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Treatment and clinical-outcomes were described in a sub-cohort of non-small-cell lung cancer (NSCLC) patients with disease-progression (PD) after epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) treatment. We retrospectively analyzed a single-institutional EGFR mutation positive (EGFRmut+) NSCLC cohort for post-TKI-PD management, and assessed overall survival (OS) and post-progression survival (PPS). All de-novo (first lung-cancer occurrence) stage IIIA-IV patients, as well as de-novo stage IV subset was analyzed. Multi-state modeling (MSM) and a Cox PH regression model with propensity score weights adjusted for clinicopathological variables between: diagnosis and PD and PD to death. 123 stage IIIA-IV patients were identified with 104 meeting RECIST-1.1-PD criteria. This RECIST-1.1-PD criteria subset included females (64.6%), Asians (39.4%), never/non-smokers (55.8%), and exon 19 deletion carriers (44.2%). Commonest treatment beyond initial-PD was continuing TKI alone (46/104), with another 21 patients continuing TKI plus additional systemic therapy. The median OS for patients who continued TKI treatment at initial-PD was 21.1 months versus 15.6 months for patients who discontinued TKI, p = 0.006. Via MSM analysis, continuing TKI at initial-PD followed by other systemic therapy was associated with an 83% reduced death risk, adjusted HR: 0.17 (95% CI: 0.07, 0.39). In the Cox PH model, ever-smokers with an exon 19 deletion had increased risk of death after PD (adjusted HR: 3.19, 95% CI: 1.54, 6.58), as did exon 21 mutation carriers, (adjusted HR: 2.10, 95% CI: 1.10, 4.00) and females (adjusted HR: 3.19, 95% CI: 1.54, 6.58). Subsequent systemic therapy after continuing TKI at initial-PD reduced the risk of death. Additionally, our data suggest that positive smoking history increases death risk for some EGFR mutation types and females.

Ki67 is a commonly used marker of cancer cell proliferation, and has significant prognostic value in breast cancer. In spite of its clinical importance, assessment of Ki67 remains a challenge, as current manual scoring methods have high inter- and intra-user variability. A major reason for this variability is selection bias, in that different observers will score different regions of the same tumor. Here, we developed an automated Ki67 scoring method that eliminates selection bias, by using whole-slide analysis to identify and score the tumor regions with the highest proliferative rates. The Ki67 indices calculated using this method were highly concordant with manual scoring by a pathologist (Pearson's r = 0.909) and between users (Pearson's r = 0.984). We assessed the clinical validity of this method by scoring Ki67 from 328 whole-slide sections of resected early-stage, hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. All patients had Oncotype DX testing performed (Genomic Health) and available Recurrence Scores. High Ki67 indices correlated significantly with several clinico-pathological correlates, including higher tumor grade (1 versus 3, P<0.001), higher mitotic score (1 versus 3, P<0.001), and lower Allred scores for estrogen and progesterone receptors (P = 0.002, 0.008). High Ki67 indices were also significantly correlated with higher Oncotype DX risk-of-recurrence group (low versus high, P<0.001). Ki67 index was the major contributor to a machine learning model which, when trained solely on clinico-pathological data and Ki67 scores, identified Oncotype DX high- and low-risk patients with 97% accuracy, 98% sensitivity and 80% specificity. Automated scoring of Ki67 can thus successfully address issues of consistency, reproducibility and accuracy, in a manner that integrates readily into the workflow of a pathology laboratory. Furthermore, automated Ki67 scores contribute significantly to models that predict risk of recurrence in breast cancer.

Neurohypophysial dysfunction is common in the first days following traumatic brain injury (TBI), manifesting as dysnatremia in approximately 1 in 4 patients. Both hyponatremia and hypernatremia can impair recovery from TBI and in the case of hypernatremia, there is a significant association with excess mortality. Hyponatremia secondary to syndrome of inappropriate antidiuretic hormone secretion (SIAD) is the commonest electrolyte disturbance following TBI. Acute adrenocorticotropic hormone (ACTH)/cortisol deficiency occurs in 10–15% of TBI patients and can present with a biochemical picture identical to SIAD. For this reason, exclusion of glucocorticoid deficiency is of particular importance in post-TBI SIAD. Cerebral salt wasting is a rare cause of hyponatremia following TBI. Hyponatremia predisposes to seizures, reduced consciousness, and prolonged hospital stay. Diabetes insipidus (DI) occurs in 20% of cases following TBI; where diminished consciousness is present, appropriate fluid replacement of renal water losses is occasionally inadequate, leading to hypernatremia. Hypernatremia is strongly predictive of mortality following TBI. Most cases of DI are transient, but persistent DI is also predictive of mortality, irrespective of plasma sodium concentration. Persistent DI may herald rising intracranial pressure due to coning. True adipsic DI is rare following TBI, but patients are vulnerable to severe hypernatremic dehydration, exacerbation of neurologic deficits and hypothalamic complications, therefore clinicians should be aware of this possible variant of DI.

