Fondazione IRCCS Istituto Nazionale dei Tumori di Milano

Introduction The Clinical Ethics Committee (CEC) of the Local Health Authority (LHA) of Reggio Emilia, Italy, is a multi-professional service established in 2020 to support healthcare professionals (HPs) in dealing with ethical issues in clinical practice. We evaluated the integration of the CEC into routine practice, 24 months after its implementation. Methods We conducted semi-structured interviews with CEC members and LHA stakeholders involved in the service implementation. The interview scripts were outlined and transcript analysis was carried out following the four concepts of Normalization Process Theory (NPT): coherence, cognitive participation, collective action, reflexive monitoring. Results Between June 2022 and January 2023, 15 participants were interviewed (12 CEC members and 3 LHA directors). All participants consider the service an important opportunity for HPs to be supported in complex situations (coherence). The CEC’s President, a bioethicist working at the LHA, played a key role ensuring the CEC’s participation and activation (cognitive participation). The main barriers to the CEC implementation were: financial sustainability, CEC members’ lack of training, absence of in-person relationships (collective action). Overall, participants reported a positive experience with the CEC, however recommended several modifications (reflexive monitoring). Conclusions We identified key components to support the normalization of CECs and enable their activation within a clinical setting. An active and sustainable CEC must be visible, accessible, understood and trusted, clear in purpose, sufficiently integrated into the life of the organisation, adequately resourced, appropriately constituted and competent, accountable and independent. These findings can inform the development of practical strategies for CECs implementation and of appropriate outcomes for further evaluation.

Background BRCA mutation carriers opting for prophylactic risk-reducing salpingo-oophorectomy (RRSO) face potential impacts on sexual functioning and body image. Aim The aim of the study was to assess the extent of sexual dysfunction (SD) and body image impairment in BRCA patients, both with and without cancer, and before and after undergoing RRSO. Methods The present cross-sectional study involved a group of BRCA-positive patients (n = 220) from the Gynecological Hereditary Cancer Risk Clinic, categorized into two different subgroups: A—premenopausal and B—postmenopausal women, with (1) or without and (2) a breast cancer (BC) diagnosis. Before RRSO and at a 6-month follow-up assessment, all participants were requested to complete a validated survey on body image (the Body Image Scale), sexual functioning (Female Sexual Function Index), and psychological well-being (the Hospital Anxiety and Depression Scale and the Pittsburgh Sleep Quality Index fatigue subscale of the Functional Assessment of Chronic Illness Therapy-Fatigue). Outcomes The outcomes include scores on measures of body image, sexual functioning, and psychological well-being across the four study groups (A1—premenopausal women with BC, A2—premenopausal women without BC, B1—postmenopausal women with BC, and B2—postmenopausal women without BC). Results After RRSO, a significant decrease in sexual function and body image was observed across all groups (P < 0.01 in A1 and B1 groups and P < 0.02 in A2 and B2 groups). The most relevant changes were observed in the premenopausal and cancer-affected BRCA carriers (A2) (P < 0.001). The multivariate logistic regression analysis identified obesity, prior cancer, depression, and fatigue as risk factors for SD, while younger age and hormone replacement therapy emerged as protective factors. Clinical implications Surgical menopause, body image concerns, anxiety, and depression contribute to the observed SD following RRSO and should be addressed by healthcare providers. Strengths and limitations This study’s strength lies in its comprehensive evaluation of the impact of RRSO on BRCA mutation carriers, both before and after the procedure. The assessment includes measures of anxiety and fatigue. The limitations of the study include possible selection bias among participants, the lack of measures for sexual distress and a control group without BRCA mutation, and the limited number of patients without SD. Conclusion Patients undergoing RRSO frequently experience substantial psychosexual dysfunction; therefore, preoperative counseling is necessary to mitigate the incidence of SD and body image concerns in this population.

