Artificial intelligence for predictive biomarker discovery in immuno-oncology: a systematic review.

BACKGROUND: The widespread use of immune checkpoint inhibitors (ICIs) has revolutionised treatment of multiple cancer types. However, selecting patients who may benefit from ICI remains challenging. Artificial intelligence (AI) approaches allow exploitation of high-dimension oncological data in research and development of precision immuno-oncology. MATERIALS AND METHODS: We conducted a systematic literature review of peer-reviewed original articles studying the ICI efficacy prediction in cancer patients across five data modalities: genomics (including genomics, transcriptomics, and epigenomics), radiomics, digital pathology (pathomics), and real-world and multimodality data. RESULTS: A total of 90 studies were included in this systematic review, with 80% published in 2021-2022. Among them, 37 studies included genomic, 20 radiomic, 8 pathomic, 20 real-world, and 5 multimodal data. Standard machine learning (ML) methods were used in 72% of studies, deep learning (DL) methods in 22%, and both in 6%. The most frequently studied cancer type was non-small-cell lung cancer (36%), followed by melanoma (16%), while 25% included pan-cancer studies. No prospective study design incorporated AI-based methodologies from the outset; rather, all implemented AI as a post hoc analysis. Novel biomarkers for ICI in radiomics and pathomics were identified using AI approaches, and molecular biomarkers have expanded past genomics into transcriptomics and epigenomics. Finally, complex algorithms and new types of AI-based markers, such as meta-biomarkers, are emerging by integrating multimodal/multi-omics data. CONCLUSION: AI-based methods have expanded the horizon for biomarker discovery, demonstrating the power of integrating multimodal data from existing datasets to discover new meta-biomarkers. While most of the included studies showed promise for AI-based prediction of benefit from immunotherapy, none provided high-level evidence for immediate practice change. A priori planned prospective trial designs are needed to cover all lifecycle steps of these software biomarkers, from development and validation to integration into clinical practice.

Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671).

BACKGROUND: Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. The RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC. PATIENTS AND METHODS: This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment-naïve advanced TC. They received ramucirumab, carboplatin and paclitaxel for six cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was objective response rate (ORR) according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Centralized radiologic review was carried out. RESULTS: From November 2018 to June 2023, 52 patients were screened and 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. The Eastern Cooperative Oncology Group performance status was 0 in 68.5% and 1 in 31.4% of patients. At the present analysis carried out some months after the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95% confidence interval (CI) 63.1% to 91.6%]. At the centralized radiological review of 33/35 assessable patients, ORR was 57.6% (95% CI 39.2% to 74.5%). After a median follow-up of 31.6 months, median PFS was 18.1 months (95% CI 10.8-52.3 months) and median OS was 43.8 months (95% CI 31.9 months-not reached). Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE ≥ grade 3. CONCLUSIONS: In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC.

Activity of osimeRTInib in non-small-cell lung Cancer with UNcommon epidermal growth factor receptor mutations: retrospective Observational multicenter study (ARTICUNO).

BACKGROUND: Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted. PATIENTS AND METHODS: The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method. RESULTS: Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy. CONCLUSION: The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.

Implementation of cardiovascular secondary prevention guidelines in clinical practice: a nationwide survey in Italy.

AIMS: To report the implementation of cardiovascular secondary prevention guidelines following a cardiovascular event in Italy. METHODS AND RESULTS: Data were collected from 878 consecutive patients, who had suffered a cardiovascular event requiring hospitalisation in the preceding 12-24 months and who presented at 49 outpatient clinics across Italy. Cardiovascular risk markers were assessed through clinical examination, interview and reviewing of patients' charts; in addition, we collected information on changes in prevalence of selected risk factors that occurred since the time of index event. At the time of evaluation, increased body mass index (BMI) was observed in 35% of patients, with 20% being obese; 26% had diabetes and 21% uncontrolled hypertension. Although 91% of patients were on statins, no measurement of low-density lipoprotein (LDL)-cholesterol was available in the previous 6 months in 27% of patients and 16% had no knowledge of any lipid parameter in the same period. In the remaining patients, LDL was <100 mg dl(-1) in 57% and <70 mg dl(-1) in 20% of them. From the time of index event to interview, prevalence of uncontrolled hypertension remained stable, from 24% to 21% of patients; according to the patients' self-reporting, smoking had declined from 32% to 13% of patients and physical inactivity from 43% to 33% of patients. CONCLUSIONS: This survey shows, in a large national cohort, a suboptimal implementation of lifestyle changes and inadequate lipid control in patients at high cardiovascular risk after a cardiovascular event. Reinforcement of patients and physicians, implementation and adherence to guidelines is needed to reduce the burden of cardiovascular disease.

