Analysis of phase III clinical trials in metastatic NSCLC to assess the correlation between QoL results and survival outcomes.

BACKGROUND: In addition to improving survival outcomes, new oncology treatments should lead to amelioration of patients' quality of life (QoL). Herein, we examined whether QoL results correlated with PFS and OS outcomes in phase III randomized controlled trials (RCTs) investigating new systemic treatments in metastatic non-small cell lung cancer (NSCLC). METHODS: The systematic search of PubMed was conducted in October 2022. We identified 81 RCTs testing novel drugs in metastatic NSCLC and published in the English language in a PubMed-indexed journal between 2012 and 2021. Only trials reporting QoL results and at least one survival outcome between OS and PFS were selected. For each RCT, we assessed whether global QoL was "superior," "inferior," or with "non-statistically significant difference" in the experimental arm compared to the control arm. RESULTS: Experimental treatments led to superior QoL in 30 (37.0%) RCTs and inferior QoL in 3 (3.7%) RCTs. In the remaining 48 (59.3%) RCTs, a statistically significant difference between the experimental and control arms was not found. Of note, we found a statistically significant association between QoL and PFS improvements (X2 = 3.93, p = 0.0473). In more detail, this association was not significant in trials testing immunotherapy or chemotherapy. On the contrary, in RCTs testing target therapies, QoL results positively correlated with PFS outcomes (p = 0.0196). This association was even stronger in the 32 trials testing EGFR or ALK inhibitors (p = 0.0077). On the other hand, QoL results did not positively correlate with OS outcomes (X2 = 0.81, p = 0.368). Furthermore, we found that experimental treatments led to superior QoL in 27/57 (47.4%) trials with positive results and in 3/24 (12.5%) RCTs with negative results (p = 0.0028). Finally, we analyzed how QoL data were described in publications of RCTs in which QoL outcomes were not improved (n = 51). We found that a favorable description of QoL results was associated with sponsorship by industries (p = 0.0232). CONCLUSIONS: Our study reveals a positive association of QoL results with PFS outcomes in RCTs testing novel treatments in metastatic NSCLC. This association is particularly evident for target therapies. These findings further emphasize the relevance of an accurate assessment of QoL in RCTs in NSCLC.

FOLFIRINOX or nab-paclitaxel plus gemcitabine in metastatic pancreatic adenocarcinoma: an observational study.

Aim: Comparison of first-line FOLFIRINOX (FFN) and nab-paclitaxel plus gemcitabine (NabGem) in patients with metastatic pancreatic ductal adenocarcinoma. Patients & methods: The authors analyzed data from 160 patients with metastatic pancreatic adenocarcinoma receiving first-line FFN (n = 43) or NabGem (n = 117). Results: FFN and NabGem were similar in median progression-free survival (24.43 vs 26.28 weeks; hazard ratio [HR]: 0.88) and medial overall survival (47.43 vs 42.86 weeks; HR: 0.90). Of the 43 patients receiving FFN, 26 (60.4%) were treated with second-line NabGem; 14/117 (12.0%) patients receiving NabGem received second-line FFN (p < 0.0001). In the FFN → NabGem and NabGem → FFN groups, median overall survival was 51.2 and 71.6 weeks (HR: 0.69; p = 0.15). In patients receiving NabGem, second-line FFN, compared with FOLFOX/CAPOX or FOLFIRI, improved median progression-free survival 2 (25.6 vs 12.1 weeks; HR: 0.47; p = 0.0067) and median overall survival 2 (39.0 vs 19.14 weeks; HR: 0.49; p = 0.032). Conclusion: First-line FFN and NabGem promote similar clinical outcomes. Second-line FFN should be considered after NabGem.

