Unlocking the potential of Molecular Tumor Boards: from cutting-edge data interpretation to innovative clinical pathways.

The emerging era of precision medicine is characterized by an increasing availability of targeted anticancer therapies and by the parallel development of techniques to obtain more refined molecular data, whose interpretation may not always be straightforward. Molecular tumor boards gather various professional figures, in order to leverage the analysis of molecular data and provide prognostic and predictive insights for clinicians. In addition to healthcare development, they could also become a tool to promote knowledge and research spreading. A growing body of evidence on the application of molecular tumor boards to clinical practice is forming and positive signals are emerging, although a certain degree of heterogeneity exists. This work analyzes molecular tumor boards' potential workflows, figures involved, data sources, sample matrices and eligible patients, as well as available evidence and learning examples. The emerging concept of multi-institutional, disease-specific molecular tumor boards is also considered by presenting two ongoing nationwide experiences.

Platinum-induced upregulation of ITGA6 promotes chemoresistance and spreading in ovarian cancer.

Platinum (PT)-resistant Epithelial Ovarian Cancer (EOC) grows as a metastatic disease, disseminating in the abdomen and pelvis. Very few options are available for PT-resistant EOC patients, and little is known about how the acquisition of PT-resistance mediates the increased spreading capabilities of EOC. Here, using isogenic PT-resistant cells, genetic and pharmacological approaches, and patient-derived models, we report that Integrin α6 (ITGA6) is overexpressed by PT-resistant cells and is necessary to sustain EOC metastatic ability and adhesion-dependent PT-resistance. Using in vitro approaches, we showed that PT induces a positive loop that, by stimulating ITGA6 transcription and secretion, contributes to the formation of a pre-metastatic niche enabling EOC cells to disseminate. At molecular level, ITGA6 engagement regulates the production and availability of insulin-like growth factors (IGFs), over-stimulating the IGF1R pathway and upregulating Snail expression. In vitro data were recapitulated using in vivo models in which the targeting of ITGA6 prevents PT-resistant EOC dissemination and improves PT-activity, supporting ITGA6 as a promising druggable target for EOC patients.

Alpelisib for PIK3CA-mutated advanced gynecological cancers: First clues of clinical activity.

OBJECTIVE: Recurrent gynecological tumors (e.g., endometrial, and ovarian cancers) are incurable diseases; therefore, new treatment options are urgently needed. The PTEN-AKT-PI3K pathway is frequently altered in these tumors, representing a potential treatment target. Alpelisib is an α-specific PI3K inhibitor approved in PIK3CA-mutated advanced breast cancer. We report outcomes from a large series of patients with PIK3CA-mutated gynecological cancers prospectively treated with alpelisib within a controlled program. METHODS: From April 2021 to December 2022, 36 patients with PIK3CA-mutated advanced gynecological cancers received alpelisib 300 mg orally once daily. Objective response (ORR) and disease control (DCR) rates provided measure of the antitumor activity of alpelisib, the primary objective of the study. RESULTS: Included patients had endometrial (17/36 [47%]), ovarian (10/36 [28%]), or other gynecological cancers (9/36 [25%]). Most patients had received 2-3 prior systemic treatments (endometrial, 47·2%; ovarian, 60%; other, 56%), and presented with visceral metastases at baseline (82%, 70%, and 56%, respectively). Overall, 17 different PIK3CA mutations were found, including 53% in the kinase domain (most commonly H1047R) and 36% in the helical domain (most commonly E545K). Overall, the ORR was 28% and DCR was 61%, with the greatest benefit observed in patients with endometrial cancer (35% and 71%, respectively). CONCLUSION: Alpelisib represents an active treatment option in patients with recurrent gynecological cancers harboring a PIK3CA mutation. These findings support the need of biomarker-driven randomized trials of PI3K inhibitors in gynecological cancers.

Incorporation of anti-PD1 or anti PD-L1 agents to platinum-based chemotherapy for the primary treatment of advanced or recurrent endometrial cancer. A meta-analysis.

