Molecular profiling of pediatric and young adult colorectal cancer reveals a distinct genomic landscapes and potential therapeutic avenues.

Colorectal cancer (CRC) is a global health concern, and the incidence of early onset (EO) CRC, has an upward trend. This study delves into the genomic landscape of EO-CRC, specifically focusing on pediatric (PED) and young adult (YA) patients, comparing them with adult (AD) CRC. In this retrospective monocentric investigation, we performed targeted next-generation sequencing to compare the mutational profile of 38 EO-CRCs patients (eight PED and 30 YA) to those of a 'control group' consisting of 56 AD-CRCs. Our findings reveal distinct molecular profiles in EO-CRC, notably in the WNT and PI3K-AKT pathways. In pediatrics, we observed a significantly higher frequency of RNF43 mutations, whereas APC mutations were more prevalent in adult cases. These observations suggest age-related differences in the activation of the WNT pathway. Pathway and copy number variation analysis reveal that AD-CRC and YA-CRC have more similarities than the pediatric patients. PED shows a peculiar profile with CDK6 amplification and the enrichment of lysine degradation pathway. These findings may open doors for personalized therapies, such as PI3K-AKT pathway inhibitors or CDK6 inhibitors for pediatric patients. Additionally, the distinct molecular signatures of EO-CRC underscore the need for age-specific treatment strategies and precision medicine. This study emphasizes the importance of comprehensive molecular investigations in EO-CRCs, which can potentially improve diagnostic accuracy, prognosis, and therapeutic decisions for these patients. Collaboration between the pediatric and adult oncology community is fundamental to improve oncological outcomes for this rare and challenging pediatric tumor.

Circulating microRNAs and therapy-associated cardiac events in HER2-positive breast cancer patients: an exploratory analysis from NeoALTTO.

PURPOSE: The relevance of cardiotoxicity in the context of HER2-positive breast cancer is likely to increase with increasing patient treatment exposure, number of treatment lines, and prolonged survival. Circulating biomarkers to early identify patients at risk of cardiotoxicity could allow personalized treatment and follow-up measures. The aim of this study is to examine the relationship between circulating microRNAs and adverse cardiac events in HER2-positive breast cancer patients. METHODS: We based our work on plasma samples from NeoALTTO trial obtained at baseline, after 2 weeks of anti-HER2 therapy, and immediately before surgery. Eleven patients experienced either a symptomatic or asymptomatic cardiac event. Circulating microRNAs were profiled in all patients presenting a cardiac event (case) and in an equal number of matched patients free of reported cardiac events (controls) using microRNA-Ready-to-Use PCR (Human panel I + II). Sensitivity analyses were performed by increasing the number of controls to 1:2 and 1:3. Normalized microRNA expression levels were compared between cases and controls using the non-parametric Kruskal-Wallis test. RESULTS: Eight circulating microRNAs resulted differentially expressed after 2 weeks of anti-HER2 therapy between patients experiencing or not a cardiac event. Specifically, the expression of miR-125b-5p, miR-409-3p, miR-15a-5p, miR-423-5p, miR-148a-3p, miR-99a-5p, and miR-320b increased in plasma of cases as compared to controls, while the expression of miR-642a-5p decreases. Functional enrichment analysis revealed that all these microRNAs were involved in cardiomyocyte adrenergic signaling pathway. CONCLUSION: This study provides proof of concept that circulating microRNAs tested soon after treatment start could serve as biomarkers of cardiotoxicity in a very early stage in breast cancer patients receiving anti-HER2 therapy.

Early stage breast cancer follow-up in real-world clinical practice: the added value of cell free circulating tumor DNA.

PURPOSE: Physical examinations and annual mammography (minimal follow-up) are as effective as laboratory/imaging tests (intensive follow-up) in detecting breast cancer (BC) recurrence. This statement is now challenged by the availability of new diagnostic tools for asymptomatic cases. Herein, we analyzed current practices and circulating tumor DNA (ctDNA) in monitoring high-risk BC patients treated with curative intent in a comprehensive cancer center. PATIENTS AND METHODS: Forty-two consecutive triple negative BC patients undergoing neoadjuvant therapy and surgery were prospectively enrolled. Data from plasma samples and surveillance procedures were analyzed to report the diagnostic pattern of relapsed cases, i.e., by symptoms, follow-up procedures and ctDNA. RESULTS: Besides minimal follow-up, 97% and 79% of patients had at least 1 non-recommended imaging and laboratory tests for surveillance purposes. During a median follow-up of 5.1(IQR, 4.1-5.9) years, 13 events occurred (1 contralateral BC, 1 loco-regional recurrence, 10 metastases, and 1 death). Five recurrent cases were diagnosed by intensive follow-up, 5 by symptoms, and 2 incidentally. ctDNA antedated disseminated disease in all evaluable cases excepted two with bone-only and single liver metastases. The mean time from ctDNA detection to suspicious findings at follow-up imaging was 3.81(SD, 2.68), and to definitive recurrence diagnosis 8(SD, 2.98) months. ctDNA was undetectable in the absence of disease and in two suspected cases not subsequently confirmed. CONCLUSIONS: Some relapses are still symptomatic despite the extensive use of intensive follow-up. ctDNA is a specific test, sensitive enough to detect recurrence before other methods, suitable for clarifying equivocal imaging, and exploitable for salvage therapy in asymptomatic BC survivors.