PEOPLE (NCT03447678), a first-line phase II pembrolizumab trial, in negative and low PD-L1 advanced NSCLC: clinical outcomes and association with circulating immune biomarkers.

BACKGROUND: The PEOPLE trial aimed to identify new immune biomarkers in negative and low programmed death-ligand 1 (PD-L1) (0%-49%) advanced non-small-cell lung cancer (aNSCLC) patients treated with first-line pembrolizumab. Here we report the main outcomes and the circulating immune biomarkers analysis. PATIENTS AND METHODS: The primary endpoint of this phase II trial was the identification of immune biomarkers associated with progression-free survival (PFS). Overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety were secondary endpoints. Absolute cell counts for 36 subsets belonging to innate and adaptive immunity were determined by multiparametric flow cytometry in peripheral blood at baseline and at first radiologic evaluation. An orthoblique principal components-based clustering approach and multivariable Cox regression model adjusted for clinical variables were used to analyze immune variables and their correlation with clinical endpoints. RESULTS: From May 2018 to October 2020, 65 patients were enrolled. After a median follow-up of 26.4 months, the median PFS was 2.9 months [95% confidence interval (CI) 1.8-5.6 months] and median OS was 12.1 months (95% CI 8.7-17.1 months). The ORR was 21.5%, DCR was 47.7% and median DoR was 14.5 months (95% CI 6.4-24.9 months). Drug-related grade 3-4 adverse events were 9.2%. Higher T cell and natural killer (NK) cell count at baseline and at the first radiologic evaluation were associated with improved PFS, DCR and OS. On the contrary, higher myeloid cell count at baseline or at the first radiologic evaluation was significantly associated with worse OS and DCR. CONCLUSIONS: Circulating immune biomarkers can contribute to predict outcomes in negative and low PD-L1 aNSCLC patients treated with first-line single-agent pembrolizumab.

Choosing wisely first line immunotherapy in non-small cell lung cancer (NSCLC): what to add and what to leave out.

Immunotherapy has dramatically changed the therapeutic scenario in treatment naïve advanced non-small cell lung cancer (NSCLC). While single agent pembrolizumab has become the standard therapy in patients with PD-L1 expression on tumor cells ≥ 50%, the combination of pembrolizumab or atezolizumab and platinum-based chemotherapy has emerged as an effective first line treatment regardless of PD-L1 expression both in squamous and non-squamous NSCLC without oncogenic drivers. Furthermore, double immune checkpoint inhibition has shown promising results in treatment naïve patients with high tumor mutational burden (TMB). Of note, the presence of both negative PD-L1 expression and low TMB may identify a subgroup of patients who has little benefit from immunotherapy combinations and for whom the best treatment option may still be platinum-based chemotherapy. To date, first-line single agent immune checkpoint blockade has demonstrated limited activity in EGFR mutated NSCLC and the combination of immunotherapy and targeted agents has raised safety concerns in both EGFR and ALK positive NSCLC patients. Finally, in EGFR mutated or ALK rearranged NSCLC, atezolizumab in combination with platinum-based chemotherapy and bevacizumab is emerging as a potential treatment option upon progression to first line tyrosine kinase inhibitors.

Endothelins enhance prostaglandin (PGE(2) and PGF(2alpha)) biosynthesis and release by human luteal cells: evidence of a new paracrine/autocrine regulation of luteal function.