IMPORTANCE: Various randomized trials have explored the efficacy of combining immune checkpoint inhibitors (ICIs) with first-line chemotherapy in advanced endometrial cancer. We aimed to summarize available data and clarify the benefit of adding immunotherapy according to the DNA mismatch repair status (deficient, dMMR or proficient, pMMR) and the specific type of agent used (anti-PD1 or anti-PD-L1). OBJECTIVE: To assess whether the addition of ICIs to standard platinum-based chemotherapy enhances progression-free survival (PFS) for patients with advanced endometrial cancer both overall and based on DNA mismatch repair status. DATA SOURCES: Electronic databases (PubMed, Embase and Cochrane Library) and conference proceedings were searched for first line, randomized and controlled trials integrating ICIs with chemotherapy for the treatment of advanced endometrial cancer published or presented by November 1, 2023. STUDY SELECTION: Five studies, comprising 2456 patients (1308 received ICIs with chemotherapy and 1148 treated with chemotherapy alone) met the selection criteria and were included in the analysis. Experimental arms included pembrolizumab, dostarlimab (anti-PD1) and durvalumab, atezolizumab and avelumab (anti-PD-L1) combined with standard three-weekly carboplatin-paclitaxel chemotherapy backbone. Endometrial carcinosarcoma were included in 3 out of 5 trials. DATA EXTRACTION AND SYNTHESIS: For comparison of PFS outcomes, extrapolation of hazard ratios (HRs), 95% confidence intervals (CI) and PFS events was performed for each included study in the overall population and according to subgroups. Data analysis was conducted using a random-effects model. RESULTS: The addition of ICIs to chemotherapy improved PFS compared to chemotherapy alone in the overall population (pooled HR, 0.63; 95 % CI, 0.52--0.76; P <.001). In the dMMR subgroup the benefit was more pronounced (pooled HR, 0.34; 95 % CI, 0.27--0.44; P <.001) and not affected by drugs used with pooled HRs of 0.39 (95 % CI, 0.28--0.55; P <.001) and 0.34 (95 % CI, 0.27--0.44; P <.001) for PD-L1 and PD1 inhibitors, respectively. For pMMR patients, a statistically significant benefit in terms of PFS was confirmed only when anti-PD1 were used (anti-PD-1: HR 0.64, 95 % CI: 0.46-0.90, P =.010 vs anti-PD-L1: HR 0.87, 95 % CI: 0.73-1.03, P =.104) CONCLUSIONS AND RELEVANCE: This meta-analysis confirmed the advantage in terms of PFS of adding ICIs to standard platinum-based chemotherapy. While dMMR patients benefit from the incorporation of both anti PD-1 or anti PD-L1, this benefit is confined to the association of anti-PD1 agents in pMMR patients. Updated analysis of trials is awaited to clarify the impact of immunotherapy on overall survival.

Prevention and management of infectious complications in patients with chronic lymphocytic leukemia (CLL) treated with BTK and BCL-2 inhibitors, focus on current guidelines.

CLL is associated with an increased risk of infectious complications. Treatment with BTK or BCL-2 inhibitors does not seem to increase significantly the risk of opportunistic infections, but the role of combination therapies including BTK and/or BCL-2 inhibitors remains to be established. Various infectious complications can be successfully prevented with appropriate risk management strategies. In this paper we reviewed the international guidelines on prevention and management of infectious complications in patients with CLL treated with BTK or BCL-2 inhibitors. Universal pharmacological anti-herpes, antibacterial or antifungal prophylaxis is not warranted. Reactivation of HBV should be prevented in HBsAg-positive subjects. For HBsAg-negative/HBcAb-positive patients recommendations differ, but in case of combination treatment should follow those for other, particularly anti-CD20, agent. Immunization should be provided preferably before the onset of treatment. Immunoglobulin therapy has favourable impact on morbidity but not mortality in patients with hypogammaglobulinemia and severe or recurrent infections. Lack of high-quality data and heterogeneity of patients or protocols included in the studies might explain differences among the main guidelines. Better data collection is warranted.

Copper nitroprusside: An innovative approach for targeted cancer therapy via ROS modulation.