Antineoplastic treatment class modulates COVID-19 mRNA-BNT162b2 vaccine immunogenicity in cancer patients: a secondary analysis of the prospective Vax-On study.

BACKGROUND: Preliminary analysis from the Vax-On study did not find a correlation between cancer treatment type and antibody response to COVID-19 vaccination. We carried out a secondary subgroup analysis to verify the effects of comprehensive cancer treatment classification on vaccine immunogenicity. METHODS: The Vax-On study prospectively enrolled patients who started a two-dose messenger RNA-BNT162b2 vaccine schedule from 9 March 2021 to 12 April 2021 (timepoint-1). Those on active treatment within the previous 28 days accounted for the exposed cases. Patients who had discontinued such treatment by at least 28 days or received intravesical therapy represented the control cases. Quantification of immunoglobulin G (IgG) antibodies against the receptor binding domain of the S1 subunit of the SARS-CoV-2 spike protein was carried out before the second dose (timepoint-2) and 8 weeks thereafter (timepoint-3). Seroconversion response was defined at ≥50 arbitrary units/ml IgG titer. Classification of antineoplastic agents was based on their pharmacodynamic properties. RESULTS: Three hundred and sixty-six patients were enrolled (86 and 260 as control and exposed cases, respectively). Univariate analysis revealed a significantly lower IgG titer after both doses of vaccine in subgroups treated with tyrosine kinase inhibitors (TKIs), multiple cytotoxic agents, alkylating agents, and topoisomerase inhibitors. At timepoint-3, seroconversion response was significantly impaired in the topoisomerase inhibitors and mechanistic target of rapamycin (mTOR) inhibitors subgroups. After multivariate testing, treatment with alkylating agents and TKIs was significantly associated with a reduced change in IgG titer at timepoint-2. Treatment with mTOR inhibitors resulted in a similar interaction at each timepoint. Cyclin-dependent kinase 4/6 inhibitor treatment was independently correlated with an incremental variation in IgG titer at timepoint-3. Specific subgroups (TKIs, antimetabolites, alkylating agents, and multiple-agent chemotherapy) predicted lack of seroconversion at timepoint-2, but their effect was not retained at timepoint-3. Eastern Cooperative Oncology Group performance status 2, immunosuppressive corticosteroid dosing, and granulocyte colony-stimulating factor use were independently linked to lower IgG titer after either dose of vaccine. CONCLUSIONS: Drugs interfering with DNA synthesis, multiple-agent cytotoxic chemotherapy, TKIs, mTOR and cyclin-dependent kinase 4/6 inhibitors differentially modulate humoral response to messenger RNA-BNT162b2 vaccine.

Delayed recovery from severe acute respiratory syndrome coronavirus-2 related anosmia predicts incomplete olfactory restoration.

OBJECTIVE: This study aimed to assess the olfactory recovery rates and patterns in a cohort of coronavirus disease 2019 positive patients, and to investigate the clinical predictors of poor long-term olfactory restoration. METHODS: An observational retrospective study was conducted on 146 patients between September 2020 and January 2021 at a tertiary referral hospital. Coronavirus disease 2019 positive patients with olfactory dysfunction were sent a modified version of the COVID-19 Anosmia Reporting Tool for Clinicians via e-mail. RESULTS: The difference in median recovery time between complete recovery and incomplete or no recovery was statistically significant. On multivariate analysis, the only significant factor associated with incomplete or no recovery was anosmia duration. CONCLUSION: After a mean time of 5.6 months from severe acute respiratory syndrome coronavirus-2 infection, persistent olfactory disorders were self-reported in 36.7 per cent of patients. Complete recovery was more likely to occur within 15 days. Given the high prevalence of coronavirus disease 2019, a large number of patients are expected to suffer from long-term olfactory morbidity.

