Synergistic effect of gefitinib and rofecoxib in mesothelioma cells

<p>Abstract</p> <p>Background</p> <p>Malignant mesothelioma (MM) is an aggressive tumor that is resistant to conventional modes of treatment with chemotherapy, surgery or radiation. Research into the molecular pathways involved in the development of MM should yield information that will guide therapeutic decisions. Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are involved in the carcinogenesis of MM. Combination of COX-2 and EGFR inhibitors, therefore, could be an effective strategy for reducing cell growth in those lines expressing the two molecular markers.</p> <p>Results</p> <p>In order to verify the effect of COX-2 and EGFR inhibitors, five MM cell lines NCI-2452, MPP89, Ist-Mes-1, Ist-Mes-2 and MSTO-211 were characterized for COX-2 and EGFR and then treated with respective inhibitors (rofecoxib and gefitinib) alone and in combination. Only MPP89, Ist-Mes-1 and Ist-Mes-2 were sensitive to rofecoxib and showed growth-inhibition upon gefitinib treatment. The combination of two drugs demonstrated synergistic effects on cell killing only in Ist-Mes-2, the cell line that was more sensitive to gefitinib and rofecoxib alone. Down-regulation of COX-2, EGFR, p-EGFR and up-regulation of p21 and p27 were found in Ist-Mes-2, after treatment with single agents and in combination. In contrast, association of two drugs resulted in antagonistic effect in Ist-Mes-1 and MPP89. In these cell lines after rofecoxib exposition, only an evident reduction of p-AKT was observed. No change in p-AKT in Ist-Mes-1 and MPP89 was observed after treatment with gefitinib alone and in combination with rofecoxib.</p> <p>Conclusions</p> <p>Gefitinib and rofecoxib exert cell type-specific effects that vary between different MM cells. Total EGFR expression and downstream signalling does not correlate with gefitinib sensitivity. These data suggest that the effect of gefitinib can be potentiated by rofecoxib in MM cell lines where AKT is not activated.</p

Analysis of a Cardiac-Necrosis-Biomarker Release in Patients with Acute Myocardial Infarction via Nonlinear Mixed-Effects Models

The release of the cardiac troponin T (cTnT) in patients with acute myocardial infarc tion (AMI) has been analyzed through a methodology based on nonlinear mixed-effects (NME) models. The aim of this work concerns the investigation of any possible relationship between clin ical covariates and the dynamics of the release of cTnT to derive more detailed and useful clinical information for the correct treatment of these patients. An ad-hoc mechanistic model describing the biomarker release process after AMI has been devised, assessed, and exploited to evaluate the im pact of the available clinical covariates on the cTnT release dynamic. The following approach was tested on a preliminary dataset composed of a small number of potential clinical covariates: em ploying an unsupervised approach, and despite the limited sample size, dyslipidemia, a known risk factor for cardiovascular disease, was found to be a statistically significant covariate. By increasing the number of covariates considered in the model, and patient cohort, we envisage that this approach may provide an effective means to automatically classify AMI patients and to investigate the role of interactions between clinical covariates and cTnT relea

Clostridioides difficile Infection in an Italian Tertiary Care University Hospital: A Retrospective Analysis

Clostridioides difficile infection (CDI) is a significant cause of morbidity and mortality, mostly in frail patients. Notification is not mandatory in Italy, and data on incidence, risk of death, and recurrence are lacking. The purpose of this study was to determine CDI incidence and risk factors for mortality and recurrence. The "ICD-9 00845" code in hospital-standardized discharged forms (H-SDF) and microbiology datasets were used to retrieve CDI cases at Policlinico Hospital, Palermo between 2013 and 2022. Incidence, ward distribution, recurrence rate, mortality, and coding rate were considered. The risk of death and recurrence was predicted through multivariable analysis. There were 275 CDIs, 75% hospital-acquired, the median time between admission and diagnosis was 13 days, and the median stay was 21 days. Incidence increased from 0.3 to 5.6% (an 18.7-fold increase) throughout the decade. Only 48.1% of cases were coded in H-SDF. The rate of severe/severe-complicated cases increased 1.9 times. Fidaxomicin was used in 17.1% and 24.7% of cases overall and since 2019. Overall and attributable mortalities were 11.3% and 4.7%, respectively. Median time between diagnosis and death was 11 days, and recurrence rate was 4%. Bezlotoxumab was administered in 64% of recurrences. Multivariable analysis revealed that only hemodialysis was associated with mortality. No statistically significant association in predicting recurrence risk emerged. We advocate for CDI notification to become mandatory and recommend coding CDI diagnosis in H-SDF to aid in infection rate monitoring. Maximum attention should be paid to preventing people on hemodialysis from getting CDI

