AVALON: The Italian cohort study on real-life efficacy of hypomethylating agents plus venetoclax in newly diagnosed or relapsed/refractory patients with acute myeloid leukemia.

BACKGROUND: Venetoclax in combination with hypomethylating agents (HMA) is revolutionizing the therapy of acute myeloid leukemia (AML). However, evidence on large sets of patients is lacking, especially in relapsed or refractory leukemia. METHODS: AVALON is a multicentric cohort study that was conducted in Italy on patients with AML who received venetoclax-based therapies from 2015 to 2020. The study was approved by the ethics committee of the participating institution and was conducted in accordance with the Declaration of Helsinki. The effectiveness and toxicity of venetoclax + HMA in 190 (43 newly diagnosed, 68 refractory, and 79 relapsed) patients with AML are reported here. RESULTS: In the newly diagnosed AML, the overall response rate and survival confirmed the brilliant results demonstrated in VIALE-A. In the relapsed or refractory AML, the combination demonstrated a surprisingly complete remission rate (44.1% in refractory and 39.7% in relapsed evaluable patients) and conferred to treated patients a good expectation of survival. Toxicities were overall manageable, and most incidents occurred in the first 60 days of therapy. Infections were confirmed as the most common nonhematologic adverse event. CONCLUSIONS: Real-life data show that the combination of venetoclax and HMA offers an expectation of remission and long-term survival to elderly, newly diagnosed patients, and to relapsed or chemoresistant AML, increasing the chance of cure through a different mechanism of action. The venetoclax + HMA combination is expected to constitute the base for triplet combinations and integration of target therapies. Our data contribute to ameliorate the understanding of venetoclax + HMA effectiveness and toxicities in real life.

Use of Sequential Multiple Assignment Randomized Trials (SMARTs) in oncology: systematic review of published studies.

Sequential multiple assignments randomized trials (SMARTs) are a type of experimental design where patients may be randomised multiple times according to pre-specified decision rules. The present work investigates the state-of-the-art of SMART designs in oncology, focusing on the discrepancy between the available methodological approaches in the statistical literature and the procedures applied within cancer clinical trials. A systematic review was conducted, searching PubMed, Embase and CENTRAL for protocols or reports of results of SMART designs and registrations of SMART designs in clinical trial registries applied to solid tumour research. After title/abstract and full-text screening, 33 records were included. Fifteen were reports of trials' results, four were trials' protocols and fourteen were trials' registrations. The study design was defined as SMART by only one out of fifteen trial reports. Conversely, 13 of 18 study protocols and trial registrations defined the study design SMART. Furthermore, most of the records considered each stage separately in the analysis, without considering treatment regimens embedded in the trial. SMART designs in oncology are still limited. Study powering and analysis is mainly based on statistical approaches traditionally used in single-stage parallel trial designs. Formal reporting guidelines for SMART designs are needed.

Fall predictors in hospitalized patients living with cancer: a case-control study.

PURPOSE: To identify fall predictors and develop an assessment tool to be used for screening hospitalized cancer patients at risk for fall. METHODS: A retrospective case-control study was conducted in 2018 at a cancer center in Northern Italy. The study participants were 448 adult cancer patients admitted to the oncology ward from 2009 to 2013. The case group consisted of 112 patients presenting at least one fall, while controls were randomly chosen by matching each case for age, sex, and admission period with three patients who did not fall. Data for the fall predictors were extracted from the electronic medical records. Conditional logistic regression was used to evaluate the association between patient's characteristics and fall risk. RESULTS: The overall prevalence of patients having at least one candidate fall predictor was high (98%). Seven of the studied variables showed an independent association with fall risk at multivariate analysis. These were tumor site, the presence of neurologic diseases, gait imbalance disorders, fatigue, and the assumption of certain medications such as diuretics, hypnotics, and opioids (odds ratios and 95% confidence intervals in brackets were 3.78 (1.78-8.13), 2.26 (1.08-4.77), 4.22 (1.87-9.52), 2.76 (1.45-5.26), 2.66 (1.52-4.66), 2.41 (1.20-4.85), and 3.03 (1.68-5.45), respectively). CONCLUSIONS: In this study, we identified falling risk factors in an Italian population of hospitalized cancer patients and developed a new risk assessment tool. An external validation is necessary before implementing our screening tool in clinical practice.

