Istituto Clinico Humanitas IRCCS
Recent publications
Purpose This retrospective study aimed to confirm the safety and long-term efficacy of a single-session combined treatment approach with transcatheter arterial embolization (TAE) and microwave ablation (MWA) for inoperable small—to intermediate-sized hepatocellular carcinomas (HCC), focusing on their combined benefits for improving local control. Materials and methods All consecutive patients with up to 2 small-to-intermediate HCC lesions (≤ 5 cm) treated with a combined single-session MWA-TAE approach were enrolled between April 2020 and October 2023. All procedures were performed in two stages: TAE and MWA. Clinical and radiological follow-up was performed 3, 6, and 12 months after treatment. Results In the 21 enrolled patients (15 males, mean age 75.9 years), post-procedural contrast-enhanced CT scans confirmed a satisfactory ablation zone in all patients (100%), with minor peri-procedural complications reported in three patients (14%). At the last 12-month follow-up, one patient (8%) displayed local tumor progression, previously classified as LR-TR equivocal at the 6-month follow-up, and half of the patients (6 patients, 50%) exhibited distant tumor progression, predominantly in the form of intra-hepatic recurrence. Conclusion The combined approach of TAE and MWA is a promising method to enhance the percutaneous treatment of small to intermediate-sized HCCs with a resulting anatomic ablation area resembling a surgical sub-segmentectomy. This technique can potentially reduce the gap between percutaneous treatment and liver resection outcomes, allowing for a safe and effective option for oncological control in patients with > 3 cm lesions. Graphical abstract
Impedance and voltage of monopolar currents are directly related. By replacing air with saline solution, a change in behavior of these currents are achieved in endoscopy, resulting in a desired coagulation effect. However, the underlying electrophysical mechanisms of this effect remain poorly explained. This investigation assessed the relationship between the electrical parameters and the surrounding environment for three high-voltage monopolar coagulation currents commonly used for therapeutic endoscopy. Six consecutive applications per setting and per environment were performed with dissection knife on porcine kidney. When transitioning from air to saline immersion, a 99% decrease in impedance was observed for all current settings tested (AirRange: 4400–8150 Ω, SalineRange: 64–71 Ω; p < 0.01 for all settings). This resulted in a 52-78% reduction in peak voltage (AirRange: 920–1165 V, SalineRange: 257–499 V; p < 0.01 for all settings), and a 237-2030% increase in power delivered (AirRange: 3–19 W, SalineRange: 50–117 W; p < 0.01 for all settings). The dramatic decrease in impedance results in a sharp reduction of voltage, explaining the coagulation effect observed when passing from air to saline-immersion therapeutic endoscopy. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-83503-3.
The European Society of Cardiology has held its annual Congress in London, UK, from 30 August to 2 September 2024. With a total of 31 800 participants, 5400 faculty and presenters, and many National Cardiac Societies and industry partners, the Congress has taken an enormous step forward to present and discuss the latest advances in cardiovascular medicine. The sizable intercontinental reach was proved by the fact that 5 of the 10 top countries, in terms of submission of abstracts, were from outside Europe: China, the USA, Japan, Korea, and Australia. This brought a great impetus for international collaboration and exchange of views, learning from different perspectives. Specifically, the field of cardiovascular imaging has been in the spotlight, remarking its growing, central, and transversal role in modern cardiovascular medicine. In this communication, we offer a summary of some notable advances in research, either in terms of novelty or clinical applicability, within the realm of four imaging modalities: echocardiography, cardiovascular magnetic resonance, computed tomography, and nuclear imaging.