Background Zoledronic acid (ZA) in combination with androgen deprivation therapy (ADT) has never proved additional activity in patients with advanced prostate cancer. However, conventional imaging is poorly reliable in monitoring disease response of metastatic bone lesions. Methods BonEnza is a randomized phase II multicenter clinical trial designed to compare activity of ADT plus Enzalutamide (E) plus/minus ZA in term of bone response rate by Whole-Body Diffusion-Weighted Magnetic Resonance Imaging (WB-DW-MRI). From February 2018 to June 2021, 126 patients with metastatic hormone-sensitive prostate cancer (mHSPC) and bone metastasis at bone scan were enrolled. Patients were randomized in a 1:1 to receive E 160 mg OD orally alone (E arm) or in combination with ZA 4 mg intravenously every 4 weeks (EZ arm). Primary endpoint of the study was overall response rate (ORR) in bone metastases, secondary endpoints were ORR with conventional imaging, progression free survival (PFS) and overall survival (OS). A logistic model was used to evaluate the association between treatment arm and ORR. Results After a median follow-up of 31.9 months, according to an intent to treat analysis, the ORR was superimposable in both arms: 69.8% (95% Confidence Interval [CI]: 57.5–79.9%), Odds Ratio: 1.00 (95%CI 0.47–2.15; p > 0.9). No advantage in favor of EZ arm over E arm emerged either in terms of PFS (Hazard Ratio [HR] 0.77, 95%CI 0.44–1.37; p = 0.4) or OS (HR 1.09; 95%CI 0.54–2.2; p = 0.8). A main limitation of this study was the inability of WB-DW-MRI to evaluate disease response in 17 patients. Conclusions ZA did not improve bone response rate to E plus ADT in mHSPC patients. WB-DW-MRI is a reliable technique to evaluate the response of prostate cancer bone metastases to systemic therapy.

The anti-EGFR agents, cetuximab and panitumumab, were the first targeted agents to be licensed in colorectal cancer and marked a significant advancement in personalized care. Initial biomarkers provided poor discrimination between responders and non-responders. Through hypothesis-led translational studies, tumor genomic negative predictive markers were identified, and treatment is now limited to patients with RAS and BRAF wild-type disease. Guidelines further recommend treatment limitation to those with left-primary tumor location (PTL). Despite such progress, anti-EGFR response remains variable within the biomarker-selected population, indicating the presence of additional mechanisms of resistance and underscoring the need for novel positive predictive biomarkers, and novel targeted agents. This review explores established and emerging predictive biomarkers of anti-EGFR efficacy, including tumor genetic alterations beyond RAS and BRAF, as well as the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG). To date, biomarker discovery and validation have largely been performed within post hoc analyses of existing clinical trial datasets. We highlight ongoing prospective clinical trials aiming to validate earlier findings and describe how novel biomarkers are being used to re-evaluate anti-EGFR agents in treatment settings where earlier trials, among non-biomarker selected populations, yielded negative results – including right-PTL, locally advanced disease, and anti-EGFR rechallenge strategies. Additionally, we discuss how our improved understanding of the molecular mechanisms underpinning anti-EGFR response and resistance is being leveraged to develop novel targeted agents.

Adequate information about patients with bone metastases could increase adherence to treatment and reduce or delay skeletal and dental complications. Limited data are available on patient awareness, the degree of information received, and adherence to specific treatment for bone metastases. ROPI (Rete Oncologica Pazienti Italia) conducted an anonymous survey from 1 February to 31 August 2022 among patients with bone metastases from solid tumors to evaluate their level of information and adherence to specific treatments and dental evaluations. Questionnaires were administered by oncologists or nurses at participating cancer centers. Analysis of 351 questionnaires revealed that 75% of patients felt “fairly/well” informed about bone metastases and skeletal complications. The oncologists were the primary source of information. More than 80% of patients reported undergoing specific treatment for bone metastases (denosumab, 48%; zoledronic acid, 46%); 93% of patients received dental evaluations before starting therapy (with dental complications in only 0.3% of patients) and 78% received information about the importance of regular dental checkups. Vitamin D and calcium supplements were taken by 83% of patients. Among patients with skeletal complications (47% of patients), bone radiotherapy was the most frequent (94%). Most patients stated that they had received information about bone metastases, skeletal complications, and specific treatments. This could increase awareness and adherence to treatment and potentially reduce or delay skeletal and/or dental complications improving patients’ quality of life and survival.