The impact of the SARS-CoV-2 pandemic on the workloads of UPMC advanced radiotherapy centers in Italy

GOALS The Advanced Radiotherapy Centers of UPMC San Pietro FBF of Rome (CC#1) and UPMC Villa Maria of Mirabella Eclano (CC#2) conducted a study to review variations in department workloads and workflows experienced during the pandemic. The potential relation between these variations and the new procedures introduced to prevent and contain the COVID-19 infection was also studied. MATERIALS AND METHODS The data used were obtained from reports present in the ARIA® system (v. 15.1 Varian Medical Systems, Palo Alto, CA, U.S.A.). To examine the workloads was used the Downtime, an indicator that directly quantifies the inactivity of the department, derived from the ratio between the daily stand-by time of the LINACs (TrueBeam STx®, Varian Medical Systems, Palo Alto, CA, U.S.A.) and the mean number of treatments performed every day. In order to examine the workflows and possible delays, we measured the time between the treatments ("Therapy intervals"). RESULTS The Downtime average at CC#1 slightly increased from 3.1% in 2019 to 3.8% in 2020. However, the monthly analysis shows significant reduction (March-April-May) and increase (November-December) peaks. At CC#2, the 2020 Downtime trend was fairly consistent (average value: 3.3%), with an increase during the first wave of the pandemic. The "5-10 min" Therapy intervals at CC#1, reviewed comparing the March-April-May 2020 quarter with 2019, were higher in the first months and lower in May; the "10-15 min" intervals were stable; the "&gt;20 min" intervals slightly increased in March 2020. At CC#2, the trend in 2020 decreased during the months of higher health care emergency and increased during the summer months. CONCLUSIONS The fact that the trends of the indicators show peaks only during the periods of major health care emergency indicates an impact of the pandemic, both on the workload and on the workflow. However, they also highlight the staff's ability to rapidly adapt to the new procedures, without affecting the overall performance of the both centers

Impatto della pandemia da SARS-CoV-2 sui workload di due centri UPMC di radioterapia ad alta specializzazione in Italia

OBIETTIVI I Centri di Radioterapia UPMC San Pietro FBF di Roma (CC#1) e UPMC Villa Maria di Mirabella Eclano (CC#2) hanno condotto uno studio con l’obiettivo di analizzare le variazioni avvenute durante la pandemia sui workload e i workflow di reparto. È stato, inoltre, ricercato l’eventuale nesso tra queste e l’introduzione di nuove procedure per la prevenzione e il contenimento del contagio da Covid-19. MATERIALI E METODI I dati utilizzati sono stati ricavati da reports presenti nel sistema ARIA (V.15.1 Varian Medical System, CA, Palo Alto, USA). Per esaminare i workload è stato utilizzato il Downtime, un indicatore che quantifica direttamente l'inattività del reparto, ricavato dal rapporto tra il tempo di standby giornaliero dei LINAC (TrueBeam STx®, Varian Medical System, CA, Palo Alto, USA) e la media di trattamenti giornalieri effettuati. Per esaminare workflow ed eventuali ritardi tra le attività, sono stati valutati gli intervalli di tempo tra una terapia e la successiva (Intervalli di terapia). RISULTATI Il Downtime nel CC#1 ha subìto un leggero aumento del valore medio dal 3.1% del 2019 al 3.8% del 2020, tuttavia l’analisi mensile mostra consistenti picchi di riduzione (marzo-aprile-maggio) e di incremento (novembre-dicembre). Per il CC#2 il trend del Downtime nel 2020 è abbastanza regolare (valore medio del 3,3%), con un incremento durante la prima ondata della pandemia. Gli Intervalli di terapia di “5-10 min” nel CC#1, analizzati confrontando il trimestre marzo-aprile-maggio 2020 col 2019, risultano maggiori per i primi mesi e ridotti a maggio; quelli di “10-15” min risultano stabili; quelli “&gt;20 min” sono leggermente aumentati a marzo 2020. Per il CC#2 il trend nel 2020 decresce nei mesi di maggiore emergenza sanitaria e incrementa nei mesi estivi. CONCLUSIONI Il fatto che i trend degli indicatori utilizzati abbiano dei picchi esclusivamente in corrispondenza dei periodi di maggiore emergenza sanitaria, è indice di un certo impatto – sia in termini di workload che di workflow – della pandemia, ma anche della capacità del personale di adattarsi in breve tempo alle nuove procedure da eseguire, senza inficiare sul rendimento generale dei Centri