Background and aims Cross-sectional imaging techniques, including intestinal ultrasonography (IUS), computed tomography enterography (CTE), magnetic resonance enterography (MRE), are increasingly used for evaluation of inflammatory bowel diseases (IBD). We aimed to systematically review literature evidence on the assessment of disease activity, and/or severity through cross-sectional imaging in IBD patients, and to offer guidance on their most effective utilization. Methods We performed a systematic review of PubMed, EMBASE, and Scopus to identify citations pertaining the assessment of disease activity, and/or severity at cross-sectional imaging techniques compared to a reference standard (i.e., other radiological techniques, endoscopy, histopathology, and surgery) in IBD patients published until December 2023. Results Overall, 179 papers published between 1990 and 2023 were included, with a total of 10988 IBD patients (9304 CD [84.7%], 1206 UC [11.0%], 38 IBD-U [0.3%], 440 unspecified [4.0%]). 39/179 studies investigated IUS, 22/179 CTE, 101/179 MRE, in the remaining papers two techniques were addressed together. In 81.6% of the papers, endoscopy (with or without histopathology) was used as a reference standard. All studies included evaluated disease activity, while just over half (100/179, 55.8%) also evaluated disease severity of the addressed cross-sectional methodology. Pooled sensitivity, specificity, and overall accuracy of IUS, MRE, and CTE compared to the reference standard were 60-99%, 60-100%, and 70-99%, respectively. Conclusion All cross-sectional imaging techniques demonstrated moderate-to-good accuracy in assessing disease activity, and severity of IBD. This finding highlights the potential, especially for MRE and IUS to be widely utilized in managing IBD in both clinical practice and clinical trials.
Purpose Obesity is increasingly at the center of modern international healthcare systems. This is a position statement of the Italian Society of Fertility and Sterility and Reproductive Medicine (SIFES-MR) aimed at evaluating the impact of female overweight on infertility in order to improve fertility outcomes, including Assisted Reproductive technology (ART) treatments. Methods The SIFES-MR writing group for this position statement was composed by Italian reproductive physicians, embryologists, and scientists with expertise in fertility evaluation, assisted reproduction technologies, and laboratory quality management. The positions stated are based on consensus by the authors, who met over a six-month period. The consensus emerged after thorough review of pertinent literature and standards concerning the impact of female overweight, complemented by extensive dialogue and discussion among the authors. Additionally, input from society members was considered, leading to revisions and eventual approval by the SIFES-MR governing council. Results An increasing number of women affected by overweight and infertility accessing to ART treatments are expected in the future. A comprehensive counseling since the first access to infertility care is mandatory and should promote weight restoration, with the aim to improve the likelihood of spontaneous unassisted conception. Careful preconceptional evaluation of obese women is strongly encouraged for counseling purpose and comorbidities should be corrected by a multidisciplinary approach before spontaneous or medically assisted conception. Indeed, female obesity is responsible for high-risk pregnancies, with potential consequences in infants and during childhood. When in vitro fertilization is indicated, the risk of venous thromboembolism exacerbated by controlled ovarian stimulation should be assessed. Conclusions Before IVF, different therapeutic approaches and expectant management to reduce overweight could be offered, and the age-related algorithm herein proposed by SIFES may represent an interesting tool for a better personalization of infertility care in these women. The treatment of infertility cannot ignore the correct management of female overweight, given the serious consequences that this condition can have on the outcomes of pregnancies and future generations. IVF specialists should tailor access and modalities of IVF treatment to this class of high-risk women.
Background Compassionate behavior plays a crucial role in medicine by fostering patient-doctor relationships, enhancing adherence, and improving care quality. While partly innate, compassion can be significantly enhanced through structured educational interventions. Despite recent efforts to integrate compassion into medical curricula, methodological challenges persist, especially in understanding how different environments influence skill expression and development. This study aims to assess the effectiveness of traditional clinical clerkships versus simulation-based training in cultivating compassion skills among medical students. Methods This retrospective longitudinal study evaluated the professional behavior and cognitive skills of 133 medical students at Humanitas University, Milan, Italy, over a three-year period from 2021 to 2024. The curriculum emphasizes problem-based learning and professional development through hospital clerkships and simulation-based training. Compassion was assessed quarterly using a standardized scorecard and continuously evaluated via a learning management system, simulation scenarios and objective structured clinical examinations (OSCEs). Results In the initial assessment, compassion scores showed no significant difference between the two settings (clerkship: 3.25 ± 0.73, simulation: 3.30 ± 0.69, p = 0.45). Over subsequent evaluations taking place in the following two years, the differences remained non-significant (p = 0.39, p = 0.22) until a notable divergence was observed in later assessments, particularly in the final evaluation at the end of 5th year study (clerkship: 3.54 ± 0.78, simulation: 3.23 ± 1.18, p = 0.023). Clerkship students demonstrated a significant increase in compassion scores over time (+ 0.29, p = 0.023), benefiting from immersive patient interactions that deepened their compassionate behavior. In contrast, simulation scores peaked slightly but not significantly in Year 4 before returning to initial levels (-0.07, 95% CI [-0.24, 0.11]), highlighting the challenge of sustaining compassionate behaviors without ongoing real-world practice. Conclusion This study emphasizes the crucial role of deliberate curriculum design in medical education. While simulation-based training offers controlled environments, it incompletely replicates the emotional depth of real patient interactions crucial for sustaining compassion. Integrating compassion-focused training into medical curricula is essential for nurturing compassionate healthcare professionals, urging immediate action to enhance compassion in medical education. Trial registration Not applicable. No health intervention has been proposed, and it’s a purely retrospective analysis on an educational methodology.