Clinical Impact of Next-Generation Sequencing Multi-Gene Panel Highlighting the Landscape of Germline Alterations in Ovarian Cancer Patients.

BRCA1 and BRCA2 are the most frequently mutated genes in ovarian cancer (OC) crucial both for the identification of cancer predisposition and therapeutic choices. However, germline variants in other genes could be involved in OC susceptibility. We characterized OC patients to detect mutations in genes other than BRCA1/2 that could be associated with a high risk of developing OC and permit patients to enter the most appropriate treatment and surveillance program. Next-generation sequencing analysis with a 94-gene panel was performed on germline DNA of 219 OC patients. We identified 34 pathogenic/likely pathogenic variants in BRCA1/2 and 38 in other 21 genes. The patients with pathogenic/likely pathogenic variants in the non-BRCA1/2 genes mainly developed OC alone compared to the other groups that also developed breast cancer or other tumors (p = 0.001). Clinical correlation analysis showed that the low-risk patients were significantly associated with platinum sensitivity (p < 0.001). Regarding PARP inhibitors (PARPi) response, the patients with pathogenic mutations in the non-BRCA1/2 genes had worse PFS and OS. Moreover, a statistically significantly worse PFS was found for every increase of one thousand platelets before PARPi treatment. To conclude, knowledge about molecular alterations in genes beyond BRCA1/2 in OC could allow for more personalized diagnostic, predictive, prognostic, and therapeutic strategies for OC patients.

Phase II Study of Dehydroepiandrosterone in Androgen Receptor-Positive Metastatic Breast Cancer.

LESSONS LEARNED: The androgen receptor (AR) is present in most breast cancers (BC), but its exploitation as a therapeutic target has been limited.This study explored the activity of dehydroepiandrosterone (DHEA), a precursor being transformed into androgens within BC cells, in combination with an aromatase inhibitor (to block DHEA conversion into estrogens), in a two-stage phase II study in patients with AR-positive/estrogen receptor-positive/human epidermal growth receptor 2-negative metastatic BC.Although well tolerated, only 1 of 12 patients obtained a prolonged clinical benefit, and the study was closed after its first stage for poor activity. BACKGROUND: Androgen receptors (AR) are expressed in most breast cancers, and AR-agonists have some activity in these neoplasms. We investigated the safety and activity of the androgen precursor dehydroepiandrosterone (DHEA) in combination with an aromatase inhibitor (AI) in patients with AR-positive metastatic breast cancer (MBC). METHODS: A two-stage phase II study was conducted in two patient cohorts, one with estrogen receptor (ER)-positive (resistant to AIs) and the other with triple-negative MBC. DHEA 100 mg/day was administered orally. The combination with an AI aimed to prevent the conversion of DHEA into estrogens. The main endpoint was the clinical benefit rate. The triple-negative cohort was closed early. RESULTS: Twelve patients with ER-positive MBC were enrolled. DHEA-related adverse events, reported in four patients, included grade 2 fatigue, erythema, and transaminitis, and grade 1 drowsiness and musculoskeletal pain. Clinical benefit was observed in one patient with ER-positive disease whose tumor had AR gene amplification. There was wide inter- and intra-patient variation in serum levels of DHEA and its metabolites. CONCLUSION: DHEA showed excellent safety but poor activity in MBC. Although dose and patient selection could be improved, high serum level variability may hamper further DHEA development in this setting.

E-cadherin Downregulation and microRNAs in Sporadic Intestinal-Type Gastric Cancer.