Role of Intrinsic Subtype Analysis with PAM50 in Hormone Receptors Positive HER2 Negative Metastatic Breast Cancer: A Systematic Review

Endocrine therapy (ET), associated with CDK 4/6 inhibitors, represents the first choice of treatment for HR+/HER2- metastatic breast cancer (mBC). Primary or secondary endocrine resistance could develop; however validated biomarkers capable of predicting such a conditions are not available. Several studies have shown that HR+/HER2- mBC comprises five intrinsic subtypes. The purpose of this systematic review was to analyze the potential correlations between intrinsic subtype, efficacy of treatment, and patient outcome. Five papers that analyzed the intrinsic subtype with PAM50 assay in patients (pts) with HR+/HER2- mBC treated with ET (alone or in combination) within seven phase III clinical trials (EGF30008, BOLERO-2, PALOMA-2,3, MONALEESA-2,3,7) were identified. Non-luminal subtypes are more frequent in endocrine-resistant pts and in metastatic sites (vs. primary tumors), have less benefit from ET, and worse prognosis. Among these, HER2-enriched subtypes are similar to HER2+ tumors and benefit from the addition of anti-HER2 agents (lapatinib) and, for less clear reasons, of ribociclib (unconfirmed data for palbociclib and everolimus). Basal-like subtypes are similar to triple-negative tumors, making them more sensitive to chemotherapy. The intrinsic subtype is also not static but can vary over time with the evolution of the disease. Currently, the intrinsic subtype does not play a decisive role in the choice of treatment in clinical practice, but has potential prognostic and predictive value that should be further investigated

Takotsubo Syndrome after Pacemaker Implantation: A Systematic Review

Background: Takotsubo syndrome (TTS) is an acute cardiac condition characterized by a temporary wall motion abnormality of the left ventricle that mimics an acute coronary syndrome (ACS). TTS usually occurs following emotional or physical triggering event. More recently, sporadic cases of TTS arising after pacemaker implantation were reported. Methods: We performed a systematic review of the available literature to provide a comprehensive overview of the current knowledge about pacemaker implantation-induced TTS. Results: The articles selected included case reports and one registry on 28 patients. Most cases occurred in women (75%), encompassing a broad age range. The mean age of the cases described was 74 years. Full recovery of cardiac function was reported in most cases (92.3%), with largely varying recovery times, on average 7 weeks. The most common comorbidity was arterial hypertension and the average ejection fraction at admission was approximately 62%. Clinical severity ranges from asymptomatic cases to severe clinical heart failure syndrome. Altogether the case fatality rate was 3.6%. Conclusions: For rare it might be, awareness about the potential to develop TTS after pacemaker implantation should prompt careful clinical monitoring, with daily electrocardiogram (ECG) monitoring and at least one echocardiographic examination prior to patients’ discharge to allow early diagnosis and minimize the clinical risk