Evaluation of the Molecular Landscape in PD-L1 Positive Metastatic NSCLC: Data from Campania, Italy.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) have increased and improved the treatment options for patients with non-oncogene-addicted advanced stage non-small cell lung cancer (NSCLC). However, the role of ICIs in oncogene-addicted advanced stage NSCLC patients is still debated. In this study, in an attempt to fill in the informational gap on the effect of ICIs on other driver mutations, we set out to provide a molecular landscape of clinically relevant oncogenic drivers in programmed death-ligand 1 (PD-L1) positive NSCLC patients. METHODS: We retrospectively reviewed data on 167 advanced stage NSCLC PD-L1 positive patients (≥1%) who were referred to our clinic for molecular evaluation of five driver oncogenes, namely, EGFR, KRAS, BRAF, ALK and ROS1. RESULTS: Interestingly, n = 93 (55.7%) patients showed at least one genomic alteration within the tested genes. Furthermore, analyzing a subset of patients with PD-L1 tumor proportion score (TPS) ≥ 50% and concomitant gene alterations (n = 8), we found that n = 3 (37.5%) of these patients feature clinical benefit with ICIs administration, despite the presence of a concomitant KRAS gene alteration. CONCLUSIONS: In this study, we provide a molecular landscape of clinically relevant biomarkers in NSCLC PD-L1 positive patients, along with data evidencing the clinical benefit of ICIs in patient NSCLC PD-L1 positive alterations.

Evaluation of the efficacy of animal-assisted therapy based on the reality orientation therapy protocol in Alzheimer's disease patients: a pilot study.

BACKGROUND: The aim of this study was to evaluate the efficacy of animal-assisted therapy (AAT) in elderly patients affected by Alzheimer's disease based on the formal reality orientation therapy (ROT) protocol. METHODS: Our study was carried out at an Alzheimer's centre for 6 months. A homogeneous sample (age, Mini-Mental State Examination (MMSE), 15-item Geriatric Depression Scale (GDS)) of 50 patients was selected at random and successively. Patients were divided into three groups: (i) 20 patients received a course of AAT (AAT group) based on the ROT protocol; (ii) 20 patients were engaged exclusively in activities based on the ROT group; and (iii) 10 patients (control group) participated in no stimulations. MMSE and GDS were administered at time 0 (T0 ) and time 1 (T1 ) to all three groups. Differences within groups between T0 and T1 for GDS and MMSE scores were analyzed by Student's t-test. Differences between group means were analyzed using an anova test with the Bonferroni-Dunn test for post-hoc comparisons. RESULTS: Both the AAT group and ROT group had improved GDS scores and showed a slight improvement in terms of mood. On the GDS, the AAT group improved from 11.5 (T0 ) to 9.5 (T1 ), and the ROT group improved from 11.6 (T0 ) to 10.5 (T1 ). At the same time, a slight improvement in cognitive function, as measured by the MMSE, was observed. In the AAT group, mean MMSE was 20.2 at T0 and 21.5 at T1 , and in the ROT group, it was 19.9 at T0 and 20.0 at T1 . In the control group, the average values of both the GDS and MMSE remained unchanged. The Bonferroni-Dunn results showed statistically significant differences between groups, particularly between the AAT group and the other two (P < 0.001). CONCLUSIONS: Pet therapy interventions based on the formal ROT protocol were effective and, compared to the ROT, provided encouraging and statistically significant results.

Prevalence of enteropathogenic bacteria in common quail (Coturnix coturnix).

The study was aimed at evaluating the prevalence of enteropathogenic bacteria (i.e. Campylobacter spp., shigatoxin-producing Escherichia coli, Salmonella spp.) in common quail (Coturnix coturnix). To achieve this goal, 70 common quails were collected during the hunting season in the Campania region (southern Italy). From each bird, cloacal swab samples were collected and subjected to culture methods, polymerase chain reaction and serotyping. The results of the present study showed a prevalence of 21.4% and 5.7% for Campylobacter spp. and shigatoxin-producing E. coli, respectively. In contrast, no Salmonella spp. was isolated. These findings show that common quail, as migratory birds, may constitute an environmental carrier of these pathogens representing a source of infection for other birds, livestock and humans.

Blinded independent central review versus local investigator assessment of PFS in RCTs of immunotherapy in advanced cancers: A systematic review and meta-analysis.