Trumpet sounds emitted by male sperm whales in the Mediterranean Sea.

Sperm whale trumpets are sounds only occasionally documented, with a well recognisable and stereotyped acoustic arrangement. This study investigated the acoustic features of the trumpets and the context in which these sounds were recorded, using acoustic data collected over 22 years, in the Pelagos Sanctuary area (North-Western Mediterranean Sea). Analysed trumpets (n = 230), recorded at the beginning of a dive after the whale fluke-up, comprised a series of acoustic units organized in short sequences. Acoustic parameters were derived for the entire trumpet and for each distinguishable unit in a trumpet. Overall, trumpet durations and their initial frequencies were higher in recordings collected when multiple whales were visually or acoustically detected in the observation area. The identity of 68 whales was assessed through photo-identification, with 29 individuals producing trumpets within and between years. The variability of the acoustic parameters appeared to be higher within the same individuals rather than between different individuals, suggesting an individual plasticity in composing and arranging units in a trumpet. Different click patterns were observed before and after the trumpets, with more complex sequences when (1) other whales were visually/acoustically detected, and (2) individuals were in suitable foraging sites (i.e., canyon areas). Trumpets were commonly followed or preceded by click patterns suited for communication, such as codas and/or slow clicks. Significant relations between the trumpet emission and the male-only long-range communication click pattern (i.e. slow clicks) emerged, supporting the hypothesis that a trumpet is a sound emitted by maturing/mature males in feeding grounds. This study provides the first evidence that trumpets were conserved in the sperm whale acoustic repertoire at the decadal timescale, persisting across years and individuals in the same area. This persistence may be functionally specific to foraging activities performed by males in a well-established feeding area.

Blood-based genomics of triple-negative breast cancer progression in patients treated with neoadjuvant chemotherapy.

BACKGROUND: As neoadjuvant chemotherapy (NAC) is increasingly used in triple-negative breast cancer (TNBC), we investigated the value of circulating tumor DNA (ctDNA) for patient monitoring prior, during, and after NAC, and circulating tumor cells (CTCs) for disease characterization at clinical progression. MATERIALS AND METHODS: Forty-two TNBC patients undergoing NAC were prospectively enrolled. Primary tumor mutations identified by targeted-gene sequencing were validated and tracked in 168 plasma samples longitudinally collected at multiple time-points by droplet digital polymerase chain reaction. At progression, plasma DNA underwent direct targeted-gene assay, and CTCs were collected and analyzed for copy number alterations (CNAs) by low-pass whole genome sequencing. RESULTS: ctDNA detection after NAC was associated with increased risk of relapse, with 2-year event-free survival estimates being 44.4% [95% confidence interval (CI) 21.4%-92.3%] versus 77.4% (95% CI 57.8%-100%). ctDNA prognostic value remained worthy even after adjusting for age, residual disease, systemic inflammatory indices, and Ki-67 [hazard ratio (HR) 1.91; 95% CI 0.51-7.08]. During follow-up, ctDNA was undetectable in non-recurrent cases with the unique exception of one showing a temporary peak over eight samples. Conversely, ctDNA was detected in 8/11 recurrent cases, and predated the clinical diagnosis up to 13 months. Notably, recurrent cases without ctDNA developed locoregional, contralateral, and bone-only disease. At clinical progression, CTCs presented chromosome 10 and 21q CNAs whose network analysis showed connected modules including HER/PI3K/Ras/JAK signaling and immune response. CONCLUSION: ctDNA is not only associated with but is also predictive of prognosis in TNBC patients receiving NAC, and represents an exploitable tool, either alone or with CTCs, for personalized TNBC management.

Bacteriotherapy in children with recurrent upper respiratory tract infections.

OBJECTIVE: Children with recurrent upper-airway infections (UI) represent a social issue for their economic burden and negative impact on families. Bacteriotherapy is a new therapeutic strategy that could potentially prevent infections. The current study tested the hypothesis that recurrent UI may be prevented by bacteriotherapy. PATIENTS AND METHODS: This open study was conducted in an outpatient clinic, enrolling 80 children (40 males, mean age 5.26±2.52 years) suffering from recurrent UI. Children were treated with a nasal spray containing Streptococcus salivarius 24SMB and Streptococcus oralis 89a, 2 puffs per nostril twice a day for a week; this course was repeated for 3 months. The evaluated parameters were: number of UI and number of school and work absences; these outcomes were compared with those recorded in the past year. RESULTS: The mean number of UI significantly diminished: from 5.98 (2.30) in the past year to 2.75 (2.43) after treatment (p<0.0001). The number of school and work absences significantly diminished (from 4.50±2.81 to 2.80±3.42 and from 2.33±2.36 to 1.48±2.16 respectively; p<0.0001 for both). CONCLUSIONS: This preliminary experiment suggests that bacteriotherapy using Streptococcus salivarius 24SMB and Streptococcus oralis89a nasal spray could prevent recurrent UI in children.