Background Pembrolizumab monotherapy is an established front-line treatment for advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) tumor proportion score (TPS)≥50%. However, real-world data on its long-term efficacy remains sparse. Methods This study assessed 5-year outcomes of first-line pembrolizumab monotherapy in a large, multicenter, real-world cohort of patients with advanced NSCLC and PD-L1 TPS≥50%, referred to as Pembro-real 5Y. Individual patient-level data (IPD) from the experimental arm of the KEYNOTE-024 trial were extracted (KN024 IPD cohort) to compare the long-term outcomes between the two cohorts. To further assess the reproducibility of clinical trial results, we reconstructed the “KN024 look-alike” cohort by excluding patients with an Eastern Cooperative Oncology Group-performance status (ECOG-PS)≥2, those requiring corticosteroids with doses ≥10 mg of prednisolone/equivalent, patients with positive/unknown epidermal growth factor receptor/anaplastic lymphoma kinase genotype, and those with pre-existing autoimmune disease. We additionally provided a hierarchical organization of determinants of long-term benefit through a conditional inference tree analysis. Results The study included 1050 patients from 61 institutions across 14 countries, with a median follow-up of 70.3 months. The 5-year survival rate was 26.9% (95% CI: 23.8% to 30.2%), and median OS was 21.8 months (95% CI: 19.1 to 25.7), while 32 (3.0%) patients who achieved a complete response remained progression-free at the data cut-off. The KN024 look-alike cohort had a 5-year survival rate of 29.3% (95% CI: 25.5% to 33.6%) and a median OS of 27.5 months (95% CI: 22.8 to 31.3). Neither the overall study population nor the KN024 look-alike cohort exhibited significantly different OS compared with the KN024 IPD cohort. By the data cut-off, 1015 patients (96.7%) had permanently discontinued treatment: 659 (64.9%) due to progressive disease, 156 (15.4%) due to toxicity, 77 (7.6%) due to treatment completion, and 106 (10.4%) due to other reasons. Overall, 222 participants (21.1%) were treated for a minimum period of 24 months, among them the 5-year survival rates were: 31.7%, 72.7%, 78.6%, 84.2% for patients who discontinued treatment due to progressive disease, toxicity, treatment completion, and other reasons, respectively. Conclusion This study provides valuable real-world evidence that confirms the long-term efficacy of pembrolizumab outside of clinical trials. Hierarchical organization indicates ECOG-PS, age and PD-L1-TPS as the most important predictors of 5-year survival, potentially informing clinical practice.
