The purpose of this editorial is to explore the potential and risks of using AI in the medical field, particularly in oncology. We describe the history of AI from its origins to the present day, highlighting its positive aspects and potential for each type of AI (expert system, machine learning, generative AI). Technologies like ChatGPT are increasingly being used across various domains; however, without proper caution, they can give rise to phenomena such as 'AI hallucinations'—responses that may appear precise, detailed, clear, and logical, but are in fact entirely fabricated and unfounded, potentially confusing those who read them. We want to caution oncologists against the unconditional use of these technologies, where human input remains still essential both in interpreting the responses and in formulating the questions.

In this paper, we explore the application of ensemble optimal control to derive enhanced strategies for pharmacological cancer treatment, and we tackle the problem of the long-term management of the disease, i.e., when the complete eradication of the tumor is not achievable. In particular, we focus on moving beyond the classical clinical approach of giving the patient the maximal tolerated drug dose (MTD), which does not properly exploit the fight among sensitive and resistant cells for the available resources. Here, we employ a Lotka-Volterra model to describe the competing subpopulations, and we enclose this system within the ensemble control framework. In the first part, we establish general results suitable for application to various cancers. Then, we carry out numerical simulations in the setting of prostate cancer treated with androgen deprivation therapy, yielding a computed policy that is reminiscent of the medical ‘active surveillance’ paradigm. Finally, inspired by the numerical evidence, we propose a variant of the celebrated adaptive therapy (AT), which we call ‘Off-On’ AT.

A 66-year-old man with stage IVB oesophageal carcinoma treated with cisplatin, 5-fluorouracil, and pembrolizumab developed gastric erosions and ulcers with lymphoplasmacytic and neutrophilic infiltrates suggestive of immune checkpoint inhibitor-induced gastritis. High-dose steroids yielded transient relief. Cytomegalovirus (CMV) DNA was later found in gastric biopsies; steroids were withdrawn, and 3 weeks of intravenous ganciclovir led to partial improvement. Subsequent haemorrhagic gastritis raised concern for underlying immunodeficiency; serum immunoglobulin G (IgG), IgA, and IgM were undetectable. Administration of intravenous immunoglobulins (0.8 g/kg) produced rapid clinical resolution. This case report underscores the need for tissue-based CMV testing and cautious steroid use in severe gastritis.

Rising rates of cancers diagnosed before the age of 50 have been reported worldwide, including in Italy. Among modifiable risk factors, excess body weight (overweight and obesity) and alcohol consumption independently and synergistically increase the risk of breast and colorectal cancers, including early-onset disease. However, the population-level burden attributable to these exposures among adolescents and young adults (AYA) remains poorly quantified. We combined a targeted overview of the literature with a quantitative Population Attributable Fraction (PAF) analysis to estimate the proportion of early-onset breast and colorectal cancers attributable to overweight/obesity, high-risk alcohol consumption, and their combined exposure in the Italian population aged 18–34 years. Sex- and age-specific prevalence data were derived from the national surveillance system “PASSI”, while relative risks were obtained from meta-analyses and large cohort studies, prioritizing estimates from early-onset populations when available. PAFs were estimated using the Bruzzi et al. method, while combined PAFs were calculated assuming independence between exposures. Uncertainty was assessed through Monte Carlo simulations and sensitivity analyses on prevalence and relative risk assumptions. Among Italian young adults aged 18–34 years, overweight and obesity together accounted for a substantial proportion of early-onset colorectal cancer cases, while high-risk alcohol consumption showed the largest individual attributable fraction. The combined contribution of excess body weight and high-risk alcohol consumption reached 16.6