The clinical application of nanomaterials for chemodynamic therapy (CDT), which generate multiple reactive oxygen species (ROS), presents significant challenges. These challenges arise due to insufficient levels of endogenous hydrogen peroxide and catalytic ions necessary to initiate Fenton reactions. As a result, sophisticated additional delivery systems are required. In this study, a novel bimetallic copper (II) pentacyanonitrosylferrate (Cu(II)NP, Cu[Fe(CN) 5 NO]) material was developed to address these limitations. This material functions as a multiple ROS generator at tumoral sites by self-inducing hydrogen peroxide and producing peroxynitrite (ONOO-) species. The research findings demonstrate that this material exhibits low toxicity towards normal liver organoids, yet shows potent antitumoral effects on High Grade Serous Ovarian Cancer (HGSOC) organoid patients, regardless of platinum resistance. Significantly, this research introduces a promising therapeutic opportunity by proposing a single system capable of replacing the need for H2O2, additional catalysts, and NO-based delivery systems. This innovative system exhibits remarkable multiple therapeutic mechanisms, paving the way for potential advancements in clinical treatments.

Silver nitroprusside as an efficient chemodynamic therapeutic agent and a peroxynitrite nanogenerator for targeted cancer therapies.

INTRODUCTION: Chemodynamic therapy (CDT) holds great promise in achieving cancer therapy through Fenton and Fenton-like reactions, which generate highly toxic reactive species. However, CDT is limited by the lower amount of catalyst ions that can decompose already existing intracellular H2O2 and produce reactive oxygen species (ROS) to attain a therapeutic outcome. OBJECTIVES: To overcome these limitations, a tailored approach, which utilizes dual metals cations (Ag+, Fe2+) based silver pentacyanonitrosylferrate or silver nitroprusside (AgNP) were developed for Fenton like reactions that can specifically kill cancer cells by taking advantage of tumor acidic environment without used of any external stimuli. METHODS: A simple solution mixing procedure was used to synthesize AgNP as CDT agent. AgNP were structurally and morphologically characterized, and it was observed that a minimal dose of AgNP is required to destroy cancer cells with limited effects on normal cells. Moreover, comprehensive in vitro studies were conducted to evaluate antitumoral mechanism. RESULTS: AgNP have an effective ability to decompose endogenous H2O2 in cells. The decomposed endogenous H2O2 generates several different types of reactive species (•OH, O2•-) including peroxynitrite (ONOO-) species as apoptotic inducers that kill cancer cells, specifically. Cellular internalization data demonstrated that in short time, AgNP enters in lysosomes, avoid degradation and due to the acidic pH of lysosomes significantly generate high ROS levels. These data are further confirmed by the activation of different oxidative genes. Additionally, we demonstrated the biocompatibility of AgNP on mouse liver and ovarian organoids as an ex vivo model while AgNP showed the therapeutic efficacy on patient derived tumor organoids (PDTO). CONCLUSION: This work demonstrates the therapeutic application of silver nitroprusside as a multiple ROS generator utilizing Fenton like reaction. Thereby, our study exhibits a potential application of CDT against HGSOC (High Grade Serous Ovarian Cancer), a deadly cancer through altering the redox homeostasis.

Laboratory and clinical management capacity for invasive fungal infections: the Italian landscape.