Background and aim Artificial intelligence (AI)-powered chatbots, such as Chat Generative Pretrained Transformer (ChatGPT), have shown promising results in healthcare settings. These tools can help patients obtain real-time responses to queries, ensuring immediate access to relevant information. The study aimed to explore the potential use of ChatGPT-generated medical Arabic responses for patients with metabolic dysfunction–associated steatotic liver disease (MASLD). Methods An English patient questionnaire on MASLD was translated to Arabic. The Arabic questions were then entered into ChatGPT 3.5 on November 12, 2023. The responses were evaluated for accuracy, completeness, and comprehensibility by 10 Saudi MASLD experts who were native Arabic speakers. Likert scales were used to evaluate: 1) Accuracy, 2) Completeness, and 3) Comprehensibility. The questions were grouped into 3 domains: (1) Specialist referral, (2) Lifestyle, and (3) Physical activity. Results Accuracy mean score was 4.9 ± 0.94 on a 6-point Likert scale corresponding to “Nearly all correct.” Kendall’s coefficient of concordance (KCC) ranged from 0.025 to 0.649, with a mean of 0.28, indicating moderate agreement between all 10 experts. Mean completeness score was 2.4 ± 0.53 on a 3-point Likert scale corresponding to “Comprehensive” (KCC: 0.03–0.553; mean: 0.22). Comprehensibility mean score was 2.74 ± 0.52 on a 3-point Likert scale, which indicates the responses were “Easy to understand” (KCC: 0.00–0.447; mean: 0.25). Conclusion MASLD experts found that ChatGPT responses were accurate, complete, and comprehensible. The results support the increasing trend of leveraging the power of AI chatbots to revolutionize the dissemination of information for patients with MASLD. However, many AI-powered chatbots require further enhancement of scientific content to avoid the risks of circulating medical misinformation.
Purpose Planar cardiac scintigraphy with [ ¹²³ I]I-mIBG is widely used to image myocardial sympathetic activity. In multicentre studies, different γ-cameras can cause variability in quantitative parameters. This study aimed to harmonise multicentre [ ¹²³ I]I-mIBG data using a custom-designed phantom and to assess its feasibility and acceptability. Methods A ‘tube and bottle’ phantom was designed to standardise the heart-to-mediastinum (H/M) ratio across 15 centres. Each centre prepared three versions of the phantom (A, B, and C) with varying pertechnetate ([ 99m Tc]Tc-O4-) activities, acquired static images using their own γ-camera, and uploaded DICOM data to a shared platform. In the phantom, the tube and bottle represent the heart and mediastinum, respectively, with the tube-to-bottle (T/B) ratio simulating the H/M ratio. The reference centre analysed the images and calculated the T/B ratios, applying linear regression for data harmonisation. A survey was conducted to assess the phantom’s usability. Results The harmonised T/B ratios for versions A and B were 20.46 ± 0.78 and 6.19 ± 0.39, respectively. The average slope and intercept of the regression line across the participating centres resulted in 1.07 ± 0.38 and − 0.82 ± 4.95. Survey feedback indicated high feasibility and acceptability, with all centres recommending the phantom for multicentre harmonisation. Conclusions The custom-made phantom effectively harmonised experimental data across different centres, supporting its use in multicentre studies to improve data consistency.
Fumarate hydratase (FH)-deficient renal cell carcinoma is an aggressive neoplasm driven by inactivating mutations of the FH gene, which cause metabolites like S-(2-succinyl)cysteine (2SC) to accumulate and trigger cascades supporting malignant transformation. Although in preclinical models the c-GAS-STING pathway is activated by fumarate metabolites, its role in humans has not been explored yet. Eleven FH-deficient renal cell carcinomas, including primary neoplasms and metastases, were retrieved and evaluated for clinical-pathological features and immunohistochemical expression of FH, 2SC (commercially available), and STING. The in-house collection accounted for 0.2% of the 2011–2023 renal cell carcinomas cohort (5/2210). Eight-on-ten cases with available follow-up behaved aggressively (local recurrence/distant metastases). All tumors revealed FH staining loss and strong and diffuse 2SC immunolabeling. At least focal STING expression was detected in most primary tumors (9/11, 82%), often (78%) in a wide percentage of cells (≥ 30%). Notably, significant STING expression was observed in all but two aggressive renal neoplasms, with one of the remaining showing increased staining in its hepatic localization, and in 86% (6/7) of neoplasms significantly expressing PD-L1. In our series, (i) FH-deficient renal cell carcinoma represents 0.2% of in-house cases; (ii) combining FH loss and positive 2SC staining now commercially available is useful in primary and secondary tumors, supporting this latter marker’s safe routine adoption; and (iii) a significant STING labeling (≥ 30%) in most of the samples, especially in those behaving aggressively and expressing PD-L1, provides novel insights regarding the molecular basis of FH-deficient renal cell carcinomas, proposing STING as a potential predictive marker.