BACKGROUD:Accurate localization of nonpalpable breast lesions in breast-conserving surgery (BCS) is essential for achieving oncological radicality, preserving cosmetic outcomes, and reducing reinterventions for positive margins. Radioguided occult lesion localization (ROLL) and magnetic seed localization (MSL) are established alternatives to wire-guided methods, but comparative evidence remains limited. METHODS:This prospective, single-centre, randomized clinical trial evaluated the noninferiority of MSL compared with ROLL in achieving negative surgical margins, assessed surgical, organizational, and patient-reported outcomes, and included a costs analysis. A total of 260 women with nonpalpable breast lesions suitable for BCS were enrolled between June 2023 and July 2025 and randomized 1:1 to ROLL or MSL. The primary endpoint was margin negativity. Secondary endpoints included calculated resection ratio (CRR), operative time, complications, hospital stay, reoperation rate, and EQ-5D-5L patient-reported outcomes. RESULTS:Negative margins were achieved in 97.7% of ROLL and 93.1% of MSL cases (p = 0.14), confirming MSL noninferiority. Median CRR was identical (1.7, p = 0.61). Overall complication rates were comparable (6.2%-MSL vs. 4.7%-ROLL, p = 0.59), although postlocalization hematoma was more frequent with MSL (17% vs. 7%, p = 0.01). Hospital stay was significantly shorter with MSL (1 vs. 2 days, p = 0.001). Operative times were similar, and surgeon experience did not influence margin status, although attendings achieved lower CRR with ROLL. EQ-5D-5L scores were comparable except for "usual activities" dimension, which favoured ROLL. CONCLUSIONS:MSL was noninferior to ROLL, with comparable safety and patient-reported outcomes. Magnetic seed localization was found to be costs-saving across all analysed subgroups. Our results show that MSL is an effective alternative for lesion localization in BCS.

Background:The 2018 American Society of Clinical Oncology/College of American Pathologists guidelines classified immunohistochemistry (IHC) 1+ or 2+, FISH-negative breast cancer as HER2-low. To date, only a few studies have investigated the role of HER2-low status in patients with hormone receptor positive/HER2- (HR+/HER2-) metastatic breast cancer (MBC) during CDK4/6 inhibitor (CDK4/6i) therapy. Methods:This is a multicentre, retrospective cohort study analysing data from patients with HR+/HER2-low and HR+/HER2-0 MBC treated with CDK4/6i as first-line or second-line therapy at the Oncology Units of IRCCS San Matteo Hospital and ICS Maugeri IRCCS in Pavia, Italy, from January 2017 to October 2023. The aim was to assess the activity and effectiveness of CDK4/6i in a real-life setting. Results:Of the 241 patients included, 240 (99.6%) were women. The median age at diagnosis was 57 years (IQR 48-65 years). Most patients had pM M0 (70.5%). At presentation, 112 (46.5%) had HER2-low and 129 (53.5%) had HER2-0 status. CDK4/6i were administered as first-line therapy in 89.2% of patients and as second-line therapy in 10.8% of patients, with palbociclib (61.4%) being the most common. The median progression-free survival during CDK4/6i therapy was 36.3 months (95% CI 23.6 months to not reached), while the median overall survival was 60.5 months (95% CI 54.4 months to not reached). Progression-free survival differed significantly between palbociclib and abemaciclib/ribociclib (24.4 versus 53.7 months; p=0.0109) and between first-line and second-line therapy (40.5 versus 21.2 months; p=0.0466). Conclusion:CDK4/6i are effective in both HER2-low and HER2-0 MBC, with HER2-low potentially benefiting more from first-line therapy.

Background/Objectives: Lung cancer (LC) remains one of the most lethal malignancies worldwide, with both environmental and occupational exposures contributing to its incidence. While oncogene-addicted tumors-defined by single driver mutations-have garnered attention due to their therapeutic implications, less is known about the mutational landscape of tumors potentially arising from occupational exposure to carcinogens. This real-life observational study aimed to assess whether previous occupational exposure to lung carcinogens correlates with distinct LC phenotypes, particularly non-oncogene-addicted (nOA) profiles. Methods: A total of 199 LC patients were enrolled across two specialized oncology centers in Northern Italy between 2021 and 2023. Each participant underwent detailed occupational history taking and molecular characterization using next-generation sequencing. Patients were stratified into nonexposed (NE), low exposed (LE), and high exposed (HE) to carcinogens for lung based on standardized questionnaires and sector-specific assessments. Results: No significant differences were found in histological subtypes across exposure groups. However, people with adenocarcinoma and high occupational exposure to lung carcinogens were more frequently characterized by a nOA phenotype compared to those with low occupational exposure. Logistic regression models-adjusted for age, sex, and smoking habits-confirmed that HE patients had a significantly higher likelihood of developing nOA tumors (OR = 3.07; 95% CI: 1.16-8.11; p = 0.023). This association persisted after adjusting for smoking habits Exposures occurring 5-10 years before diagnosis seemed to be associated with an increased nOA profile. Conclusions: These findings suggest that high levels of exposure to occupational carcinogens impact LC phenotypes. Indeed, these phenotypes are more complex to treat and show the worst prognosis. Assessing the occupational exposure to lung carcinogens during work may offer prognostic insights and support the request for more adequate compensation for the patients. Further studies are warranted to validate these results and to explain the mechanisms that produce the differences observed in LC phenotypes in people with high exposure to occupational carcinogens.