BACKGROUND: We assessed the laboratory diagnosis and treatment of invasive fungal disease (IFD) in Italy to detect limitations and potential for improvement. METHODS: The survey was available online at www.clinicalsurveys.net/uc/IFI management capacity/, and collected variables such as (a) institution profile, (b) perceptions of IFD in the respective institution, (c) microscopy, (d) culture and fungal identification, (e) serology, (f) antigen detection, (g) molecular tests, (h) susceptibility testing and (i) therapeutic drug monitoring (TDM). RESULTS: The laboratory capacity study received responses from 49 Italian centres, with an equitable geographical distribution of locations. The majority of respondents (n = 36, 73%) assessed the occurrence of IFD as moderate-high, with Aspergillus spp. being the pathogen of highest concern, followed by Candida spp. and Mucorales. Although 46 (94%) of the institutions had access to microscopy, less than half of them performed direct microscopy on clinical specimens always when IFD was suspected. Cultures were available in all assessed laboratories, while molecular testing and serology were available in 41 (83%), each. Antigen detection tests and antifungal drugs were also generally accessible (> 90%) among the participating institutions. Nevertheless, access to TDM was limited (n = 31, 63%), with a significant association established between therapeutic drug monitoring availability and higher gross domestic product per capita. CONCLUSIONS: Apart from TDM, Italy is adequately prepared for the diagnosis and treatment of IFD, with no significant disparities depending on gross domestic product. Future efforts may need to focus on enhancing the availability and application of direct microscopic methods, as well as TDM, to promote optimal treatment and better patient outcomes.

Safety and effectiveness of fifth generation cephalosporins for the treatment of methicillin-resistant staphylococcus aureus bloodstream infections: a narrative review exploring past, present, and future.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) is a major issue in healthcare, since it is often associated with endocarditis or deep site foci. Relevant morbidity and mortality associated with MRSA-BSIs forced the development of new antibiotic strategies; in particular, this review will focus the attention on fifth-generation cephalosporins (ceftaroline/ceftobiprole), that are the only ß-lactams active against MRSA. AREAS COVERED: The review discusses the available randomized controlled trials and real-world observational studies conducted on safety and effectiveness of ceftaroline/ceftobiprole for the treatment of MRSA-BSIs. Finally, a proposal of MRSA-BSI treatment flowchart, based on fifth-generation cephalosporins, is described. EXPERT OPINION: The use of anti-MRSA cephalosporins is an acceptable choice either in monotherapy or combination therapy for the treatment of MRSA-BSIs due to their relevant effectiveness and safety. Particularly, their use may be advisable in combination therapy in case of severe infections (including endocarditis or persistent bacteriemia) or in monotherapy in subjects at higher risk of drugs-induced toxicity with older regimens. On the contrary, caution should be taken in case of suspected/ascertained central nervous system infections due to inconsistent data regarding penetration of these drugs in cerebrospinal fluid and brain tissues.

Management of metastatic endometrial cancer: physicians' choices beyond the first line after approval of checkpoint inhibitors.

Introduction: Endometrial cancer (EC) represents 3.4% of all newly diagnosed cancer cases and is responsible for 2.1% of all cancer-related deaths. Approximately 10%-15% of women with EC are diagnosed with advanced-stage disease, resulting in a reported 5-year survival rate of only 17% for those with distant metastases. A better understanding of its molecular features has ushered in a new era of immunotherapy for the treatment of EC, allowing for alternative therapeutic approaches, even in cases of advanced disease. Methods: We administered a multi-choice online survey for Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) members. The questionnaire was available for 2 months, starting in October 2022. Our objective was to evaluate the current attitude of incorporating molecular characterization of EC into routine clinical practice, appraise the implementation of newly available therapies, and compare the outcomes with the previous survey conducted in April-May 2021 to ascertain the actual changes that have transpired during this recent time period. Results: The availability of molecular classification in Italian centers has changed in 1 year. Seventy-five percent of centers performed the molecular classification compared with 55.6% of the previous survey. Although this percentage has increased, only 18% performed all the tests. Significant changes have occurred in the administration of new treatments in EC patients in MITO centers. In 2022, 82.1% of the centers administrated dostarlimab in recurrent or advanced MMR-deficient (dMMR) EC experiencing disease progression after platinum-based chemotherapy regimens, compared to only 24.4% in 2021. In 2022, 85.7% of the centers already administrated the pembrolizumab plus lenvatinib combination as a second-line therapy for MMR-proficient (pMMR) patients with advanced or recurrent EC who had progressed from first-line platinum-based therapy. Conclusion: Both the therapeutic and diagnostic scenarios have changed over the last couple of years in MITO centers, with an increased prescription of immune checkpoint inhibitors and use of the molecular classification.