Background and study aims. Hybrid argon plasma coagulation (H-APC) is a novel technique for the ablation of neoplastic Barrett Esophagus (BE), consisting in submucosal fluid injection and subsequent APC of visible BE. Aim of this study was to assess H-APC efficacy, safety and tolerability. Patients and methods. We prospectively included patients undergoing H-APC ablation at 4 Italian Hospitals from September 2022 to March 2024. Patients with BE C3M5 maximum extent, low- or high-grade dysplasia (LGD, HGD) or residual BE after endoscopic resection (ER) of visible lesions were included. Patients who had undergone previous ablative treatments were excluded. The primary endpoints were the complete eradication of intestinal metaplasia (CE-IM) and dysplasia (CE-D). The secondary endpoints were safety in terms of major and minor adverse events (AEs) and tolerability, assessed using pain (0-10) and dysphagia (0-5) scores within 7 days post-ablation. (NCT05645679) Results. Among the 51 enrolled patients (mean C 0.43 cm (SD 0.72), mean M 2.20 cm (SD 1.09)) who completed the treatment (80 H-APC sessions), 45.1% (23/51) had prior ER of visible lesions . All patients achieved both CE-IM and CE-D (51/51), requiring a mean of 1.51 (SD 0.83) sessions. Only one case of fever and absolute dysphagia was observed, 1/51 (1,96%) AEs. Regarding tolerability, mean pain score was 1.3 (SD 1.99) while mean dysphagia score was 1.28 (SD 0.56). Conclusions. The H-APC technique showed promising results in terms of effectiveness and safety with a good tolerability in achieving initial CE-IM and CE-D in a selected population of BE patients.
552 Background: HIMALAYA showed that D+T and D are effective options for unresectable hepatocellular carcinoma (uHCC). However, data on outcomes according to the adherence to HIMALAYA inclusion criteria in routine clinical practice are lacking. Methods: In the context of a prospectively maintained database including 1293 patients (pts) with uHCC treated with immunotherapy, we analysed pts treated with D+T or D across 8 centres in USA, Asia and Europe. Pts who met >1 key exclusion criterion of HIMALAYA (prior systemic therapy, Child-Pugh class B-C, Vp4 thrombosis) were defined HIMALAYA-OUT and compared with HIMALAYA-IN pts for overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) by RECIST 1.1 and treatment-related adverse events (TRAEs) per CTCAE v.5.0. Results: Up to February 2024, 108 pts (mean age 66 years, male sex 81%) started D+T (n=69, 64%) or D (n=39, 36%). 62 pts (57%) were treated in 1° line and 46 (43%) in >2° line. Child-Pugh class was A in 67 pts (62%). Vp4 was present in 17 pts (16%). 31 pts (29%) were HIMALAYA-IN and 19/31 (61%) received D+T. After a median follow-up of 4.3 months (m, 95%CI 3.3-4.9), median OS (mOS) was 11.5 m and 12-m OS rate was 42%. mOS was not reached in HIMALAYA-IN pts (12-m OS rate 62%) and 8.9 m (95%CI 6.0-12.1) in HIMALAYA-OUT pts. Survival hazard ratio (HR) for HIMALAYA IN vs OUT was 0.28 (95%CI 0.09-0.93, p=0.037). Median PFS was 2.6 m (95% CI 2.2-5.2) overall, 4.6 m (95%CI 2.1-8.5) in HIMALAYA-IN and 2.6 m (95%CI 1.9-5.2) in HIMALAYA-OUT pts (HR 0.70, 95%CI 0.38-1.30, p=0.266). ORR and DCR (evaluable in 53 pts, 49%) were 15.1% (95%CI 6.5-29.7%) and 43.4% (95%CI 27.5-65.1) (Table). Any grade TRAEs occurred in 31.5% (95% 21.8-44.0%), grade 3-4 TRAEs in 8.3% (95%CI 3.8-15.8%), TRAEs requiring systemic corticosteroids in 8.3% (95%CI 3.8-15.8%) and discontinuation due to toxicity in 3.7% (95%CI 1.0-9.5%). Conclusions: