Alain Hendlisz

RESEARCH INTERESTS

Digestive Oncology
Radiation Oncology
Nuclear Medicine
Response assessment

Scopus Publications

Management of high-grade neuroendocrine neoplasms: impact of functional imaging
O Islam, K Sarti, L Verbruggen, V Vandersmissen, K Vanden Bulcke, L Annys, C Verslype, J L Van Laethem, H Rezaei Kalantari, J Janssens,et al.
Bioscientifica
Gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) exhibit substantial biological heterogeneity, impacting clinical management and outcomes. In 2019, the WHO subdivided the grade 3 (G3) neuroendocrine neoplasms (NEN) characterised by Ki-67 > 20% into the well-differentiated G3 neuroendocrine tumour (NET) and G3 poorly differentiated neuroendocrine carcinoma (NEC) subgroups. Since this update, questions about the prognostic implications and best treatment strategies for NET G3 and NEC remain. Therefore, we initiated a real-world retrospective observational cohort study using data from 225 NEC and 58 NET G3 patients treated in Belgium. Analysis of patient and tumour characteristics and the effect of survival was conducted. Most frequent primary locations were pancreatic (32.9%) and colorectal (21.5%), and 71.8% was diagnosed with stage IV disease. Median overall survival (mOS) was higher in NET G3 (41.3 months (m)) compared to NEC (13.2m). Of those who underwent functional imaging, fluorodeoxyglucose–positron emission tomography (18F-FDG-PET) imaging was positive in 90.6 and 95.6% of the NET G3 and NEC patients, respectively, and somatostatin receptor (SSTR) expression was seen in 97.4 and 66.0%, respectively. The latter was linked to better mOS, suggesting the added value of performing both SSTR imaging and 18F-FDG-PET for high-grade (HG) NEN to provide prognostic information and to possibly expand therapeutic options, which are currently reserved for lower-grade NEN patients. Moreover, while debated, in our population, primary surgery was performed in 92 and 73.5% of locoregional NET G3 and NEC cases, respectively, indicating that surgery can be considered in locoregional setting. Finally, platinum–etoposide was the predominant first-line treatment in metastatic NEC, with no significant survival difference between carboplatin and cisplatin.


Rationale and Design of the COPERNIC Trial: A Study of On-treatment ctDNA Changes in Chemo-refractory Colorectal Cancer Patients
Irene Assaf, Giacomo Bregni, Geraldine Anthoine, Thomas Aparicio, Pascal Artru, Meher Ben Abdelghani, Marc Buyse, Benoist Chibaudel, Elisabeth Coart, Marie Diaz,et al.
Elsevier BV



Evolution of dosimetric parameters through PRRT and potential impact on clinical practice: data from the prospective phase II LUMEN study
Rachele Danieli, Magdalena Mileva, Gwennaëlle Marin, Paulus Kristanto, Wendy Delbart, Bruno Vanderlinden, Zéna Wimana, Alain Hendlisz, Hugo Levillain, Nick Reynaert,et al.
Springer Science and Business Media LLC



Ectopic ACTH-Dependent Cushing's Syndrome Emerging at a Late Stage of a Mixed Histology Neuroendocrine Neoplasm: A Case Report
Michel Meyers, Ahmad Awada, Ioannis Karfis, Daphné t'Kint de Roodenbeke, Hugo Couvert, Charlotte Hanssens, Alain Hendlisz, and Natacha Driessens
S. Karger AG
Introduction: Neuroendocrine neoplasms encompass well-differentiated tumors (NETs) and poorly differentiated carcinomas (neuroendocrine carcinomas [NECs]), which are distinguished by their clinical behavior and molecular characteristics. They can cause paraneoplastic syndromes, such as ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome (CS), necessitating prompt recognition and management due to severe hypercortisolism. Case Presentation: A 66-year-old patient with a 3-year history of metastatic mixed neuroendocrine-non-neuroendocrine neoplasm with a NEC and adenocarcinoma component originating from the vulva presented to the emergency department with dyspnea and fatigue. Upon clinical examination, we found widespread hyperpigmentation, a moon-face appearance, hirsutism, buffalo hump, and muscle atrophy. Laboratory investigations revealed severe hypokalemia (2.3 mmol/L), elevated serum cortisol (1,726 nmol/L) and ACTH (194 ng/L) levels. Urinary free cortisol measurement was 21-fold the upper limit of the reference range (3,614.0 nmol/24 h), and cortisol concentration did not decrease after 1mg-dexamethasone suppression test (1,812 nmol/L for an expected value <50 nmol/L), confirming the ACTH-dependent CS. Thoracoabdominal computed tomography (CT) scan demonstrated progressive neoplastic disease in the liver, kidney, lymph nodes, peritoneum, and lungs. Brain magnetic resonance imaging indicated multifocal metastatic infiltration but no evidence of pituitary adenoma. Interestingly, despite a previously negative 68Ga-DOTATATE positron emission tomography (PET)/CT performed 1 year prior, there was moderate somatostatin receptor (SSTR) expression in lymphatic, pulmonary, peritoneal, and bone tissues, suggesting the presence of a component with redifferentiation and re-expression of the SSTR. After the workup, the patient was admitted to a supportive care facility. Hypercortisolism symptoms were effectively managed with an adrenal enzyme inhibitor (ketoconazole) in combination with somatostatin analogs. Unfortunately, the patient was too frail to benefit from peptide receptor radionuclide therapy (PRRT). Conclusion: This redifferentiation phenomenon in neuroendocrine tumors should be further investigated as patients might be, under certain conditions, eligible for PRRT. Therefore, we suggest that newly occurring paraneoplastic syndromes in patients with NEC should always be evaluated using 68Ga-DOTATATE PET/CT.