BACKGROUND:Remarkable advancements in the therapeutic armamentarium for medullary thyroid cancer (MTC) have been observed in the last 10 years. The current understanding of driver mutations, such as RET and RAS, has enabled the development of new therapies for advanced and metastatic disease, demonstrating improved efficacy. PATIENT FINDINGS:A patient with RET-positive hereditary MTC developed multiple skin cancers (basal cell and squamous cell carcinomas) along with progression of MTC after 12 years of treatment with vandetanib. Once surgery to manage skin cancers has been excluded, the patient received a combination of selpercatinib and cemiplimab, and has been on this treatment at the full dose for 15 months, with ongoing therapy. SUMMARY:The combination of selpercatinib and cemiplimab was possible, with no new safety signals observed.

Background:Invasive disease-free survival in adjuvant treatment of HR+/HER2- early-stage breast cancer is improved by the use of CDK4/6 inhibitors. However, to date, minimal data are available on their safety and effectiveness in older patients (≥70 years old). Methods:A retrospective, multi-centre cohort study was conducted in two oncology centres in Pavia, Italy. Patients had to have received at least 3 months of therapy with adjuvant abemaciclib (a CDK4/6 inhibitor). Data on demographics, toxicity, dose reductions and clinical outcomes were analysed. Analyses were descriptive, with continuous variables reported as median (IQR) and categorical variables as counts and percentages. Results:Fifty-four patient records were reviewed (median age 55; six patients ≥70 years (older-age subgroup). Adverse events of any grade were reported in 53/54 patients (98.1%), most commonly haematological and gastrointestinal. Dose reductions occurred more frequently and earlier in the older-age subgroup (66.7% versus 45.8%; median 4.2 versus 8.3 months). Toxicities were generally of low-moderate grade and manageable. Conclusion:During adjuvant abemaciclib, low-moderate-grade toxicities were common, particularly haematological and gastrointestinal events. Older patients showed a numerically higher rate of dose reductions, suggesting a potential need for personalized dosing and early monitoring in this subgroup. These findings should be considered hypothesis-generating and warrant confirmation in larger prospective studies.

Recent advancements in health care digitalization opened the collection and availability of big data, whose analysis requires artificial intelligence-based technologies to facilitate the development of predictive tools supporting decision making in clinical practice. In this context, the idea of constructing ‘digital worlds’ to evaluate the performance of such novel tools becomes more attractive. Digital twins (DTs) are ‘digital objects’ characterized by a bi-directional interaction with their ‘real-world counterparts’. DTs aim to enhance predictions further by leveraging both the predictive capabilities of digital simulations and the continuous updating of real-life data—ideally incorporating clinical records, multiomics data, and patient-reported outcomes. DTs can potentially integrate these diverse data into virtual models applicable across pre-clinical to clinical studies. Running simulations in silico on cancer cells or cancer patients’ DTs can provide valuable insights into cancer biology, clinical practice, and health care education, with the added value of reducing costs and overcoming many common limitations of current studies (limited number of variables, challenges in recruiting patients with rare tumors, lack of real-life feedback). Despite their significant potential, DTs are still in their infancy, facing numerous unsolved technical and ethical challenges that hinder their application in clinical practice.

BACKGROUND & AIMS:The prevalence and clinical significance of vitamin B12 alterations in patients with cancer are poorly understood. We aimed to assess the prevalence and risk factors of vitamin B12 depletion or hypervitaminosis in patients with cancer. METHODS:We retrospectively included hospitalised patients with cancer in 2017-2022. Plasma B12 levels were stratified as very low (VL, <200 pg/ml), low (L, 200-299 pg/ml), normal (N, 300-812 pg/ml), or high (H, ≥813 pg/ml). We collected demographic and several clinical data (e.g., comorbidities, nutritional status, ECOG-PS, cancer site and stage). Univariate and multivariate analyses for factors associated to the vitamin B12 status were fitted. RESULTS:788 patients (F/M ratio 1.05, median age 72 years, [25th, 75th percentiles 62, 78 years]) were included. Vitamin B12 was VL in 14.1%, L in 19.4%, N in 49.4%, and H in 17.1% cases. Vitamin B12 distribution increased significantly as function of ECOG-PS levels. Patients with breast cancer were characterized by the highest median B12 value, while colorectal cancer patients by the lowest. Vitamin B12 was also significantly higher in advanced compared to early-stage patients as well as in those who had liver failure. Multivariate analysis showed that the probability of H vs. VL B12 levels was significantly increased in patients with hypoproteinemia, hypo-prealbuminemia, and ECOG-PS≥2, and decreased in those with colorectal and gastric cancer. CONCLUSION:Vitamin B12 impairment is common in cancer patients. Increased vitamin B12 is associated with an impaired clinical status, while vitamin B12 depletion is more common in early-stage cancer and in elderly patients.