Introduction There is a general need for sharing practical examples of Patient and Public Involvement (PPI) within the research field to learn from and inspire. The aim of this article is to describe our process evaluation of PPI within the development process of the EUonQoL‐Kit, a new set of quality of life questionnaires aimed at people with (past experience of) cancer. Methods Five co‐researchers (people with cancer and informal caregivers) were recruited and received training and support from a dedicated team of researchers. Involvement in the development process of the EUonQoL‐Kit consisted of four major events: two workshops, a consensus meeting and a stakeholder forum. We have collected event documents, that is, meeting agendas, presentation slides, minutes of the events and minutes of meetings with co‐researchers before and after the events, and qualitatively analysed these using the Cube Framework. Results Our process evaluation showed that, over time, discussions evolved from focusing on the technical aspects of the EUonQoL‐Kit to co‐researchers' experiences as input for the questionnaires. Researchers' inexperience with PPI prompted the organisation of a training workshop. After this, researchers prepared the co‐researchers better for the meetings and engaged them more actively by asking specific questions. All these developments contributed to a more active participation of co‐researchers. Conclusion PPI in the development process of the EUonQoL‐Kit was a learning process. Factors that helped include allocating time and resources, actively creating space for co‐researchers' input, providing support by researchers specifically responsible for the PPI activities and realising the importance of informal contact. Future PPI efforts should incorporate these principles from the start to facilitate successful collaboration between researchers and co‐researchers. Patient or Public Contribution People with cancer and informal caregivers played a significant role in this study. They were involved as co‐researchers in all stages of the development process of the EUonQoL‐Kit. In addition, they were involved in the qualitative analysis of the data presented in this article, the writing of the project report and the writing of this article as co‐authors.

Purpose: Treatment options for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) after failure of immune checkpoint inhibitor (ICI) treatment and platinum-based chemotherapy are limited. Preliminary data suggested monalizumab plus cetuximab had clinical activity in R/M HNSCC. Participants and methods: INTERLINK-1 (NCT04590963) was a double-blind, phase III study. Participants with R/M HNSCC who had received ICI therapy and progressed despite platinum-based chemotherapy were randomized 2:1 to monalizumab (750 mg, fortnightly) or placebo, plus cetuximab (400 mg/m2 loading dose, then 250 mg/m2, weekly). The primary endpoint was overall survival (OS) in participants with non-oropharyngeal cancer (OPC) or human papillomavirus (HPV)-negative OPC (HPV-unrelated analysis set). Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). Results: At data cut-off, 216 participants were randomized in the HPV-unrelated analysis set; 145 to monalizumab plus cetuximab and 71 to placebo plus cetuximab. Median OS was 8.8 months for monalizumab plus cetuximab versus 8.6 months for placebo plus cetuximab (hazard ratio [HR], 1.00; 95% CI, 0.66–1.54); median PFS was 3.6 versus 3.8 months, respectively (HR, 1.11; 95% CI, 0.79–1.57); and ORR was 15.2% versus 23.9%, respectively. INTERLINK-1 was terminated after a preplanned interim analysis showed futility criteria were met (predetermined futility HR >0.874). Grade 3–4 treatment-related adverse events were reported in 18.3% and 17.2% of participants treated in the monalizumab and placebo arms, respectively. Conclusions: Monalizumab plus cetuximab did not improve OS compared with placebo plus cetuximab. The safety profile of the combination was consistent with safety observations for cetuximab monotherapy.