Tolerability of pulsed high-dose L-AmB as pre-emptive therapy in patients at high risk for intra-abdominal candidiasis: A phase 2 study (LAMBDA study).

BACKGROUND: Intra-abdominal candidiasis (IAC) has a high mortality rate. However, the correct management of a critically ill patient with suspected IAC remains unclear. The aim of this study was to evaluate the safety of pulsed high-dose liposomal amphotericin B (L-AmB) in patients with suspected IAC managed with a beta-D-glucan (BDG)-guided strategy. METHODS: This phase 2 prospective study enrolled adult patients with intra-abdominal sepsis following surgery. Patients received a single dose of L-AmB 5 mg/kg on day 1. On day 3, L-AmB was discontinued in patients with a negative basal BDG result, and continued (3 mg/kg/daily) in patients with a positive basal BDG result or microbiologically confirmed IAC. The primary endpoint was the occurrence of adverse events, defined using the Common Toxicity Criteria classification. RESULTS: In total, 40 patients were enrolled from January 2019 to August 2022. Fifteen (37.5%) patients were male, and the median age was 65 [interquartile range (IQR) 49-76] years. Thirty-one (77.5%) patients underwent urgent surgery, and the principal indication was secondary/tertiary peritonitis (n=22, 55%); half of the patients had undergone a previous surgical operation within the preceding 30 days. Five (12.5%) patients met the criteria for septic shock at enrolment. The median APACHE II score on admission to the intensive care unit was 12 (IQR 10-15). IAC was excluded in 33 (85%) patients, but IAC was probable and proven in five (12.5%) and two (5%) patients, respectively. The single dose of L-AmB 5 mg/kg was well tolerated in all patients, and no early or late severe adverse events related to the drug were reported. L-AmB was discontinued in 65% of patients following a negative basal BDG result. The all-cause 30-day mortality rate was 15%, and no deaths were related to L-AmB administration or uncontrolled IAC. The mortality rates for patients with and without proven IAC were 0% and 15.8%, respectively (P=0.99). CONCLUSIONS: The rate of proven IAC among critically ill high-risk patients was low (5%). A single dose of L-AmB 5 mg/kg, with prompt withdrawal in the case of a basal negative BDG result, seems to be a safe and effective approach in this population.

Association of ADME gene polymorphisms on toxicity to CDK4/6 inhibitors in patients with HR+ HER2- metastatic breast cancer.

A wide interindividual variability in therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) palbociclib, ribociclib and abemaciclib, among patients with HR+/HER2- metastatic breast cancer has been reported. This study explored the impact of genetic polymorphisms in ADME genes (responsible for drug absorption, distribution, metabolism, and elimination) on CDKis safety profiles in 230 patients. Selected endpoints include grade 3/4 neutropenia at day 14 of the first treatment cycle, early dose-limiting toxicities (DLTs), and dose reductions within the initial three cycles. Our analysis revealed associations between these endpoints and polymorphisms in CYP3A4, CYP3A5, ABCB1, and ABCG2 genes. Their impact on CDKis plasma concentrations (Ctrough) was also examined. Specifically, ABCB1 c.1236C>T and c.2677C>T polymorphisms correlated significantly with grade 3/4 neutropenia at day 14 (OR 3.94, 95% CI 1.32-11.75; p = 0.014 and OR 3.32, 95% CI 1.12-9.85; p = 0.030). Additionally, ABCB1 c.3435C>T was associated with an elevated risk of early DLTs and dose reductions (OR 3.28, 95% CI 1.22-8.84, p = 0.019; OR 2.60, 95% CI 1.20-5.60, p = 0.015). Carriers of the CYP3A4*22 allele also demonstrated in univariate a higher risk of early DLTs (OR 3.10, 95% CI 1.01-9.56, p = 0.049). Furthermore, individuals with the ABCB1 1236T-3435T-2677T(A) variant haplotype exhibited significant associations with grade 3/4 neutropenia at day 14 (OR 3.36, 95% CI 1.20-9.41; p = 0.021) and early DLTs in univariate (OR 3.08, 95% CI 1.19-7.95; p = 0.020). Homozygous carriers of the ABCB1 T-T-T(A) haplotype tended to have a higher mean ribociclib Ctrough (934.0 ng/mL vs. 752.0 ng/mL and 668.0 ng/mL). Regardless preliminary, these findings offer promising insights into the role of pharmacogenetic markers in CDKis safety profiles, potentially contributing to address the interindividual variability in CDKis responses.