BackgroundTo assess the impact of location versus number of extra-pulmonary metastatic sites (EPMS) on survival in stage IV non-small cell lung cancer (NSCLC).Methods and materialsRetrospective analysis was conducted on patients diagnosed during 1999–2013 with stage IV, M1b (AJCC 7th edition) NSCLC using the large, institutional Glans-Look Database, which contains patient demographic, clinical, pathological, treatment, and outcome information. We assessed the impact of location and number of EPMS and identified correlates of overall survival using the Kaplan–Meier method and Cox regression.ResultsWe identified a total of 2065 NSCLC patients with EPMS. Median age was 67 (IQR 58–75) years, 52% were men, and 78% were current or former smokers. 60% had one EPMS, and 40% had two or more EPMS. Among those with only one EPMS, most frequent organ involvement included bone (40%), brain (32%), and liver (13%). Median overall survival (mOS) was worst in those with liver metastasis and best in those with adrenal metastasis (2.0 vs. 5.2 months, p = 0.015). However, outcomes based on site of organ involvement were not significantly different in multivariable analysis. Compared to patients with one EPMS, individuals with two or more EPMS experienced worse outcomes (mOS ≤ 2.9 vs. 3.9 months, p < 0.001), and were associated with worse prognosis in Cox regression analysis (HR 1.5, 95% CI 1.3–1.7, p < 0.001).ConclusionsNumber rather than location of EPMS is a prognostic factor in patients with stage IV M1b NSCLC. This information is relevant for accurate prognostication, stratification of participants in future clinical trials, and timely and appropriate advanced care planning.

The Posidonia oceanica decline due to climate change and other anthropogenic pressures, such as chemical pollution, is well known in the scientific community. However, a comprehensive study of the full content of the organic micropollutants found in this significant seagrass has not yet been carried out. Second, an eco-friendly extraction procedure that does not require a large sample, preserves the seagrass’s ecological integrity and functions, and follows green-chemistry principles, is lacking. These information gaps represent the aims of this study. For this purpose, trials with diverse simple and affordable extraction methods to detect one of the most ubiquitous contaminants (polycyclic aromatic hydrocarbons or PAHs) were conducted. As a result, the use and validation of a polytron homogenizer and an ultrasonic bath were proposed for the extraction of priority PAHs from tissues of P. oceanica and marine sediments, respectively. Tissues (leaves and rhizomes) of P. oceanica and sediment samples were collected, extracted, and subjected to a thorough analysis, i.e., target, suspect, and unknown screenings, using gas chromatography coupled to high resolution mass spectrometry (GC-Q-Orbitrap MS). Target analysis revealed seven priority parent-PAHs, whilst during the suspect screening, four PAH-derivatives and three other parent-PAHs were tentatively identified. In the additional third unknown analysis, 11 structures, several with concerning toxicity, were also tentatively identified. Numerous of the identified compounds showed elevated detection frequency in the environmental samples, even reaching 100%, such as the cases of the parent-PAHs (naphthalene, phenanthrene and retene), some PAH-derivatives, one UV stabilizer, and plastic additives along with pesticides. The methods proposed here should be considered for future monitoring of P. oceanica, as well as the three-way analytic approach (target, suspect and unknown), to obtain a more real and accurate idea of the organic micropollutants content in the environment.

Chronic hypernatraemia is a rare clinical entity. In the younger population, hypernatraemia is often a consequence of failure to generate thirst in response to osmotic stimuli.We report the case of a male patient admitted with severe hypernatraemia (plasma sodium 175 mmol/L) on return from holidays. His urine was maximally concentrated at 894 mOsm/kg—suggestive of normal vasopressin reserve. MRI of the brain showed a large extra-axial cyst, with preservation of the posterior pituitary bright spot. Formal osmoregulatory studies demonstrated normal osmoregulated vasopressin secretion and normal thirst, but no appropriate drinking behaviour.This patient illustrates a unique pathophysiological disconnect between thirst appreciation and the central drive to drink, in the context of normal osmoregulatory function. It is likely that this disconnect is related to the patient’s large intracranial cyst.The management challenge is to maintain appropriate fluid intake in order to prevent recurrent severe hypernatraemia.