CDH1 gene, encoding E-cadherin, is a tumor suppressor gene frequently altered in gastric cancers (GCs) of both diffuse (DGC) and intestinal (IGC) histotypes, albeit through different mechanisms. The study aimed to characterize CDH1 expression in sporadic IGC and to investigate whether microRNAs (miRs) are involved in its transcriptional control. We evaluated CDH1 expression by quantitative real-time PCR (RT-qPCR) in 33 IGC patients and found a significant downregulation in tumor tissues compared to normal counterparts (p-value = 0.025). Moreover, 14 miRs, predicted to be involved in CDH1 regulation in both a direct and indirect manner, were selected and analyzed by RT-qPCR in an independent case series of 17 IGCs and matched normal tissues. miR-101, miR-26b, and miR-200c emerged as significantly downregulated and were confirmed in the case series of 33 patients (p-value < 0.001). Finally, we evaluated EZH2 expression, a target of both miR-101 and miR-26b, which showed significant upregulation in IGCs (p-value = 0.005). A significant inverse correlation was observed between EZH2 overexpression and CDH1, miR-101, and miR-26b levels (p-value < 0.001). Our results reinforce the link between CDH1 and IGC, highlighting the role of miRs in its transcriptional control and improving our understanding of GC subtypes and biomarkers.

The ANDROMEDA prospective cohort study: predictive value of combined criteria to tailor breast cancer screening and new opportunities from circulating markers: study protocol.

BACKGROUND: In recent years growing interest has been posed on alternative ways to screen women for breast cancer involving different imaging techniques or adjusting screening interval by breast cancer risk estimates. A new research area is studying circulating microRNAs as molecular biomarkers potentially useful for non invasive early detection together with the analysis of single-nucleotide polymorphisms (SNPs). The Andromeda study is a prospective cohort study on women attending breast cancer screening in a northern Italian area. The aims of the study are: 1) to define appropriate women risk-based stratifications for personalized screening considering different factors (reproductive, family and biopsy history, breast density, lifestyle habits); 2) to evaluate the diagnostic accuracy of selected circulating microRNAs in a case-control study nested within the above mentioned cohort. METHODS: About 21,000 women aged 46-67 years compliant to screening mammography are expected to be enrolled. At enrolment, information on well-known breast cancer risk factors and life-styles habits are collected through self-admistered questionnaires. Information on breast density and anthropometric measurements (height, weight, body composition, and waist circumference) are recorded. In addition, women are requested to provide a blood sample for serum, plasma and buffy-coat storing for subsequent molecular analyses within the nested case-control study. This investigation will be performed on approximately 233 cases (screen-detected) and 699 matched controls to evaluate SNPs and circulating microRNAs. The whole study will last three years and the cohort will be followed up for ten years to observe the onset of new breast cancer cases. DISCUSSION: Nowadays women undergo the same screening protocol, independently of their breast density and their individual risk to develop breast cancer. New criteria to better stratify women in risk groups could enable the screening strategies to target high-risk women while reducing interventions in those at low-risk. In this frame the present study will contribute in identifying the feasibility and impact of implementing personalized breast cancer screening. TRIAL REGISTRATION: NCT02618538 (retrospectively registered on 27-11-2015.).

Impact of admission to hospice on pain intensity and type of pain therapies administered.

PURPOSE: The primary aim of this study was to evaluate pain intensity changes in patients admitted to a hospice. The secondary objective was to evaluate whether these changes in pain were accompanied by modifications in therapies and drugs used to treat pain. PATIENTS AND METHODS: This retrospective study included 96 patients admitted to a hospice for a minimum of 7 days who received pain therapy. An 11-point (0-10) numerical rating scale (NRS) was used to assess pain on a daily basis. A repeated measures analysis of variance was performed to evaluate pain intensity changes over time. RESULTS: Mean ± SD pain NRS values of the entire group were 2.58 ± 2.61 on day 1 and 1.40 ± 1.72 on day 7 (P = 0.002). Restricting the analysis to patients with moderate to severe pain at the time of hospice admission, results were even more significant. In fact, mean ± SD pain NRS was 5.51 ± 1.24 for patients with pain ≥4 at admission and 1.76 ± 1.91 for the same patients after 7 days (P < 0.001). A significant increase in the number of patients receiving morphine was observed from day 1 to day 7 (24 to 41, respectively, P = 0.001) and in those receiving drugs via parenteral routes (subcutaneous or intravenous) from 10 to 27 (P = 0.002) CONCLUSIONS: Admission to a hospice and the hospice environment led to a significant reduction in reported pain intensity for the patients included in this study, mainly those with moderate to severe pain at the time of admission. This decrease in pain was accompanied by a significant increase in the use of morphine, especially via parenteral routes, but not by a higher mean equivalent daily dose of oral morphine per patient.