Ursodeoxycholic Acid Does Not Improve COVID-19 Outcome in Hospitalized Patients.

Ursodeoxycholic acid (UDCA) was demonstrated to reduce susceptibility to SARS-CoV-2 infection in vitro and improve infection course in chronic liver diseases. However, real-life evidence is lacking. We analyzed the impact of UDCA on COVID-19 outcomes in patients hospitalized in a tertiary center. Between January 2020 and January 2023, among 3847 patients consecutively hospitalized for COVID19, 57 (=UDCA group) were taking UDCA. The UDCA and the control groups (n = 3790) did not differ concerning comorbidities including diabetes mellitus type 2 (15.8% vs. 12.8%) and neoplasia (12.3% vs. 9.4%). Liver diseases and vaccination rate were more common in the UDCA group (14.0% vs. 2.5% and 54.4% vs. 30.2%, respectively). Overall mortality and CPAP treatment were 22.8 % and 15.7% in the UDCA, and 21.3% and 25.9% in the control group. Mortality was similar (p = 0.243), whereas UDCA was associated with a lower rate of CPAP treatment (OR = 0.76, p < 0.05). Treatment with UDCA was not an independent predictor of survival in patients hospitalized for COVID-19.

Dual combined antiviral treatment with remdesivir and nirmatrelvir/ritonavir in patients with impaired humoral immunity and persistent SARS-CoV-2 infection.

Despite global vaccination efforts, immunocompromized patients remain at high risk for COVID-19-associated morbidity. In particular, patients with impaired humoral immunity have shown a high risk of persistent infection. We report a case series of adult patients with B cell malignancies and/or undergoing B cell targeting therapies with persisting SARS-CoV-2 infection and treated with a combination antiviral therapy of remdesivir and nirmatrelvir/ritonavir, in three Italian tertiary academic hospitals. A total of 14 patients with impaired adaptive humoral immunity and prolonged SARS-CoV-2 infection were treated with the dual antiviral therapy. The median age was 60 (IQR 56-68) years, and 11 were male. Twelve patients had B cell lymphoma, one patient had chronic lymphocytic leukemia and one patient had multiple sclerosis. Thirteen out of 14 patients had received prior B cell-targeting therapies, consisting of anti-CD20 monoclonal antibodies in 11 patients, and chimeric antigen receptor T therapy in 2 patients. The median time between diagnosis and therapy start was 42.0 (IQR 35-46) days. Seven patients had mild, 6 moderate and one severe disease. Nine patients had signs of interstitial pneumonitis on chest computed tomography scans before treatment. The median duration of nirmatrelvir/ritonavir and remdesivir combination therapy was 10 days. All patients showed resolution of COVID-19-related symptoms after a median of 6 (IQR 4-11) days and viral clearance after 9 (IQR 5-11) days. Combination therapy with remdesivir and nirmatrelvir/ritonavir is a promising treatment option for persistent COVID-19 in immunocompromized patients with humoral immunity impairment, worthy of prospective comparative trials.

Clinical impact of body mass index on palbociclib treatment outcomes and effect on exposure.