Clear cell renal carcinoma (ccRCC) can occur in young people and could be associated with an aggressive behavior. While for the first-line treatment in metastatic disease, there is an agreement to rely on an immunotherapy (IO)-based combination regimen, no standard second-line regimens exist. Generally, tyrosine kinase inhibitors (TKIs) are employed, even in sequence, although no trials have demonstrated yet the best succession. Herein, we present the case of a 39-year-old male, with a very aggressive ccRCC with somatic VHL mutation and distant metastases at diagnosis. He was treated with four different lines of therapies, including TKIs, with progressive multiple tumor deposits. Lenvatinib alone as the fifth line was able to induce a remarkable and prolonged tumor shrinkage with manageable toxicities.

BACKGROUND:Data regarding the clinical outcome of patients with immune checkpoint inhibitor (ICI)-induced colitis are scant. We aimed to describe the 12-month clinical outcome of patients with ICI-induced colitis. MATERIALS AND METHODS:This was a retrospective, European, multicentre study. Endoscopy/histology-proven ICI-induced colitis patients were enrolled. The 12-month clinical remission rate, defined as a Common Terminology Criteria for Adverse Events diarrhoea grade of 0-1, and the correlates of 12-month remission were assessed. RESULTS:Ninety-six patients [male:female ratio 1.5:1; median age 65 years, interquartile range (IQR) 55.5-71.5 years] were included. Lung cancer (41, 42.7%) and melanoma (30, 31.2%) were the most common cancers. ICI-related gastrointestinal symptoms occurred at a median time of 4 months (IQR 2-7 months). An inflammatory bowel disease (IBD)-like pattern was present in 74 patients (77.1%) [35 (47.3%) ulcerative colitis (UC)-like, 11 (14.9%) Crohn's disease (CD)-like, 28 (37.8%) IBD-like unclassified], while microscopic colitis was present in 19 patients (19.8%). As a first line, systemic steroids were the most prescribed drugs (65, 67.7%). The 12-month clinical remission rate was 47.7 per 100 person-years [95% confidence interval (CI) 33.5-67.8). ICI was discontinued due to colitis in 66 patients (79.5%). A CD-like pattern was associated with remission failure (hazard ratio 3.84, 95% CI 1.16-12.69). Having histopathological signs of microscopic colitis (P = 0.049) and microscopic versus UC-/CD-like colitis (P = 0.014) were associated with a better outcome. Discontinuing the ICI was not related to the 12-month remission (P = 0.483). Four patients (3.1%) died from ICI-induced colitis. CONCLUSIONS:Patients with IBD-like colitis may need an early and more aggressive treatment. Future studies should focus on how to improve long-term clinical outcomes.

Background: Breast cancer is the most frequent tumour worldwide, and the HR+/HER2- + /HER2 - subtype is the most common. For this tumour type, endocrine therapy (ET) is the mainstay of treatment. The association of ET and CDK4/6 inhibitors (CDK4/6i) represents the gold standard for first-line or second-line therapies. However, the optimal therapeutic strategy after CDK4/6i progression is still a matter of debate, with several randomized clinical trials still ongoing. Patients and methods: This is an observational, prospective, real-world study including women with HR+/ + / HER2- - metastatic breast cancer progressing to palbociclib plus ET. Patients received either ET or chemotherapy (CT). The primary objective was the evaluation of efficacy of the different therapeutic strategies after palbociclib in terms of median progression-free survival 2. Secondary objectives were the activity of therapeutic strategies measured with the clinical benefit rate, evaluation of the parameters used for the treatment choice, and progression-free survival 1 related to palbociclib plus ET treatment. Results: Overall, 48 patients (median age 53, range 33-78 years) were included. The median progression-free survival 2 was of 5 months in the overall cohort (95% CI 4-48 months) with a statistically significant difference between the two therapeutic strategies adopted (ET versus CT, 10 months versus 5 months, respectively). Regarding secondary objectives, the clinical benefit rate was 55.2% in the CT cohort and 50% in ET. Moreover, women treated with CT had a greater number of visceral metastases and a shorter median progression-free survival 1 than patients who received ET. Conclusions: ET and CT represent two possible therapeutic alternatives for patients progressing on CDK4/6i plus ET. The choice is based on clinical parameters, with a potential preference for ET.