Purpose: Peritoneal metastases (PM) in colorectal cancer (CRC) portend a poor prognosis. We sought to elucidate molecular features differentiating primary tumors (PTs) from PMs and actionable targets facilitating transcoelomic dissemination and progression. Experimental Design: We performed multi-omic profiling of 227 samples from 136 patients, including 56 primary tumor (PT) and 120 synchronous PMs comprising 34 matched PT-PM pairs. Whole exome, and bulk RNA-seq analysis was conducted to identify underlying genomic aberrations and transcriptomic differences between primary and peritoneal lesions. We spatially characterized the microenvironment of tumor-stroma compartments and studied the roles of stromal phenotypes in promulgating tumorigenesis. Results: Whole exome sequencing found genomic alterations and clonality patterns between PTs and PMs remain broadly similar. Transcriptomic profiles however, suggest a transition as tumors reach the peritoneum towards a more mesenchymal tumor profile and fibrotic tumor microenvironment. Applying spatial profiling, we identify a fibro-collagenous and immune-infiltrated stromal phenotype (stromal cluster [SC] 2) characterized by increased cancer-associated fibroblasts, memory B cells, M2 macrophages and T-cell exhaustion. These findings were orthogonally validated by multiplex immunohistochemistry. Patients with SC2 stroma had poorer survival and were characterized by high SERPINE-1 (PAI-1) expression. PM in patients with SC2 stroma were associated with enriched oncogenic pathways such as TGF-β. PAI-1 inhibition of CRC PM cell-lines with a novel biologic demonstrated reduced IL2-STAT5 and TGF-β pathways and cell death. Conclusions: Our findings unveil distinctive and actionable molecular signatures, offering deeper insights into the intricate crosstalk between tumor cells and stromal microenvironments enabling PM in CRC.

Surgery for soft tissue sarcoma is complex and requires specific expertise. It involves the en bloc removal of the tumor along with surrounding healthy tissue to ensure microscopic negative margins, in order to maximize the chance of cure. However, the extent of surgery should be tailored to the type and subtype of the soft tissue sarcoma. Soft tissue sarcomas encompass over 70 histologic entities, each characterized by distinct behaviors, recurrence patterns, and responses to treatment. Various treatment modalities are available, including radiotherapy, chemotherapy with different agents, and isolated limb perfusion. The strategy should be personalized, considering the tumor type, size, location, sensitivity to treatments, and the patient’s preferences. When patients are referred after an initial unplanned resection and no macroscopic tumor remains, immediate re-excision versus delayed wider resection upon recurrence should be discussed. Regionalizing soft tissue sarcoma care significantly improves the overall outcome.

Objectives Potential coeliac disease (PCD) is defined by the presence of positive CD-specific autoantibodies with a normal/extremely mildly damaged intestinal mucosa. This study sought to examine the progression of PCD in children maintaining a gluten-containing diet and to identify risk factors associated with the onset of CD. A comparative literature review was conducted to assess the results in the context of existing evidence. Methods A retrospective cohort study was performed on 67 children diagnosed with PCD between January 2005 and January 2022, with a maximum follow up of 53 months. The associations between baseline clinical characteristics and the development of CD were assessed using hazard ratios (HR). Results Nineteen percent (19 %) (12/67, cumulative incidence) of PCD children, with a median age of 4.3 years, progressed to CD during a median follow up period of 30 months. A fluctuating trend in tissue transglutaminase IgA (tTG-IgA) levels was observed in 35.8 % (24/67) of the children, while 46.2 % (31/67) showed tTG-IgA negativization. In univariable analysis, the presence of autoimmune disease and one-year increase in age at diagnosis were significantly associated with CD progression [HR=17.7 (95%CI: 3.0–106.8; p=0.0017) and HR=1.3 (95%CI: 1.1–1.5; p=0.0125), respectively]. Conclusions Our study confirms that only a small proportion of PCD children progress to CD. It also highlights that advancing age and the presence of autoimmune disease are the main risk factors for the development of villous atrophy. A better understanding of tTG-IgA trend during follow up could help in the management of PCD children.

Lung cancer patients often have difficulties in their relationships with doctors due to limited time and poor communication about their illness and treatment. Similarly, clinicians find it challenging to convey complex medical information and manage patients’ and caregivers’ emotional responses. These difficulties can cause anxiety and distress for both parties, potentially affecting treatment adherence. Tailored decision aid tools may enhance communication and support shared decision-making. This qualitative study involved semi-structured interviews with ten oncologists, conducted between February and April 2023, to explore their views on communication during consultations. Thematic analysis revealed that physicians often lack adequate time to explain disease details and treatment options and struggle with delivering negative prognoses. They also report difficulties in handling patients’ emotional reactions and express a need for communication support. Participants emphasized the importance of tools that facilitate informed and personalized decision-making, highlighting their potential to improve patient care. The study offers insights for future research and practical recommendations for enhancing oncologist-patient communication.