The impact of body mass index (BMI) on treatment outcomes in patients with cancer is gaining increasing attention given the limited data available. The aim of this study was to investigate the contribution of BMI on the safety and efficacy profile of palbociclib in 134 patients with metastatic luminal-like breast cancer treated with palbociclib and endocrine therapy (ET). Normal-weight and underweight patients (BMI<25) were compared with overweight and obese (BMI≥25). Detailed clinical and demographic data were collected. Patients with a BMI<25 had a higher incidence of relevant-hematologic toxicities (p = 0.001), dose reduction events (p = 0.003), and tolerated lower dose intensities (p = 0.023) compared to patients with a BMI≥25. In addition, patients with a BMI<25 had significantly shorter progression-free survival (log-rank p = 0.0332). A significant difference was observed in the subgroup of patients for whom systemic palbociclib concentrations were available: patients with a BMI<25 had a 25% higher median minimum plasma concentrations (Cmin) compared to BMI≥25. This study provides compelling evidence for a clinically relevant contribution of BMI in discriminating a group of patients who experienced multiple toxicities that appeared to affect treatment adherence and lead to poorer survival. BMI could become a valuable tool for personalizing the starting dose of palbociclib to improve its safety and efficacy.

What do clinicians mean by epidemics' preparedness.

BACKGROUND: Infectious disease pandemics and epidemics pose significant global threats, and the risk of emerging infectious diseases has increased because of factors such as international connections, travel, and population density. Despite investments in global health surveillance, much of the world remains unprepared to manage infectious disease threats. OBJECTIVES: This review article discusses the general considerations and lessons learned from the COVID-19 pandemic in terms of epidemic preparedness. SOURCES: Non-systematic search on PubMed, scientific society websites, and scientific newspapers (performed in April 2023). CONTENT: Key factors for preparedness include robust public health infrastructure, adequate allocation of resources, and effective communication between stakeholders. This narrative review emphasizes the need for timely and accurate dissemination of medical knowledge, as well as addressing the challenges of misinformation and infodemics. It also highlights the importance of quick availability of diagnostic tests and vaccines, ensuring equitable access to these technologies. The role of scientific coordination in developing treatment strategies and the safety and mental well-being of healthcare workers are discussed. Lastly, it should be emphasized the need for medical training, multidisciplinary teams, new technologies and artificial intelligence, and the active role of infectious disease physicians in epidemic preparedness efforts. IMPLICATIONS: From clinicians' perspective, healthcare authorities play a crucial role in epidemic preparedness even by providing resource management plans, ensuring availability of essential supplies and training, facilitating communication, and improving safe infection management.

Identify Drug-Resistant Pathogens in Patients with Community-Acquired Pneumonia.

A substantial increase in broad-spectrum antibiotics as empirical therapy in patients with community-acquired pneumonia (CAP) has occurred over the last 15 years. One of the driving factors leading to that has been some evidence showing an increased incidence of drug-resistant pathogens (DRP) in patients from a community with pneumonia, including methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Research has been published attempting to identify DRP in CAP through the implementation of probabilistic approaches in clinical practice. However, recent epidemiological data showed that the incidence of DRP in CAP varies significantly according to local ecology, healthcare systems and countries where the studies were performed. Several studies also questioned whether broad-spectrum antibiotic coverage might improve outcomes in CAP, as it is widely documented that broad-spectrum antibiotics overuse is associated with increased costs, length of hospital stay, drug adverse events and resistance. The aim of this review is to analyze the different approaches used to identify DRP in CAP patients as well as the outcomes and adverse events in patients undergoing broad-spectrum antibiotics.

LC-MS/MS Method for the Quantification of PARP Inhibitors Olaparib, Rucaparib and Niraparib in Human Plasma and Dried Blood Spot: Development, Validation and Clinical Validation for Therapeutic Drug Monitoring.

Poly (ADP-ribose) polymerase inhibitors (PARPis) are becoming increasingly meaningful in oncology, and their therapeutic drug monitoring (TDM) might be beneficial for patients. Several bioanalytical methods have been reported for PARPis quantification in human plasma, but advantages might be obtained using dried blood spot (DBS) as a sampling technique. Our aim was to develop and validate a liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for olaparib, rucaparib, and niraparib quantification in both human plasma and DBS matrices. Additionally, we aimed to assess the correlation between the drug concentrations measured in these two matrices. DBS from patients was obtained using Hemaxis DB10 for volumetric sampling. Analytes were separated on a Cortecs-T3 column and detected with electrospray ionization (ESI)-MS in positive ionization mode. Validation was performed according to the latest regulatory guidelines, in the range (ng/mL) 140-7000 for olaparib, 100-5000 for rucaparib, and 60-3000 for niraparib, within the hematocrit (Hct) range 29-45%. The Passing-Bablok and Bland-Altman statistical analyses revealed a strong correlation between plasma and DBS for olaparib and niraparib. However, due to the limited amount of data, it was challenging to establish a robust regression analysis for rucaparib. To ensure a more reliable assessment, additional samples are required. The DBS-to-plasma ratio was used as a conversion factor (CF) without considering any patient-related hematological parameters. These results provide a solid basis for the feasibility of PARPis TDM using both plasma and DBS matrices.