We have previously shown that endothelin-1 (ET-1) is normally found in human luteal cells, where it is able to significantly inhibit both basal and hCG-induced progesterone production. To further expand our comprehension of the possible roles of endothelins (ETs) in luteal physiology, in this study we used primary cultures of luteal cells exposed to graded doses of ET-1 and ET-3; PGF(2alpha) and PGE(2) were assayed in the culture medium to investigate whether ETs also influence cyclooxygenase activity in these cells. We found that both ETs are able to significantly stimulate PGF(2alpha) and PGE(2) release in a dose- and time-dependent manner. ET-1 was always more effective than ET-3. Experiments with two endothelin receptor antagonists (the BQ485 and BQ788 compounds, which block the ET-A and ET-B receptors, respectively) showed that the two endothelins induce PG production through different receptors and signaling pathways. In conclusion, here we demonstrate the ability of ETs to influence PG synthesis and release from human luteal cells. As PGs are deeply involved in corpus luteum activity, and ETs were also able to influence progesterone production, the present new data suggest an interesting interplay among progesterone, PGs, and ETs in the control of corpus luteum physiology.

IGF-I levels in prepubertal and pubertal children with Down syndrome.

BACKGROUND: Growth retardation is a main feature of Down syndrome but it is still unclear whether an alteration of the GH/IGF-I axis is present in this condition. Concerning IGF-I levels, they have been found reduced by some authors but normal by others. METHODS: On these bases, IGF-I levels have been assessed from prepubertal to late pubertal stages of gonadal maturation in a large group of children and adolescents with Down syndrome (DS, 68 M, 45 F, 12.5 +/- 0.6 yr; prepubertal n = 39, pubertal n = 74) with those in a group of normal children and adolescents (NS, 75 M, 87 F; 11.1 +/- 0.4 yr; prepubertal n = 94, pubertal n = 68). RESULTS: Within each group, IGF-I levels were gender-independent while showed age-related variations with positive association with pubertal stage--peaking up in pubertal stage IV--(DS: r = 0.6, NS: r = 0.4, both p < 0.0001) and testosterone (DS: r = 0.6, NS: r = 0.5, p < 0.001) or estradiol (DS: r = 0.6, NS: r = 0.5, p < 0.001) levels. Considering whole groups, mean IGF-I levels in DS were slightly but significantly lower than those in NS (257.9 +/- 12.5 vs 310.8 +/- 12.6 micrograms/l, p < 0.02). Analyzing individual IGF-I levels in DS with respect to normal ranges per pubertal stage, more than 85% of IGF-I levels resulted within the normal limits. These results demonstrate that IGF-I levels in DS patients are generally within the normal range--though a slight reduction of mean IGF-I levels is present--and follow normal age-related variations with clear cut increase at puberty and positive association with gonadal steroid levels. CONCLUSIONS: This evidence points toward the need to clarify the GH/IGF-I axis function and activity in DS patients.

[The behavior of lecithin cholesterol acyltransferase (LCAT) in acute viral hepatitis and post-hepatitis cirrhosis]. / Comportamento della LCAT nelle epatiti acute virali e nelle cirrosi postepatitiche.

The behaviour of LCAT was examined in acute viral hepatitis and post-hepatic cirrhosis. In the former case, the enzyme was also investigated during remissions. The influence of cholestasis on LCAT activity was evaluated. Depression was noted in cirrhosis and the acute stage of hepatitis, whereas enhanced values were observed during remissions. Depression of the enzyme by cholestasis is explained in a variety of ways.

[L-carnitine in the treatment of chronic myocardial ischemia. An analysis of 3 multicenter studies and a bibliographic review]. / La L-carnitina nel trattamento dell'ischemia miocardica cronica. Analisi dei risultati di tre studi multicentrici e rassegna bibliografica.

The authors selected, from a general sample of 3525 cardiopathic patients treated with 2 g daily of L-carnitine during 1 year, 220 stable effort angina TNT-responder patients, presenting more than 15 anginal episodes per month; moreover, other 59 anginal patients in congestive heart failure have been taken into account. The evaluation of the results obtained in these samples has been done in parallel with the ones of cardiopathic patients studied in 2 multicentric trials carried out, according to a very similar protocol, in Switzerland (148 patients treated at the same posology for 6 months) and Germany (143 patients, 3 months of treatment). The analysis of the three trials showed net reduction of both rate of anginal episodes and therapeutic use of nitrates, substantiated by improvement of physical performance (demonstrated by ergometric test in the German trial) as well as of the quality of life (the Swiss trial). Furthermore, from the general sample of 3525 patients the authors selected 737 subjects with clearly pathological levels of plasma cholesterol, in order to evaluate the effect of L-carnitine treatment on lipidemic parameters; after 12 months of administration only 282 patients showed abnormal levels of cholesterolemia. Analysis of the results of the three trials and a review of the literature on carnitine identify the compound as a fundamental drug for the treatment of patients with myocardial ischemia.