Preliminary observational data from DT-Real study suggest a reproducible efficacy and safety of D+T and D in pts with uHCC fitting the inclusion criteria of HIMALAYA in routine clinical practice. HIMALAYA IN (n=31) HIMALAYA IN HIMALAYA OUT (n=77) HIMALAYA OUT D+T (n=19) D (n=12) D+T (n=50) D (n=27) mOS (m, 95%CI) NR NR NR 8.9 (6.0-12.2) 11.2 (6.6-13.2) 4.9 (2.6-12.2) 12-m OS (%) 61.8 63 88.9 37.2 37.4 44.4 mPFS (m, 95%CI) 4.6 (2.1-8.4) 8.5 (2.1-8.5) 2.4 (1.6-2.5) 2.6 (1.9-5.2) 2.4 (1.8-6.7) 2.6 (1.8-5.2) ORR (%,95%CI) (N=53) 23.1 (4.8-67.4) 25.0 (5.1-73.1) 0 12.5 (4.1-29.2) 13.8 (3.8-35.3) 9.1 (0.2-50.6) DCR (%, 95%CI) 46.2 (16.9-100) 50.0 (18.3-100) 0 42.5 (24.8-68.1) 41.4 (21.4-72.2) 45.4 (14.8-100) Any grade TRAEs (%,95%CI) 32.3 (15.5-59.3) 31.6 (11.6-68.7) 33.3 (9.1-85.4) 31.2 (20.0-46.4) 28.0 (15.3-47.0) 37.1 (17.8-68.1) Grade 3-4 TRAEs (%, 95%CI) 9.7 (2.0-28.3) 15.8 (3.3-46.1) 0 7.8 (2.9-17.0) 4.0 (0.5-14.4) 14.8 (4.0-38.0)
135 Background: GEVO, a humanized monoclonal antibody, binds to interleukin-1β (IL-1β) and inhibits its activity. We report results from a phase Ib study of GEVO + SoC anticancer therapies in pts with mCRC/mGEC/mRCC. Methods: This open-label study enrolled pts aged ≥18 years in cohorts A (first line mCRC, [A]), B (second line [2L] mCRC, [B]), C (2L mGEC, [C]) and D (2L/third line mRCC, [D]). The primary objectives were to determine the pharmacodynamically-active dose (PAD) of GEVO monotherapy in A/B, the safety and tolerability, and the recommended dose for expansion (RDE) of GEVO + SoC in A/B/C/D, and the efficacy of GEVO + SoC at RDE in A/B/C measured by the progression-free survival (PFS) rate. The proof of concept (PoC) criteria for PFS rates were ≥42% at 15 months (m) (lower 80% CI limit ≥29%) in A, ≥48% at ~9 m (lower 80% CI limit ≥37%) in B, ≥51% at 6 m (lower 60% CI limit ≥38%) in C. The relationship between baseline levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and IL-1β, and on-treatment decrease of circulating tumor DNA (ctDNA) levels with clinical response was explored. Results: As of March 1, 2023, 71 (A), 62 (B), 26 (C) and 7 pts (D) were treated. The PAD was established as 120 mg GEVO intravenous (IV) every 4 weeks (Q4W) and the RDE as 120 mg GEVO IV Q4W + SoC. There were 2 dose-limiting toxicities: grade 4 decreased neutrophil count (1 pt in C) and grade 3 hyponatremia (1 pt in D). The most frequent grade ≥3 treatment-related adverse events (≥15% of all pts) were neutropenia (A/B: 21.1%/22.6%), decreased neutrophil count (A/B/C: 18.3%/17.7%/15.4%) and hyponatremia (D: 28.6%). The PFS rates were 29.0% (80% CI: 20.4, 38.2), 39.4% (80% CI: 29.8, 48.9), 20.0% (60% CI: 13.3, 27.6) in A/B/C, respectively. In B, median PFS and overall survival (OS) were significantly longer in pts with baseline hs-CRP <10 mg/L (low [L]) than ≥10 mg/L (high [H]), IL-6 <9.58 pg/mL (L) than ≥9.58 pg/mL (H), and IL-1β <0.12 pg/mL (L) than ≥0.12 pg/mL (H). In A + B, a median on-treatment decrease of ctDNA fraction by >72% (H) was associated with significantly longer OS. Conclusions: The safety and tolerability of GEVO combinations was acceptable. The primary PFS rates did not meet the PoC criteria. Baseline levels of hs-CRP, IL-6 and IL-1β in pts with 2L mCRC, and on-treatment reduction of ctDNA in pts with 1L + 2L mCRC may have prognostic value. Clinical trial information: NCT03798626 . Variables PFS HR (95% CI) p-value OS HR (95% CI) p-value Ahs-CRP L / HIL-6 L / HIL-1β L / H 1.74 (0.81, 3.73)1.38 (0.70, 2.72)1.50 (0.74, 3.01) 0.1550.3520.259 1.99 (0.66, 5.98)1.73 (0.71, 4.20)0.98 (0.38, 2.52) 0.2210.2250.973 Bhs-CRP L / HIL-6 L / HIL-1β L / H 2.56 (1.27, 5.18)2.92 (1.33, 6.40)2.41 (1.13, 5.13) 0.0090.0070.022 3.04 (1.40, 6.60)3.25 (1.43, 7.36)3.60 (1.54, 8.44) 0.0050.0050.003 A + BctDNA decrease L / H 0.65 (0.39, 1.10) 0.108 0.45 (0.24, 0.83) 0.011