Metabolic syndrome in castration-resistant prostate cancer patients treated with abiraterone.

BACKGROUND: Metabolic syndrome (MS) has not yet been studied in castration-resistant prostate cancer (CRPC) men treated with novel hormonal therapies. The study aims to assess the impact of MS on outcome from time starting abiraterone. PATIENTS AND METHODS: We retrospectively evaluated a consecutive series of metastatic CRPC patients treated with abiraterone after docetaxel failure. MS, as defined by modified Adult Treatment Panel (ATP) III criteria, was assessed at the time of initiation of abiraterone, during treatment and follow-up. RESULTS: Sixty-seven of 178 patients evaluated (37.6%) met MS criteria at baseline, before abiraterone initiation, whereas for 11 (9.9%) without MS before treatment with abiraterone this occurred during treatment. Median PFS was equal to 4.7 months for patients with MS versus 9 months for those without MS. Patients with MS had an increased risk of 71% of progression or death for all causes than patients without MS (HR = 1.7, 95% CI [1.2-2.4], P = 0.03). Median OS was 14.7 months and 22.3 months in patients with and without MS, respectively. After adjusting for covariates, MS resulted not significantly associated to OS (HR = 1.42, 95% CI [0.91-2.22], P = 0.073). CONCLUSIONS: The presence of MS is a significant risk factor for shorter PFS in CRPC patients treated with abiraterone, even if it does not show a significant impact on OS. A prospective evaluation is warranted.

Coronally advanced flap with and without connective tissue graft for the treatment of multiple gingival recessions: a comparative short- and long-term controlled randomized clinical trial.

AIM: The aim of this study was to compare short- and long-term root coverage and aesthetic outcomes of the coronally advanced flap (CAF) alone or in combination with a connective tissue graft (CTG) for the treatment of multiple gingival recessions. METHODS: Fifty patients with multiple (≥2) adjacent gingival recessions (≥2 mm) in the upper jaw were enrolled. Twenty-five patients were randomly assigned to the control group (CAF), and the other 25 patients to the test group (CAF + CTG). Clinical outcomes were evaluated at 6 months, 1 and 5 years. The aesthetic evaluations were made 1 and 5 years after the surgery. RESULTS: No statistically significant difference was demonstrated between the two groups in terms of Rec Red and complete root coverage (CRC) at 6 months and 1 year. At 5 years, statistically greater recession reduction and probability of CRC, greater increase in buccal KTH and better contour evaluation made by an independent periodontist were observed in the CAF + CTG group. Better post-operative course and better colour match were demonstrated in CAF-treated patients both at 1 and 5 years. CONCLUSIONS: CAF + CTG provided better CRC at 5 years; keloid formation due to graft exposure was responsible for the worse colour match evaluation.

Baseline and Longitudinal Neutrophil-to-Lymphocyte Ratio as Prognostic Factor for Metastatic Colorectal Cancer: A Secondary Analysis of the ITACa Randomized Trial.