BACKGROUND: Assessment of Progression-free survival (PFS) events by investigators might be inaccurate in randomized controlled trials (RCTs) with open-label design. We explored differences in PFS evaluated by blinded independent central review (BICR) or local investigator assessment (IA) in trials testing immunotherapy (IO) in advanced cancers. METHODS: We systematically reviewed articles of RCTs investigating IO in advanced tumors, published in PubMed-indexed journals up to December 2023. For each RCT, we collected PFS results by BICR and by local IA. We calculated the discrepancy index (DI) as the ratio of BICR and IA Hazard Ratios (HRBICR/HRIA) for PFS. An overall DI and relative confidence interval (CI) were calculated using a fixed-effect model weighted for the inverse of variance. FINDINGS: Only 32/140 (22.9 %) RCTs reported both BICR and local IA PFS data, including 17,054 patients. PFS was the sole primary endpoint in 19/32 (59.4 %) and a co-primary endpoint 9/32 (28.2 %) trials. The study design was open label or double-blind in 17/32 (53.1 %) and 15/32 (46.9 %) RCTs, respectively. The overall DI was 1.07 (95 % CI 1.01-1.13; I2 =0, p = 0.02), revealing a more optimistic analysis of results in favor of local IA. In the 17 open-label trials, the overall DI was 1.09 (95 % CI 1.02-1.17, I2 =0, p = 0.02), revealing a more favorable interpretation of PFS results by local investigators. INTERPRETATION: We found a statistically significant difference between BICR and local IA of PFS in trials of IO in cancer. These results suggest that the double assessment is recommended in RCTs testing IO, especially in open-label trials. FUNDING: This work was supported by the MFAG27826-2022 grant (Dr. Alberto Servetto).

Prognostic analysis and outcomes of metastatic pancreatic cancer patients receiving nab-paclitaxel plus gemcitabine as second or later-line treatment.

BACKGROUND: Pancreatic cancer (PC) first-line therapy often consists of polychemotherapy regimens, but choosing a second-line therapy after disease progression, especially following first-line FOLFIRINOX, remains a clinical challenge. This study presents results from a large, multicenter, retrospective analysis of Italian patients with metastatic PC (mPC) treated with Nab-paclitaxel/Gemcitabine (AG) as second or later line of treatment. Main objective of the study is to identify prognostic factors that could inform treatment decisions. METHODS: The study included 160 mPC patients treated with AG in 17 Italian institutions. AG was administered according to labelling dose, until disease progression, unacceptable toxicity or patient refusal. Variations in schedules, dose modifications, supportive measures, and response evaluation were determined by individual clinicians' practice. RESULTS: AG was well-tolerated and exhibited promising clinical activity. The overall response rate (ORR) and the disease control rate (DCR) were 22.5% and 45.6%, respectively. Median progression-free survival (PFS) and overall survival (OS) were 3.9 and 6.8 months, respectively. Among the patients who received AG as a second-line therapy (n = 111, 66.9%), median PFS and OS were 4.2 and 7.4 months, respectively. Notably, in the 76 patients (68%) receiving AG after first-line FOLFIRINOX, an ORR of 19.7% and a DCR of 46.0% were observed, resulting in a median PFS of 3.5 and median OS of 5.7 months. The study identified specific clinical or laboratory parameters (LDH, NLR, fasting serum glucose, liver metastases, ECOG PS, and first-line PFS) as independent prognostic factors at multivariate level. These factors were used to create a prognostic nomogram that divided patients into three risk classes, helping to predict second-line OS and PFS. CONCLUSIONS: This study represents the largest real-world population of mPC patients treated with AG as a second or later line of therapy. It supports the feasibility of this regimen following first-line FOLFIRINOX, particularly in patients with specific clinical and laboratory characteristics who derived prolonged benefit from first-line therapy.

Tackling Antibiotic and Antifungal Resistance in Domestic Animals, Synanthropic Species, and Wildlife: A Global Health Imperative.

Antibiotic resistance (ABR) and antifungal resistance (AFR) arise when microorganisms evolve mechanisms to resist pharmacological treatments [...].

Research Note: Cecal microbiota harbored by free-range chickens may influence the reduction of Helicobacter pullorum relative abundance.