¹⁷⁷Lu-DOTATATE PRRT Safety and Organ-at-Risk Dosimetry in Patients With Gastroenteropancreatic Neuroendocrine Tumors: Data From the Prospective Phase 2 LUMEN Study
Magdalena Mileva, Camille Van Bogaert, Gwennaëlle Marin, Rachele Danieli, Carlos Artigas, Hugo Levillain, Lieveke Ameye, Loubna Taraji-Schiltz, Konstantinos Stathopoulos, Zéna Wimana,et al.
Ovid Technologies (Wolters Kluwer Health)
Purpose The aim of this study was to assess the association among toxicity, dosimetry of organs-at-risk, and disease progression in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with 177Lu-DOTATATE. Patients and Methods Thirty-seven patients with GEP-NETs underwent 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in a single-arm, prospective, phase 2 study, where patients were followed up with blood tests, isotopic glomerular filtration rate (iGFR), and imaging examinations (CT/MRI and PET) every 6 months until disease progression. Adverse events (AEs) graded per CTCAEv4.03 and occurring during treatment were collected and followed up until resolution. Dosimetry, including biologically effective doses (BEDs) to kidneys, BED to bone marrow, and absorbed dose (AD) to spleen, was performed after each PRRT cycle. Statistical analyses explored associations among dosimetry, toxicity, and patient progression free-survival. Results The most common AEs were anemia and lymphopenia (65%), followed by thrombocytopenia and fatigue (each 51%), alopecia (46%), and nausea (41%). The most common grade ≥3 AE was lymphopenia (43%). There was no grade ≥3 nephrotoxicity. The median iGFR % decrease was 11% (P < 0.001), at a median follow-up of 23 months. iGFR %decrease and renal BED did not correlate (Spearman ρ = −0.09). Similarly, no significant association was found between bone marrow BED or spleen AD and the grades of hematological toxicities. We observed no association between progression free-survival and either the decline of renal function or the occurrence of hematological toxicities during PRRT. Conclusions This study confirms the safety profile of 177Lu-DOTATATE PRRT in patients with GEP-NETs irrespective of the dosimetry of organs at risk. Kidney, bone marrow, and spleen dosimetry measures were not associated with renal or hematological toxicity.


PD-L1 Expression in Paired Samples of Rectal Cancer
Mina Coussement, Roberta Fazio, Alessandro Audisio, Reem El Khoury, Fatima-Zahra Abbassi, Irene Assaf, Chiara Conti, Chiara Gallio, Nada Benhima, Giacomo Bregni,et al.
MDPI AG
Immune checkpoint inhibitors and immune-related biomarkers are increasingly investigated in rectal cancer (RC). We retrospectively analysed PD-L1 expression in diagnostic biopsy and resection samples from RC patients treated at our centre between 2000 and 2020. PD-L1 immunostaining (22C3 clone) was evaluated according to tumour proportion (TPS), immune cell (ICS), and the combined positive score (CPS). Eighty-three patients were included. At diagnosis, PD-L1 expression ≥1%/≥5% was observed in 15.4%/0%, 80.7%/37.4%, and 69.2%/25.6% of patients based on TPS, ICS, and CPS, respectively. At surgery, the respective figures were 4.6%/1.5%, 60.2%/32.5%, and 50.7%/26.2%. Using the 1% cut-off and regardless of the scoring system, PD-L1 was less expressed in surgery than biopsy samples (p ≤ 0.04). In paired specimens, PD-L1-ICS reduction was especially observed following neoadjuvant long-course (chemo)radiotherapy (p = 0.03). PD-L1-ICS of ≥5% in surgical samples (HR: 0.17; p = 0.02), and a biopsy-to-surgery increase in PD-L1-ICS (HR: 0.19; p = 0.04) was predictive for longer disease-free survival, while the PD-L1-ICS of either ≥1% (HR 0.28; p = 0.04) or ≥5% (HR 0.19; p = 0.03) in surgical samples and the biopsy-to-surgery increase in PD-L1-ICS (HR: 0.20; p = 0.04) were associated with better overall survival. Our study suggests that PD-L1 expression in RC is largely reflective of immune cell infiltration, and its presence/increase in surgical samples predicts better outcomes.