PURPOSE: We aimed to investigate the prognostic role of baseline and longitudinal levels of neutrophil-to-lymphocyte ratio (NLR) in patients with metastatic colorectal cancer (mCRC) treated with chemotherapy + bevacizumab (CT + B) or chemotherapy only. Additionally, we investigated whether treatment outcomes were mediated by the longitudinal biomarker. METHODS: Data from an Italian randomized phase III trial were used. The main end point was progression-free survival (PFS). To address research questions, a series of joint models of longitudinal and survival data were specified, and the direct and indirect treatment effects were quantified. RESULTS: Data for 239 patients, 113 (47.3%) treated with CT + B and 126 (52.7%) with CT only, were included in the analyses. The effect of NLR seemed to be mediated by the longitudinal trajectory of the biomarker. Only in the patient subgroup treated with CT + B, the baseline NLR retained a direct effect on PFS. Regarding the effect of treatment on PFS, two scenarios were observed. In the subgroup of patients with low baseline, NLR bevacizumab showed a direct protective effect only (hazard ratio [HR], 0.66 [95% CI, 0.45 to 0.98]), whereas in the subgroup with high baseline NLR, there was evidence for an adverse direct effect (HR, 1.63 [95% CI, 1.03 to 2.57]) and a protective indirect-which is mediated by the longitudinal biomarker-effect (HR, 0.71 [95% CI, 0.55 to 0.90]). CONCLUSION: In our study, inflammatory indexes collected longitudinally showed a significant adverse prognostic role, thus suggesting the collection and use of such data for better clinical decision making. In the specific setting, we considered this is particularly important as the treatment effect seemed to be modified by both the baseline and longitudinal inflammation statuses. However, further research is needed to understand the possible factors underlying these results.

Rare Driver Mutations in Advanced, Oncogene-Addicted Non-Small Cell Lung Cancer: A North Italian, Real-World, Registry Experience.

The real-world, retrospective, NEROnE registry investigated the impact of next-generation sequencing (NGS) in advanced non-small-cell lung cancer (NSCLC) patients (pts) at three oncology units in the north of Italy between January 2020 and December 2022. We focused on the clinical characterization and outcomes of NSCLC with rare molecular alterations: EGFR exon 20 insertion, non-activating EGFR mutations, BRAF V600E and non-V600, ROS1 and RET rearrangements, MET, ErbB2, and FGFR mutations. Overall, these represented 6.4% (62/970) of the pts analysed with NGS in the daily practice. The most heavily represented rare alterations were ROS1 rearrangement (15 pts-24%) and MET exon 14 skipping mutation (11 pts-18%). No associations were found with the demographic and clinical features. Forty-nine pts received targeted therapies, of which 38.8% were first- and 9.8% were second-line. The remaining pts received chemotherapy and/or immunotherapy. In terms of the clinical outcomes, although not statistically significant, a tendency toward shorter OS was seen when therapies other than specific targeted therapies were used (HR: 1.84, 95% CI: 0.79-4.33, p = 0.158). The pts with co-mutations (19.4%) seemed to receive an advantage from the front-line chemotherapy-based regimen. Finally, an NLR score (a well-known inflammatory index) ≥ 4 seemed to be related to shorter OS among the pts treated with immunotherapy alone or in combination with chemotherapy (HR: 2.83, 95% CI: 1.08-7.40, p = 0.033). Prospective evaluations need to be performed to clarify whether these indexes may help to identify patients with oncogene-addicted NSCLC who could benefit from immunotherapy.

The effect of weight status, lifestyle, and body image perception on health-related quality of life in children: a quantile approach.

PURPOSE: To evaluate the effect of excess weight, lifestyle factors, and body image on HRQoL in a sample of school-aged children. METHODS: Cross-sectional data of 4,338 thirteen-year-old children were collected in 2007 as part of the So.N.I.A project, a nutritional surveillance study in a northern Italian region. A two-stage sampling design was used in order to gain a Health District representative sample of the regional population. HRQoL was assessed using the EQ-5D-Y questionnaire completed by the children at school. The association between weight categories, defined by means of the International Obesity Task Force cut points, physical exercise, and body image perception and HRQoL as measured by the EQ-Visual Analogue Scale was studied by means of a quantile regression analysis. RESULTS: Of the participants, 891 (20.5 %) and 210 (4.84 %) were overweight and obese, respectively, with 1,922 (44.3 %) children exercising <2 h per week. Results from the quantile regression showed a decreased HRQoL for girls compared with boys, overweight or obese children who do little weekly exercise, and body image dissatisfaction, especially in the lower tail of the VAS distribution. CONCLUSIONS: Excess weight, sedentary behavior, and an unsatisfactory self-perception are associated with reduced HRQoL in this population-based sample. Quantile regression can help to highlight differences in the effects along all of the outcome distribution.