[The feasibility and tolerability of prolonged treatment with low doses of heparin-calcium administered subcutaneously in infarct patients. A multicenter clinical study]. / Fattibilità e tollerabilità di un trattamento prolungato con basse dosi di eparina calcica per via sottocutanea in pazienti infartuati. Studio clinico multicentrico.

Practical feasibility and clinical tolerability of low dose heparin given subcutaneously for the prevention of reinfarction were evaluated in this open, multicentric trial of post-marketing surveillance. 309 investigators participated. 2830 evaluable patients (2090 M, 709 F, mean age 63 years) who had in the previous 2 years a myocardial infarction were treated subcutaneously with calcium heparin (Calciparina Italfarmaco, 0.5 ml prefilled syringe) at the daily dosage of 12.500 U. The foreseen treatment length was of 1 year; after 6 months of daily injections, calcium heparin could be taken for cycles of 30 days, with 10 day intervals. The enrolled patients resulted to be representative of the population affected with ischemic cardiopathy. One year treatment with calcium heparin was completed by 2040 patients (72.1%); about 1/4 of the patients did not complete the protocol. Patient's subjective decision to withdraw accounted for 46.3% of withdrawals; poor tolerability accounted for 15% of withdrawals (3.8% of total patients). Overall, 237 patients (8.4%) suffered from adverse reactions (353 complaints). Local reactions at the injection site accounted for 60% of total adverse reactions, involving 7.5% of total cases. To follow, allergic reactions (2.5%) and other different types of adverse reaction (incidence less than 0.5%). By analyzing the reactions that provoked drug withdrawal, no organ or function (e.g.: haemostasis) were found to be at risk during the heparin treatment. 64 patients died during the trial. These deaths were in prevalence due to cardiovascular diseases: ventricular fibrillation, cardiac failure, arterial thromboembolism (cardiac reinfarction, stroke).(ABSTRACT TRUNCATED AT 250 WORDS)

The metabolic status modulates the effect of metformin on the antimullerian hormone-androgens-insulin interplay in obese women with polycystic ovary syndrome.

CONTEXT: In the adult ovary, antimullerian hormone (AMH) is produced by the granulosa cells of preantral and small antral follicles and negatively regulates folliculogenesis. AMH is overproduced in the polycystic ovary and was recently proposed to play a role in the ovulatory dysfunction of polycystic ovary syndrome (PCOS). OBJECTIVE: The aim of the study was to investigate the effects of metformin administration on AMH levels in relation with the clinical and endocrine-metabolic parameters in obese women with PCOS. DESIGN AND SETTING: We conducted a pilot prospective study in an academic research environment. PATIENTS: We studied 28 obese PCOS women. INTERVENTIONS: We performed ultrasonographic pelvic exams, hirsutism score evaluation, hormonal profile assays, oral glucose tolerance test, euglycemic hyperinsulinemic clamp, and lipid profile at baseline and after 6 months of metformin treatment (850 mg twice a day orally). MAIN OUTCOME MEASURES: We measured AMH, hormonal assays, ultrasound aspect of the ovaries, and indexes of glucose and insulin metabolism. RESULTS: Insulin secretion and body mass index significantly decreased after treatment. Almost 70% of subjects experienced an amelioration of menstrual irregularities. Mean androstenedione, testosterone, and 17-hydroxyprogesterone levels and hirsutism score were significantly improved by metformin. However, no significant changes in AMH levels occurred. Data were further analyzed after dividing patients on the basis of pretreatment insulinemic response to the oral glucose tolerance test; metformin was effective in reducing insulin secretion, AMH levels, and, interestingly, ovarian volume exclusively in PCOS patients with hyperinsulinism; none of these changes occurred in the normoinsulinemic group. CONCLUSIONS: Metformin differentially affects the interplay between insulin and the ovarian function in obese PCOS women; the presence of hyperinsulinemia seems to be predictive of the efficacy of the treatment.