Background:Advanced breast cancer (ABC) is characterized by multidimensional clinical complexity that is usually not considered in randomized clinical trials. In the present real-life study, we investigated the link between clinical complexity and quality of life of patients with HR+/HER2- ABC treated with CDK4/6 inhibitors. Methods:We evaluated multimorbidity burden assessed with the Cumulative Illness Rating Scale (CIRS), polypharmacy and patient-reported outcomes (PROs). PROs were assessed at baseline (T0), after 3 months of therapy (T1), and at disease progression (T2) using EORTC QLC-C30 and QLQ-BR23 questionnaires. Baseline PROs and changes between T0 and T1 were evaluated amongst patients with different multimorbidity burden (CIRS <5 and ≥5) and polypharmacy (<2 or ≥2 drugs). Results:From January 2018 to January 2022, we enrolled 54 patients (median age 66 years, IQR 59-74). The median CIRS score was 5 (IQR 2-7), whilst the median number of drugs taken by patients was 2 (IQR 0-4). No changes in QLQ-C30 final scoring between T0 and T1 were observed in the overall cohort (p=0.8944). At T2, QLQ-C30 global score deteriorated with respect to baseline (p=0.0089). At baseline, patients with CIRS ≥5 had worse constipation than patients without comorbidities (p<0.05) and a lower trend in the median QLQ-C30 global score. Patients on ≥2 drugs had lower QLQ-C30 final scores and worse insomnia and constipation (p<0.05). No change in QLQ-C30 final score from T0 to T1 was observed (p>0.05). Conclusion:Multimorbidity and polypharmacy increase the clinical complexity of patients with ABC and may affect baseline PROs. The safety profile of CDK4/6 inhibitors seems to be maintained in this population. Further studies are needed to assess clinical complexity in patients with ABC.This article is part of the Tackling clinical complexity in breast cancer Special Issue: https://www.drugsincontext.com/special_issues/tackling-clinical-complexity-in-breast-cancer/.

The association of ET and CDK 4/6 inhibitors (CDK 4/6i) is the gold standard of treatment in women with HR+/HER2- MBC. The optimal therapeutic strategy after CDK 4/6i progression is still a matter of debate. The present study aimed to evaluate the benefit of the different treatments adopted in a real-world context. In this prospective study we included women with HR+/HER2- MBC progressing to ET plus palbociclib (P). Either ET or chemotherapy (CT) were prescribed taking into account:1) site and burden of disease (visceral/plurimetastatic vs bone only/oligometastatic); 2) median PFS1 (<4 months vs ≥4 months); 3) tolerability profile; 4) patient’s preferences. Primary objective was median progression-free survival 2 (PFS2). Secondary aims: analysis of the determinants of physician’s choice, clinical benefit rate (CBR), impact of neutrophil-to lymphocyte ratio (NLR), monocyte-to lymphocyte ratio (MLR), platelet-to lymphocyte ratio (PLR) and body mass index (BMI) on PFS2. From May 2017 to October 2021, 78 pre- and postmenopausal patients were enrolled and 56 were evaluable for the final analysis: 18 had received ET plus P as 1st line, 38 in ≥2nd line; 22 patients were excluded because they were still on therapy at the time of the last follow-up. At progression 15 patients (26.7%) received ET (everolimus+exemestane 8, fulvestrant 7) and 41 (73.2%) were treated with CT (eribulin, capecitabine, nab-paclitaxel, vinorelbine). In the whole population mPFS1 was 17.5 months; mPFS2 was 5 months in the overall cohort (95% CI = 4-48 months) with a significant difference between ET and CT (10 months vs 5 months, p=0.035); CBR was 50% and 55.2%, in ET and CT, respectively. At multivariate analysis CT prescription was associated to a higher visceral burden and a shorter mPFS1. Elevated NLR and PLR were correlated with worse PFS2 in both treatment groups, while no impact of MLR and BMI was observed. In this real life experience, treatments beyond ET plus P failure provided limited but comparable clinical benefit. The physician’s choice was clearly driven by visceral burden of disease; the inflammatory status seems to have a detrimental effect on PFS2.