Within the double context of the worldwide crisis and the crisis of the Romanian economy, of the factors that contribute to the achievement of performance within the economic system an important role, as far as ensuring an increased level of productivity is concerned, is played by the agricultural inputs. The analysis carried out upon the market of agricultural inputs in Romania underline a decrease of performance of the domestic input producers in front of an increased external competitiveness, which also has a strong impact upon the food industry

Klinefelter syndrome (KS) is the most common cause of primary hypogonadism in male patients; however, the diagnosis of KS is frequently delayed or missed. This delay can lead to undesirable outcomes for patients, especially considering that individuals with KS have a higher risk of developing specific malignancies, including breast cancer, non-Hodgkin’s lymphoma and mediastinal germ cell tumours. We present a case of a male patient in his 60s, where the established diagnosis of metastatic bilateral breast cancer prompted us to investigate and subsequently confirm a diagnosis of KS. This case highlights the diagnostic challenges of KS and emphasises the unfavourable consequences of a delayed diagnosis. We aim to raise awareness and enhance physicians’ understanding of KS and its non-reproductive manifestations, with a view to promote early recognition and improve patient outcomes.

The Posidonia oceanica decline due to climate change and other anthropogenic pressures, such as chemical pollution, is well known in the scientific community. However, a comprehensive study of the full content of the organic micropollutants found in this significant seagrass has not yet been carried out. Second, an eco-friendly extraction procedure that does not require a large sample, preserves the seagrass's ecological integrity and functions, and follows green-chemistry principles, is lacking. These information gaps represent the aims of this study. For this purpose, trials with diverse simple and affordable extraction methods to detect one of the most ubiquitous contaminants (polycyclic aromatic hydrocarbons or PAHs) were conducted. As a result, the use and validation of a polytron homogenizer and an ultrasonic bath were proposed for the extraction of priority PAHs from tissues of P. oceanica and marine sediments, respectively. Tissues (leaves and rhizomes) of P. oceanica and sediment samples were collected, extracted, and subjected to a thorough analysis, i.e., target, suspect, and unknown screenings, using gas chromatography coupled to high resolution mass spectrometry (GC-Q-Orbitrap MS). Target analysis revealed seven priority parent-PAHs, whilst during the suspect screening, four PAH-derivatives and three other parent-PAHs were tentatively identified. In the additional third unknown analysis, 11 structures, several with concerning toxicity, were also tentatively identified. Numerous of the identified compounds showed elevated detection frequency in the environmental samples, even reaching 100%, such as the cases of the parent-PAHs (naphthalene, phenanthrene and retene), some PAH-derivatives, one UV stabilizer, and plastic additives along with pesticides. The methods proposed here should be considered for future monitoring of P. oceanica, as well as the three-way analytic approach (target, suspect and unknown), to obtain a more real and accurate idea of the organic micropollutants content in the environment.

Background: We examined clinical outcomes in a population-based cohort of EGFR mutant advanced NSCLC patients, exploring the potential role of factors including tumour EGFR mutation fraction and cellularity in predicting outcomes. Methods: A cohort of patients with EGFR mutant advanced NSCLC was identified ( N =293); clinical outcomes, pathologic and treatment details were collected. Tumour response was determined from radiology and clinical notes. Association between demographic and pathologic variables EGFR TKI response, time to treatment failure (TTF) and overall survival (OS) was examined using logistic regression and proportional hazards regression. EGFR TKI response rates were summarised by percent mutation fraction to explore their association. Results: Higher mutation fraction was associated with greater EGFR TKI response rate (odds ratio 1.58, 95% CI=1.21–2.07, P =0.0008), longer TTF (hazard ratio 0.80, 95% CI=0.68–0.92, P =0.003) and better OS (hazard ratio 0.81, 95% CI=0.67–0.99, P =0.04). However, even in patients with ⩽5% mutation fraction, response rate was 34%. Females had longer TTF ( P =0.02). Conclusions: EGFR mutation fraction in tumour samples was significantly associated with response, TTF and OS. Despite this, no lower level of mutation fraction was detected for which EGFR TKI should be withheld in those with activating EGFR mutations.