Machine Learning Application Identifies Germline Markers of Hypertension in Patients With Ovarian Cancer Treated With Carboplatin, Taxane, and Bevacizumab.

Pharmacogenomics studies how genes influence a person's response to treatment. When complex phenotypes are influenced by multiple genetic variations with little effect, a single piece of genetic information is often insufficient to explain this variability. The application of machine learning (ML) in pharmacogenomics holds great potential - namely, it can be used to unravel complicated genetic relationships that could explain response to therapy. In this study, ML techniques were used to investigate the relationship between genetic variations affecting more than 60 candidate genes and carboplatin-induced, taxane-induced, and bevacizumab-induced toxicities in 171 patients with ovarian cancer enrolled in the MITO-16A/MaNGO-OV2A trial. Single-nucleotide variation (SNV, formerly SNP) profiles were examined using ML to find and prioritize those associated with drug-induced toxicities, specifically hypertension, hematological toxicity, nonhematological toxicity, and proteinuria. The Boruta algorithm was used in cross-validation to determine the significance of SNVs in predicting toxicities. Important SNVs were then used to train eXtreme gradient boosting models. During cross-validation, the models achieved reliable performance with a Matthews correlation coefficient ranging from 0.375 to 0.410. A total of 43 SNVs critical for predicting toxicity were identified. For each toxicity, key SNVs were used to create a polygenic toxicity risk score that effectively divided individuals into high-risk and low-risk categories. In particular, compared with low-risk individuals, high-risk patients were 28-fold more likely to develop hypertension. The proposed method provided insightful data to improve precision medicine for patients with ovarian cancer, which may be useful for reducing toxicities and improving toxicity management.

3D dynamic cultures of HGSOC organoids to model innovative and standard therapies.

High-grade serous ovarian cancer (HGSOC) needs new technologies for improving cancer diagnosis and therapy. It is a fatal disease with few options for the patients. In this context, dynamic culture systems coupling with patient-derived cancer 3D microstructures could offer a new opportunity for exploring novel therapeutic approaches. In this study, we optimized a passive microfluidic platform with 3D cancer organoids, which allows a standardized approach among different patients, a minimum requirement of samples, multiple interrogations of biological events, and a rapid response. The passive flow was optimized to improve the growth of cancer organoids, avoiding the disruption of the extracellular matrix (ECM). Under optimized conditions of the OrganoFlow (tilting angle of 15° and an interval of rocking every 8 min), the cancer organoids grow faster than when they are in static conditions and the number of dead cells is reduced over time. To calculate the IC 50 values of standard chemotherapeutic drugs (carboplatin, paclitaxel, and doxorubicin) and targeted drugs (ATRA), different approaches were utilized. Resazurin staining, ATP-based assay, and DAPI/PI colocalization assays were compared, and the IC 50 values were calculated. The results showed that in the passive flow, the IC 50 values are lower than in static conditions. FITC-labeled paclitaxel shows a better penetration of ECM under passive flow than in static conditions, and cancer organoids start to die after 48 h instead of 96 h, respectively. Cancer organoids are the last frontiers for ex vivo testing of drugs that replicate the response of patients in the clinic. For this study, organoids derived from ascites or tissues of patients with Ovarian Cancer have been used. In conclusion, it was possible to develop a protocol for organoid cultures in a passive microfluidic platform with a higher growth rate, faster drug response, and better penetration of drugs into ECM, maintaining the samples' vitals and collecting the data on the same plate for up to 16 drugs.