Bet v 1 sensitization modulates allergenic molecular immune response.

Summary: Background Allergy is characterized by allergen-specific IgE production. Molecular-based allergy diagnostic allows to define the precise sensitization profile. Bet v 1 is the major allergen of the PR-10 family. It has been reported that pan-allergens could affect the sensitization panel in adults. This study aimed to evaluate the impact of Bet v 1 sensitization on sensitization pattern in a large sample of children. Methods Serum IgE molecular components were assessed by ISAC method. Sera from 1,205 children, 708 males (58.76%) and 497 females (41.24%), median age 8.61 years (4.93 - 12.54 years) were analyzed. Results A total of 354 PR-10-positive subjects were detected out of 1,205 subjects. Bet v 1 positive children were significantly more frequently sensitized to other molecules belonging to PR-10 family and noteworthy also to other allergenic families than Bet v 1 negative children. Conclusions The present study demonstrates that Bet v 1 sensitization may significantly affect the sensitization pattern in children living in Genoa, a Mediterranean city located in a birch-free area.

Gut microbiota characterisation in obese patients before and after bariatric surgery.

Intestinal microbiota analysis of obese patients after bariatric surgery showed that Proteobacteria decreased after laparoscopic sleeve gastrectomy (SG), while it increased after laparoscopic gastric bypass (LGB). Comparing to normal weight (NW) patients, obese patients that were selected for SG showed an almost equal amount of Firmicutes and Bacteroidetes and the ratio was not affected by the surgery. Obese patients before LGB showed a predominance of Bacteroidetes, whose amount regained a relative abundance similar to NW patients after surgery. Obese patients before LGB showed the predominance of Bacteroides, which decreased after surgery in favour of Prevotella, a bacterium associated with a healthy diet. The bacteria detected at the highest percentages belonged to biofilm forming species. In conclusion, in this study, we found that the characterization of the gut microbial communities and the modality of mucosal colonisation have a central role as markers for the clinical management of obesity and promote the maintenance of good health and the weight loss.

Correlation between the reflux finding score and the reflux symptom index in patients with laryngopharyngeal reflux.

LaryngoPharyngeal Reflux (LPR) is characterized by symptoms, signs, and/or tissue damage resulting from the aggression of the gastrointestinal contents in the upper airways. The Reflux Finding Score (RFS) assesses the laryngeal signs through laryngoscopy. The Reflux Symptom Index (RSI) scores the LPR symptoms. The objective of this real-world study was to compare RFS with RSI in a cohort of Italian LPR patients. Globally, 3932 patients with LPR were evaluated and RFS and RSI were assessed in all subjects. A moderate correlation was found between RSI and RFS (r=0.484, p<0.0001). In conclusion, the RSI and RFS can easily be included in the LPR work-up as objective and consistent parameters, with low cost and high practicality. Based on these clinical outcomes, the specialist can easily use these tests in clinical practice.

Relieving laryngopharingeral reflux (RELIEF) survey in otolaryngology - the viewpoint of the otorhinolaryngologist.

Laryngopharyngeal Reflux (LPR) should be considered as part of extraesophageal reflux (EER). This reflux involves respiratory structures other than, or in addition to, the oesophagus. A new medical device for the treatment of gastric reflux, including LPR, has been launched in Italy: Marial®. Therefore, the aim of the present survey was to analyse the prescriptive behaviour both considering the past or current treatments and clinical features during a specialist routine visit. The current survey was conducted in 86 Otorhinolaryngological centers, distributed in all of Italy. Globally, 4.418 subjects [47% males and 53% females, 50.1 (14.5) years-of-age] were visited. The visits included laryngoscopy, Reflux Finding Score (RFS) and Reflux Symptom Index (RSI) questionnaires. The total RSI median score was 15 (12-19) and the total median RFS value was 10 (8-12). Interestingly, a significant change in the new drug prescription was observed (p<0.0001): over two-third of patients (67%) received Marial® as monotherapy, whereas PPI plus add-on were prescribed to almost one-third of the patients. PPI alone was prescribed in less than 1%. In conclusion, LPR is a common disorder characterized by typical signs and symptoms; LPR patients may be correctly identified and scored by evidence-based criteria. In addition, the present survey reported that LPR treatment has been considerably changed by the introduction of a new medical device.