Impact of the time interval between primary or interval surgery and adjuvant chemotherapy in ovarian cancer patients.

Introduction: Primary debulking surgery (PDS), interval debulking surgery (IDS), and platinum-based chemotherapy are the current standard treatments for advanced ovarian cancer (OC). The time to initiation of adjuvant chemotherapy (TTC) could influence patient outcomes. Methods: We conducted a multicenter retrospective cohort study of advanced (International Federation of Gynecology and Obstetrics (FIGO) stage III or IV) OC treated between 2014 and 2018 to assess progression-free survival (PFS) and overall survival (OS) in relation to TTC. All patients underwent a germline multigene panel for BRCA1/2 evaluation. Results: Among the 83 patients who underwent PDS, a TTC ≥ 60 days was associated with a shorter PFS (hazard ratio (HR) 2.02, 95% confidence interval (CI) 1.04-3.93, p = 0.038), although this association lost statistical significance when adjusting for residual disease (HR 1.52, 95% CI 0.75-3.06, p = 0.244, for TTC and HR 2.73, 95% CI 1.50-4.96, p = 0.001, for residual disease). Among 52 IDS patients, we found no evidence of an association between TTC and clinical outcomes. Ascites, type of chemotherapy, or germline BRCA1/2 mutational status did not influence TTC and were not associated with clinical outcomes in PDS or IDS patients. Discussion: In conclusion, longer TTC seems to negatively affect prognosis in patients undergoing PDS, especially those with residual disease.

Plasma microRNA ratios associated with breast cancer detection in a nested case-control study from a mammography screening cohort.

Mammographic breast cancer screening is effective in reducing breast cancer mortality. Nevertheless, several limitations are known. Therefore, developing an alternative or complementary non-invasive tool capable of increasing the accuracy of the screening process is highly desirable. The objective of this study was to identify circulating microRNA (miRs) ratios associated with BC in women attending mammography screening. A nested case-control study was conducted within the ANDROMEDA cohort (women of age 46-67 attending BC screening). Pre-diagnostic plasma samples, information on life-styles and common BC risk factors were collected. Small-RNA sequencing was carried out on plasma samples from 65 cases and 66 controls. miR ratios associated with BC were selected by two-sample Wilcoxon test and lasso logistic regression. Subsequent assessment by RT-qPCR of the miRs contained in the selected miR ratios was carried out as a platform validation. To identify the most promising biomarkers, penalised logistic regression was further applied to candidate miR ratios alone, or in combination with non-molecular factors. Small-RNA sequencing yielded 20 candidate miR ratios associated with BC, which were further assessed by RT-qPCR. In the resulting model, penalised logistic regression selected seven miR ratios (miR-199a-3p_let-7a-5p, miR-26b-5p_miR-142-5p, let-7b-5p_miR-19b-3p, miR-101-3p_miR-19b-3p, miR-93-5p_miR-19b-3p, let-7a-5p_miR-22-3p and miR-21-5p_miR-23a-3p), together with body mass index (BMI), menopausal status (MS), the interaction term BMI * MS, life-style score and breast density. The ROC AUC of the model was 0.79 with a sensitivity and specificity of 71.9% and 76.6%, respectively. We identified biomarkers potentially useful for BC screening measured through a widespread and low-cost technique. This is the first study reporting circulating miRs for BC detection in a screening setting. Validation in a wider sample is warranted.Trial registration: The Andromeda prospective cohort study protocol was retrospectively registered on 27-11-2015 (NCT02618538).

Digital Guardian Angel Supported by an Artificial Intelligence System to Improve Quality of Life, Well-being, and Health Outcomes of Patients With Cancer (ONCORELIEF): Protocol for a Single Arm Prospective Multicenter Pilot Study.