Helicobacter pullorum is recognized as an emerging food-borne pathogen that may colonize the intestinal tract and the liver of avian species and humans causing several gastrointestinal and liver diseases. However, not all strains are reported to be capable of causing clinical disease, thus making poultry as reservoir for the zoonotic transmission of the infection through carcass contamination of broilers at slaughter. In poultry, the prevalence of this bacterium could be underestimated and the available data mainly refer to conventional rearing systems, whereas free-range and organic breedings have been poorly investigated. Therefore, this study was aimed to characterize the caecal microbiota community of free-range grown chickens and determine the presence and the relative abundance of H. pullorum by using NGS-based 16S rDNA sequencing. A total of 18 chickens reared for 56 d on a semi-extensive management system were euthanized at two time points: 9 birds at 28 d of age (before have access to outdoor; I = Indoor) and other 9 birds at 56 d of age (before slaughter; O = Outdoor). Cecal contents were collected for microbiota analyses. H. pullorum was detected in the cecum of 16/18 samples and its proportion in indoor was significantly higher than outdoor chickens (2.46 and 0.52%, respectively; P < 0.05), showing 78.8% of decrease with the outdoor access of the chickens. Therefore, it may be assumed that the potential for zoonotic infection is less likely. Moreover, H. pullorum was negatively correlated with 17 bacterial species as significantly more abundant in Outdoor microbial caecal communities. Among these, we highlighted the presence of Mucispirillium schaedleri and Oscillospira, already previously associated with a healthy gut and thus representing promising gut bacterial markers for host health. Our findings suggest that alternative production systems with outdoor access, may play a crucial role in the establishment of a healthy gut microbiota, which in turn might prevent colonization of harmful bacteria such as Helicobacter pullorum.

SARS-CoV-2 Affects Both Humans and Animals: What Is the Potential Transmission Risk? A Literature Review.

In March 2020, the World Health Organization Department declared the coronavirus (COVID-19) outbreak a global pandemic, as a consequence of its rapid spread on all continents. The COVID-19 pandemic has been not only a health emergency but also a serious general problem as fear of contagion and severe restrictions put economic and social activity on hold in many countries. Considering the close link between human and animal health, COVID-19 might infect wild and companion animals, and spawn dangerous viral mutants that could jump back and pose an ulterior threat to us. The purpose of this review is to provide an overview of the pandemic, with a particular focus on the clinical manifestations in humans and animals, the different diagnosis methods, the potential transmission risks, and their potential direct impact on the human-animal relationship.

Role of FGFR3 in bladder cancer: Treatment landscape and future challenges.

Bladder cancer is a heterogeneous malignancy and is responsible for approximately 3.2% of new diagnoses of cancer per year (Sung et al., 2021). Fibroblast Growth Factor Receptors (FGFRs) have recently emerged as a novel therapeutic target in cancer. In particular, FGFR3 genomic alterations are potent oncogenic drivers in bladder cancer and represent predictive biomarkers of response to FGFR inhibitors. Indeed, overall âˆ¼50% of bladder cancers have somatic mutations in the FGFR3 -coding sequence (Cappellen et al., 1999; Turner and Grose, 2010). FGFR3 gene rearrangements are typical alterations in bladder cancer (Nelson et al., 2016; Parker et al., 2014). In this review, we summarize the most relevant evidence on the role of FGFR3 and the state-of-art of anti-FGFR3 treatment in bladder cancer. Furthermore, we interrogated the AACR Project GENIE to investigate clinical and molecular features of FGFR3-altered bladder cancers. We found that FGFR3 rearrangements and missense mutations were associated with a lower fraction of mutated genome, compared to the FGFR3 wild-type tumors, as also observed in other oncogene-addicted cancers. Moreover, we observed that FGFR3 genomic alterations are mutually exclusive with other genomic aberrations of canonical bladder cancer oncogenes, such as TP53 and RB1. Finally, we provide an overview of the treatment landscape of FGFR3-altered bladder cancer, discussing future perspectives for the management of this disease.

Consensus Statement on Animals' Relationship with Pediatric Oncohematological Patients, on Behalf of Infectious Diseases and Nurse Working Groups of the Italian Association of Pediatric Hematology-Oncology.

Contact with animals in pediatric oncohematologic patients is associated with many benefits, but the risk of contracting zoonoses, even if low, must be considered by clinicians. In order to assess the awareness about this topic, we surveyed the Italian pediatric oncohematology centers, which resulted in heterogeneous responses. The Infectious Diseases Working Group and the Nurse Working Group of the Italian Association of Pediatric Hematology-Oncology, together with veterinarians from the National Federation of Italian Veterinarians, drew up a consensus document to unify the indications to be given to families with the aim of guaranteeing a safe interaction between patients and animals and improving the collaboration of clinicians with veterinarians and families.

