disease, is currently in progress and different molecular oncogenic pathways leading to the growth and progression of MPM have been characterized with recent pharmaceutical developments. However, further in-depth analysis still needs to be done for a more advanced deciphering of the step-by-step process leading from early increased mesothelial cell proliferation to invasive mesothelioma, from which we are expecting the development of definitively effective therapy. Thus, this review is an overview of the recent advances in the biology of MPM and their potential therapeutic applications in the field of MPM diagnosis and treatment.

Early diagnosis and treatment of renal cell carcinoma of native kidney in kidney transplantation.

BACKGROUND: The frecuency of malignancies in renal transplant (RT) patients is increasing. Renal cell carcinoma (RCC) of native kidneys is one of the most frequent and its outcome can be more aggressive than in general population. OBJECTIVE: To evaluate the incidence and prognosis of RCC in renal transplant patients followed in our transplantation unit. METHODS: Between January 1997 and December 2009, 683 patients underwent kidney transplant at our hospital. Ultrasonography of the native kidneys was annually performed in all renal transplant patients. When suspect solid masses were found at ultrasonography, patients underwent computed tomography. If the suspicion was confirmed, nephrectomy was performed. RESULTS: 14 radical nephrectomies were performed in 12 patients due to suspect CCR. In 11 nephrectomies (corresponding to 9 patients), anatomopathologic diagnosis was CCR (incidence 1.5%). Histologic stage was T1N0M0 in all cases. In the other 3 RT, the diagnosis was complicated renal cyst. Those patients without carcinoma had polycystic kidney disease. The time on dialysis before CCR diagnosis was 36.7 ± 24.3 months and the interval between RT and diagnosis was 39 ± 25.8 months. After a mean follow-up of 58.6 ± 38.6 months, the outcome of all cases has been excellent, without tumor recurrence. CONCLUSIONS: Annual renal ultrasonography plays a key role in the early diagnosis of CRR. The early treatment of this pathology is associated with an excellent prognosis in RT patients.

Characterization of Vibrio tapetis strains isolated from diseased cultured Wedge sole (Dicologoglossa cuneata Moreau).

The first isolation of Vibrio tapetis from Wedge sole (Dicologoglossa cuneata) is reported. The bacterium was recovered from ulcers of ailing cultured fish, from two different outbreaks occurred in spring 2005. The four isolates found (a200, a201, a204 and a255) were biochemically, genetically and serologically characterized and diagnosis was confirmed by PCR V. tapetis specific primers and multilocus sequencing analysis (MLSA). The isolates constituted a homogeneous phenotypic and genotypic group, being distinct to the already serological and genetic groups defined within the species. A virulence evaluation of the isolate a255 was also carried out; however this strain was unable to induce disease in fry and juvenile Wedge sole.

Generic parameterization for a pharmacokinetic model to predict Cd concentrations in several tissues of different fish species.

In the present work, a set of generic parameters was proposed for a pharmacokinetic model, with the objective of predicting Cd concentration in the tissues of diverse fish species under different environmental conditions. Cd concentrations in a number of tissues of Oncorhynchus mykiss and Cyprinus carpio were estimated by a structurally identifiable multicompartmental model (unique solution). The 13 generic parameters of the model comprised exchange rates, tissue-blood partition coefficients, and weight-corrected elimination rate constants accounting for the routes of water respiration, excretion and egestion. On the other hand, absorption efficiencies from water and food were considered to be condition-specific and estimated for each experiment. These two parameters reflected the differences in fish exposure to diet (food type and metal concentration) or water (water chemistry and bioavailable metal concentration). A data set of 27 experiments of Cd bioaccumulation in fish tissues was compiled for model calibration. The selected dynamics on trout and carp were performed under very different experimental conditions, involving water and/or food exposure, different fish weights and exposure concentrations and the presence/absence of depuration periods. Model predicted, for most compartments and experiments, the tendency of Cd dynamics. However, accumulation in liver and kidney was underestimated in approximately a half of the experiments, due mainly to a rapid metallothionein (MT) sequestration phenomena and subsequent saturation on liver and kidney produced under high exposure concentrations. On the other hand, both generic and condition-specific parameter values were in accordance with the values reported in literature when available. Therefore, the results obtained in this work are an initial step indicating that a generic global input parameter set could be applied to physiology-based pharmacokinetic (PBPK) models for estimating Cd accumulation in fish in different types of scenarios.

Immunohistochemical expression of somatostatin receptors in digestive endocrine tumours.

INTRODUCTION: Somatostatin receptors are expressed in a large number of human tumours. The somatostatin receptors types 1-5 expression in a series including 100 gastro-entero-pancreatic endocrine tumours were analysed. METHODS: From a prospectively built database of patients with gastro-entero-pancreatic endocrine tumours referred from three institutions, 100 cases with clinical and pathological data were selected. Somatostatin receptors expression by immunohistochemistry with somatostatin receptor types 1-5 antibodies in tissue paraffin sections were studied and correlated with the histological diagnosis according to the WHO classification, location and functional status. RESULTS: Of the 100 cases, 67 were gastrointestinal tumours, 25 pancreatic and 8 liver metastasis of unknown origin. Thirty-one of them were functioning tumours: 2 insulinomas, 5 gastrinomas, 1 glucagonoma and 23 carcinoids. Somatostatin receptors expression was observed in 94 tumours. The six negative cases were all non-functioning tumours. Somatostatin receptors 2a and 5 were highly expressed (86 and 62%, respectively), and surprisingly found even in poorly differentiated endocrine carcinomas. Somatostatin receptors expression was less frequent in pancreatic than in gastrointestinal tumours. Well-differentiated neoplasms had a higher density of somatostatin receptors. Only SSTR2a showed membrane staining. CONCLUSIONS: Immunohistochemistry revealed that somatostatin receptors were highly expressed in both primary and metastatic gastro-entero-pancreatic endocrine tumours with heterogeneous staining distribution. It proved to be a reliable technique even in small tumour samples.