635 Background: The optimal treatment for patients (pts) with advanced HCC who progress on an ICI-containing regimen has not been defined. In pts who progressed on one prior ICI regimen, regorafenib plus pembrolizumab (rego + pembro) showed modest anti-tumor activity (primary completion analysis: overall objective response rate 7.4%, all partial responses [PR]) and an expected safety profile (NCT04696055; El-Khoueiry, ASCO 2024). We conducted additional exploratory analyses of tumor markers to gain insights into the clinical results. Methods: Overall, 95 adults with unresectable advanced HCC (C-P Class A, BCLC stage B/C, ECOG PS 0/1) received oral regorafenib 90 mg once daily 3 weeks on/1 week off plus pembrolizumab 400 mg i.v. every 6 weeks. Prior treatment: Cohort 1 = atezolizumab + bevacizumab (n=68); Cohort 2 = any other ICI alone or in combination (n=27). Biomarker analyses in subsets of pts explored potential correlations with clinical benefit (defined as tumor response or stable disease [SD] ≥ 4 months). Immune cell subtypes in blood were analyzed by flow cytometry. Tumor immune markers were assessed by immunohistochemistry. Gene expression profiling in tumor samples was by RNAseq. Results: Twenty-one pts had baseline samples for RNAseq, 7 of whom had clinical benefit (n= 3 Cohort 1 [including 1 PR], n=4 Cohort 2). Pts with clinical benefit had differential gene expression at baseline including enriched expression of genes associated with Notch, Hedgehog, fibroblast, TGF-β, and insulin-like growth factor binding protein signaling; in contrast, there was higher expression of genes associated with myeloid derived suppressor cells in pts without clinical benefit. Of note, tumor samples from pts in this study had increased Tregs and T-cell exhaustion signatures compared with pts treated with rego + pembro in a first-line study (NCT03347292).Analyses of available paired tumor samples from 4 patients (n=2 SD, n=2 progressive disease) found reductions in activated fibroblast, TGF-β, and collagen gene expression signatures from baseline to Week 6 Day 1 of treatment. Conclusions: Rego + pembro had modest activity in pts who progressed on one prior ICI-based regimen. Exploratory biomarker analyses suggest different gene expression in pts with or without clinical benefit. Clinical benefit was associated with enriched expression of genes in Notch, Hedgehog, fibroblast, and TGF-β pathways. Pre- and post-treatment biopsies showed reductions in fibroblast, TGF-β, and collagen gene expression, which are known features of HCC. In the context of the limitations of small sample size and absence of a control arm, these findings are hypothesis generating and consistent with HCC biology and regorafenib mechanism of action. Clinical trial information: NCT04696055 .
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631 members
Alessandra Casarotti
  • Department of Neurosurgery
Elena Albé
  • Department of Ophthalmology
Roberta Maselli
  • Department of Gastroenterology
Sergio Marchini
  • Cancer Pharmacology
Alberto Bizzi
  • Diagnostic Imaging, Neuroradiology Division
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Rozzano, Italy