RET rearrangements in non-small cell lung cancer: Evolving treatment landscape and future challenges.

The Rearranged during Transfection (RET) oncogene has been extensively investigated in solid malignancies, particularly thyroid cancer and non-small cell lung cancer (NSCLC), and represents an attractive therapeutic target. RET rearrangements occur in 1-2% of lung adenocarcinomas, where they function as potent oncogenic drivers. Importantly, tumors harboring RET fusions are particularly sensitive to RET tyrosine kinase inhibitors. Results of the LIBRETTO-001 and ARROW clinical trials led to the approval of novel potent and selective RET inhibitors, selpercatinib and pralsetinib, able to overcome the limits of previously used multikinase inhibitors. Herein, we review the most relevant evidences about the role of RET signaling in NSCLC. In addition, we interrogated the Project GENIE database to investigate common clinical and molecular features of RET-fusion positive NSCLC. This analysis revealed that RET rearrangements occurred more frequently in younger and light smoker patients and were associated with a lower tumor mutational burden, compared to RET-fusion negative tumors. Moreover, we assessed and described the differences between RET genomic alterations in NSCLC and thyroid cancers. Finally, we summarized how the treatment landscape of RET-rearranged NSCLC has changed in the last few years, which are the available data about the recognized mechanisms of resistance to RET inhibitors and the challenges for future development of novel therapeutic strategies, aiming to improve management of patients with RET-fusion positive NSCLC.

Prevalence and Phenotypic Antimicrobial Resistance among ESKAPE Bacteria and Enterobacterales Strains in Wild Birds.

Antimicrobial resistance (AMR) is a current public health issue globally. To counter this phenomenon and prioritize AMR in the health sector, the World Health Organization (WHO) published a list of bacterial pathogens against which the development of new antimicrobial agents is urgently needed, designating the ESKAPE pathogens (i.e., Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) with a 'priority status'. Moreover, the One Health High Level Expert Panel (OHHLEP) states that human health is closely linked to animal and environmental health, thus promoting a holistic One Health approach in order to be prepared to address possible emerging health threats from the human-animal-environment interface. Wild birds may host and spread pathogens, integrating the epidemiology of infectious diseases. The aim of this study was to examine the role of wild birds as a source of ESKAPE bacteria and other antibiotic-resistant enterobacterales. A total of fifty strains within the ESKAPE group were detected in 40/163 cloacal samples of examined birds (24.5%). Additionally, different strains of enterobacterales were detected in 88/163 cloacal samples (53.9%). Isolated strains exhibited antimicrobial resistance, including towards critically important antibiotics (e.g., third, fourth, fifth generation cephalosporins, fluoroquinolones) for human medicine. Our results confirm that wild birds are potential reservoirs of several pathogens and antimicrobial-resistant bacteria and that they could be involved in the dissemination of those bacteria across different environments, with resulting public health concerns.

Health-related quality of life is underestimated and underreported in phase III clinical trials in NSCLC.

Major associations of medical oncologists remark that novel anticancer treatments should guarantee improvement of survival outcomes as well as of patients' quality of life (QoL). Herein, we investigated QoL assessment and reporting in phase III randomized controlled trials (RCTs) testing new drugs in metastatic non-small cell lung cancer (NSCLC), published between 2010 and 2021. We selected 172 RCTs for further analysis. Only 2/172 (1.2%) trial included QoL among primary study endpoints. Of note, 40/172 (23.3%) trials did not include QoL assessment among endpoints. The majority of RCTs (102/172, 59.3%) did not report QoL results in primary publications. Particularly, RCTs testing immunotherapy, target therapy and chemotherapy did not disclose QoL data in primary publications in 97.0%, 51.5% and 46.5% of cases, respectively. Next, we found that only 43/95 (45.3%) positive studies reported QoL results in primary articles. Of the 102 trials missing QoL data in primary manuscripts, only 21 (20.6%) disclosed QoL results in a secondary publication. Finally, we found a common fail in adherence to CONSORT-PROs items in publications reporting QoL results. In summary, our study reveals a relevant inadequate assessment and under-reporting of QoL in RCTs of novel systemic treatments for patients with metastatic NSCLC.