BACKGROUND: According to Europe's Beating Cancer Plan, the number of cancer survivors is growing every year and is now estimated at over 12 million in Europe. A main objective of the European Commission is to ensure that cancer survivors can enjoy a high quality of life, underlining the role of digital technology and eHealth apps and tools to achieve this. OBJECTIVE: The main objective of this study is the development of a user-centered artificial intelligence system to facilitate the input and integration of patient-related biopsychosocial data to improve posttreatment quality of life, well-being, and health outcomes and examine the feasibility of this digitally assisted workflow in a real-life setting in patients with colorectal cancer and acute myeloid leukemia. METHODS: A total of 60 patients with colorectal cancer and 30 patients with acute myeloid leukemia will be recruited from 2 clinical centers: Universitätsmedizin der Johannes Gutenberg-Universität Mainz (Mainz, Germany) and IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" (IRST, Italy). Psychosocial data (eg, emotional distress, fatigue, quality of life, subjective well-being, sleep problems, and appetite loss) will be collected by questionnaires via a smartphone app, and physiological data (eg, heart rate, skin temperature, and movement through step count) will be collected by a customizable smart wrist-worn sensor device. Each patient will be assessed every 2 weeks over their 3-month participation in the ONCORELIEF study. Inclusion criteria include patients with the diagnosis of acute myeloid leukemia or colorectal cancer, adult patients aged 18 years and older, life expectancy greater than 12 months, Eastern Cooperative Oncology Group performance status ≤2, and patients who have a smartphone and agree to use it for the purpose of the study. Exclusion criteria include patients with a reduced cognitive function (such as dementia) or technological illiteracy and other known active malignant neoplastic diseases (patients with a medical history of treated neoplastic disease are included). RESULTS: The pilot study started on September 1, 2022. As of January 2023, we enrolled 33 patients with colorectal cancer and 7 patients with acute myeloid leukemia. As of January 2023, we have not yet started the data analysis. We expect to get all data in June 2023 and expect the results to be published in the second semester of 2023. CONCLUSIONS: Web-based and mobile apps use methods from mathematical decision support and artificial intelligence through a closed-loop workflow that connects health professionals and patients. The ONCORELIEF system has the potential of continuously identifying, collecting, and processing data from diverse patient dimensions to offer health care recommendations, support patients with cancer to address their unmet needs, and optimize survivorship care. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) 00027808; https://drks.de/search/en/trial/DRKS00027808. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/45475.

Comparative Analysis of Free-Circulating and Vesicle-Associated Plasma microRNAs of Healthy Controls and Early-Stage Lung Cancer Patients.

In recent years, circulating extracellular miRNAs have emerged as a useful tool for the molecular characterization and study of tumors' biological functions. However, the high heterogeneity in sample processing, isolation of circulating fraction, RNA extraction, and sequencing hamper the reproducibility and the introduction of these biomarkers in clinical practice. In this paper, we compare the content and the performance of miRNA sequencing in plasma-derived samples processed with different isolation protocols. We tested three different fractions of miRNA from healthy-donor human blood: whole plasma (WP), free-circulating (FC) and EV-associated, isolated by either column (ccEV) or size exclusion chromatography (secEV) miRNAs. An additional cohort of 18 lung cancer patients was analyzed. Protein profiles of ccEV and secEV were compared and miRNA expression profiles were assessed through sequencing. Slight differences were found between ccEV and secEV expressions of typical EV markers. Conversely, sequencing performance and the mirnome profile varied between RNA extracted using different isolation methods. Sequencing performance was better in FC samples. Higher varieties of miRNAs were identified in WP and FC with respect to ccEV and secEV. Analysis of free-circulating and EV-associated miRNA profiles in lung cancer patients demonstrated the reliability of the biomarkers identifiable on plasma with these approaches.

Wide Next-Generation Sequencing Characterization of Young Adults Non-Small-Cell Lung Cancer Patients.