Inadequate health-related quality of life assessment and reporting in phase III clinical trials of immune checkpoint inhibitors in solid cancers: A systematic review.

We systematically reviewed QoL assessment and reporting in RCTs of immune checkpoint inhibitors (ICIs) in solid cancers published between 2013 and 2021. None of the 106 eligible trials included QoL among primary endpoints. QoL results were non-disclosed in 83/106 (78.3%) primary publications. QoL assessment was disclosed exclusively in study protocol and not in methods of the manuscript in 48.5% of publications. In 27.8% of articles, QoL assessment was disclosed in the methods but non-reported among the results. Only in 44.3% of trials missing QoL results in primary manuscripts, QoL data were reported in a secondary publication. A relevant delay occurred in secondary publications, with a median time to secondary articles with QoL results of 33.6 months. Our analysis revealed a significant underreporting of QoL in RCTs of ICIs in solid cancers. Altogether, absent or delayed disclosure of QoL results affect a complete evaluation of clinical benefit of new anticancer treatments.

Salmonella typhimurium DT104 in farmed rabbits.

A total of 1,000 rectal samples were collected from rabbits coming from 25 rabbit farms in southern Italy. All samples were processed for isolation of Salmonella spp. by standard culture method based on the ISO 6579:2002 method. Salmonella spp. was isolated from 1/25 rabbit farms analyzed. In particular, four out of 1,000 rectal swab samples, taken from young rabbits, were serotyped as S. Typhimurium and phage typed as S. Typhimurium DT104. All the isolates were resistant to ampicillin, chloramphenicol, streptomycin, sulfamethoxazole, and tetracycline (ACSSuT pentaresistance type). The findings of the present study suggest the rabbit as potential carrier of S. Typhimurium DT104.

The Research of Standardized Protocols for Dog Involvement in Animal-Assisted Therapy: A Systematic Review.

Dogs are considered the most important species involved in animal-assisted therapy (AAT), and the scientific literature focuses on the benefits linked to the involvement of dogs in various therapeutic areas. In this study, we carried out a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, exploring the scientific literature from the last 5 years (2016-2021) on three databases (PubMed, Scopus, and Web of Science) to highlight the characteristics of the dogs involved in AATs. Based on the scientific literature relevant to such dogs, we considered different parameters (i.e., number, age, sex, breed, temperament, methods of choice and training, health status, research goals, and activities with dogs) to include studies in our paper. After screening 4331 papers identified on the searched databases, we selected 38 articles that met the inclusion criteria. Analysis of the included articles showed that the characteristics of the dogs were neglected. Our findings indicated a lack of information about the dogs, as well as the absence of standardized and univocal criteria for dog selection, training programs, and health protocols.

Presence of Campylobacterjejuni and C. coli in Dogs under Training for Animal-Assisted Therapies.

This study was conducted to evaluate the presence of Campylobacter (C.) jejuni and C. coli in dogs at five dog training centers in Southern Italy. A total of 550 animals were sampled by collecting rectal swabs. The samples were processed to detect thermotolerant Campylobacter spp. by culture and molecular methods. Campylobacter spp. were isolated from 135/550 (24.5-95% confidence interval) dogs. A total of 84 C. jejuni (62.2%) and 51 C. coli (37.8%) isolates were identified using conventional PCR. The dog data (age, sex, breed, and eating habits) were examined by two statistical analyses using the C. jejuni and C. coli status (positive or negative) as dependent variables. Dogs fed home-cooked food showed a higher risk of being positive for C. jejuni than dogs fed dry or canned meat for dogs (50.0%; p < 0.01). Moreover, purebred dogs had a significantly higher risk than crossbred dogs for C. coli positivity (16.4%; p < 0.01). This is the first study on the prevalence of C. jejuni and C. coli in dogs frequenting dog training centers for animal-assisted therapies (AATs). Our findings emphasize the potential zoonotic risk for patients and users involved in AATs settings and highlight the need to carry out ad hoc health checks and to pay attention to the choice of the dog, as well as eating habits, in order to minimize the risk of infection.