Molecular characterization of advanced non-small-cell lung cancer (NSCLC) is mandatory before any treatment decision making. Next-generation sequencing (NGS) approaches represent the best strategy in this context. The turnaround time for NGS methodologies and the related costs are becoming more and more adaptable for their use in clinical practice. In our study, we analyzed a case series of young (under 65 years old) NSCLC patients with a wide NGS gene panel assay. The most frequent altered genes were TP53 (64.55%), followed by KRAS (44.1%), STK11 (26.9%), CDKN2A (21.5%), CDKN2B (14.0%), EGFR (16.1%), and RB1 (10.8%). Tumor mutational burden (TMB) was also evaluated. Considering the cut-off of 10 mut/Mb, 62 (68.9%) patients showed a TMB < 10 mut/Mb, whereas 28 (31.1%) showed a TMB ≥ 10 mut/Mb. STK11 and KRAS mutations were significantly associated with a higher TMB (p = 0.019 and p = 0.004, respectively). Conversely, EGFR and EML4-ALK alterations were more frequently found in tumors with low TMB (p = 0.019 and p < 0.001, respectively). We compared results obtained from this approach with those obtained from a single or few genes approach, observing perfect concordance of the results.

High Levels of Circulating Monocytic Myeloid-Derived Suppressive-Like Cells Are Associated With the Primary Resistance to Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: An Exploratory Analysis.

Background: Immunotherapy has become the standard of care for non-small cell lung cancer (NSCLC) patients. Some patients experience primary resistance to immunotherapy. Currently, we lack a marker of resistance to immunotherapy. Myeloid-derived suppressive-like cells (MDSCs) can reduce tumor response rate and survival outcomes. Methods: This is an exploratory prospective observational study on metastatic NSCLC patients starting immunotherapy. Baseline peripheral blood samples were collected. Monocytic (M)-MDSCs were analyzed by flow cytometry. The main clinical outcomes were tumor response, progression-free survival (PFS), and overall survival (OS). The association between MDSC levels and tumor response was assessed. The association of PFS with OS was investigated using the Kaplan-Meier method and the Cox proportional hazards model. Results: Twenty-two patients were included. The median M-MDSC value was higher in patients with progressive disease than patients with stable disease or partial response, p = 0.045. The median MDSC value in the overall population was 1.9. We found worse PFS (HR = 2.51; p = 0.046) and OS (HR = 2.68; p = 0.042) in patients with M-MDSC values higher than the median. Conclusions: In this exploratory analysis, high M-MDSC levels are strongly associated with primary resistance to immunotherapy. If validated in larger studies, MDSC levels in blood samples could help to select NSCLC patients for higher benefit from immunotherapy.

Prognosis of ALK-rearranged non-small-cell lung cancer patients carrying TP53 mutations.

Non-small-cell lung cancer (NSCLC) is the primary cause of cancer-related death. Gene rearrangements involving the anaplastic lymphoma kinase (ALK) tyrosine kinase identify a clinical and molecular subset of NSCLC patients, who benefit from the monotherapy with ALK tyrosine kinase inhibitors. Nonetheless, responsiveness to TKIs and prognosis of these patients are influenced by several factors, including resistance mechanisms and mutations affecting genes involved in key molecular pathways of cancer cells. In a cohort of 98 NSCLC patients with ALK gene rearrangements, we investigated the role of Tumor Protein (TP53) gene mutations in predicting patients prognosis. TP53 mutations were evaluated in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS).Results: In patients with available clinical and TP53 mutation information, we found that 13 patients (20.3%) were affected by TP53 mutations. Considered together, even though showing a trend, TP53 mutations were not associated with PFS and OS. Considering the different TP53 mutations by functionality in terms of disruptive and non-disruptive mutations, we observed that TP53 non-disruptive mutations were able to predict worse OS in the overall case series. Moreover, a worse PFS was seen in the subgroup of patients with TP53 non-disruptive mutation, in first-, second-, and third line of treatment. Our results show that mutations affecting TP53 gene, especially non-disruptive mutations, are able to affect prognosis of ALK-rearranged NSCLC patients.