State-of-the-art and trends in fibroblast growth factor receptor-directed therapies in gastro-intestinal malignancies
Charlotte Hanssens, Oumnia Mouna, Michel Meyers, and Alain Hendlisz
Ovid Technologies (Wolters Kluwer Health)
Purpose of review This review is timely and relevant due to the increasing recognition of the significance of the fibroblast growth factor receptor (FGFR) family in cancer biology. Understanding the role of FGFRs and their dysregulation in various cancers is crucial for developing targeted therapies and improving patient outcomes. Recent findings The review highlights the importance of the FGFR family in cellular processes such as growth, proliferation, and survival. It discusses how abnormalities in FGFR2, including overexpression, gene amplification, and other genetic alterations, contribute to cancer progression, particularly in gastro-intestinal cancers. The paper also emphasizes the promising results of FGFR-targeted therapies, especially tyrosine kinase inhibitors, in certain cancers such as cholangiocarcinoma and oesophagogastric cancers. Summary The findings underscore the potential of FGFR-targeted therapies in treating cancers with FGFR dysregulation. However, the review also addresses the challenges associated with these therapies, including toxicities and mechanisms of resistance. Understanding these complexities is essential for optimizing the efficacy of FGFR-targeted treatments and improving patient outcomes in clinical practice and research efforts.


Beyond 'the good, the bad and the ugly': let us put rectal cancer patients at the centre of the decision making
Francesco Sclafani, Chiara Conti, Chiara Gallio, and Alain Hendlisz
Ovid Technologies (Wolters Kluwer Health)



Non-operative management after immune checkpoint inhibitors for early-stage, dMMR/MSI-H gastrointestinal cancers
Roberta Fazio, Alessandro Audisio, Valentina Daprà, Chiara Conti, Nada Benhima, Fatima-Zahara Abbassi, Irene Assaf, Alain Hendlisz, and Francesco Sclafani
Elsevier BV



Development of Clinical Radiomics-Based Models to Predict Survival Outcome in Pancreatic Ductal Adenocarcinoma: A Multicenter Retrospective Study
Ayoub Mokhtari, Roberto Casale, Zohaib Salahuddin, Zelda Paquier, Thomas Guiot, Henry C. Woodruff, Philippe Lambin, Jean-Luc Van Laethem, Alain Hendlisz, and Maria Antonietta Bali
MDPI AG
Purpose. This multicenter retrospective study aims to identify reliable clinical and radiomic features to build machine learning models that predict progression-free survival (PFS) and overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC) patients. Methods. Between 2010 and 2020 pre-treatment contrast-enhanced CT scans of 287 pathology-confirmed PDAC patients from two sites of the Hopital Universitaire de Bruxelles (HUB) and from 47 hospitals within the HUB network were retrospectively analysed. Demographic, clinical, and survival data were also collected. Gross tumour volume (GTV) and non-tumoral pancreas (RPV) were semi-manually segmented and radiomics features were extracted. Patients from two HUB sites comprised the training dataset, while those from the remaining 47 hospitals of the HUB network constituted the testing dataset. A three-step method was used for feature selection. Based on the GradientBoostingSurvivalAnalysis classifier, different machine learning models were trained and tested to predict OS and PFS. Model performances were assessed using the C-index and Kaplan–Meier curves. SHAP analysis was applied to allow for post hoc interpretability. Results. A total of 107 radiomics features were extracted from each of the GTV and RPV. Fourteen subgroups of features were selected: clinical, GTV, RPV, clinical & GTV, clinical & GTV & RPV, GTV-volume and RPV-volume both for OS and PFS. Subsequently, 14 Gradient Boosting Survival Analysis models were trained and tested. In the testing dataset, the clinical & GTV model demonstrated the highest performance for OS (C-index: 0.72) among all other models, while for PFS, the clinical model exhibited a superior performance (C-index: 0.70). Conclusions. An integrated approach, combining clinical and radiomics features, excels in predicting OS, whereas clinical features demonstrate strong performance in PFS prediction.


Prediction of ¹⁷⁷Lu-DOTATATE PRRT Outcome Using Multimodality Imaging in Patients with Gastroenteropancreatic Neuroendocrine Tumors: Results from a Prospective Phase II LUMEN Study
Magdalena Mileva, Gwennaëlle Marin, Hugo Levillain, Carlos Artigas, Camille Van Bogaert, Clémentine Marin, Rachele Danieli, Amelie Deleporte, Simona Picchia, Konstantinos Stathopoulos,et al.
Society of Nuclear Medicine
Our objective was to predict the outcome of peptide receptor radionuclide therapy (PRRT) using multimodality imaging and tumor dosimetry on gastroenteropancreatic neuroendocrine tumor (GEP-NET) lesions and patients. Methods: This prospective study included patients with progressive GEP-NETs. Treatment consisted of 4 cycles of 7.4 GBq of 177Lu-DOTATATE. Imaging parameters were measured on 68Ga-DOTATATE PET/CT (SUVmax/mean, somatostatin receptor [SSTR] tumor volume [TV], total lesion SSTR expression, and tumor-to-blood and tumor-to-spleen ratios), 18F-FDG PET/CT (SUVmax/mean, metabolically active TV, and total lesion glycolysis), and diffusion-weighted MRI (apparent diffusion coefficient) in a maximum of 5 target lesions per patient at approximately 10 wk after each injection. Tumor dosimetry was performed using SPECT/CT at 3 time points for every cycle. Baseline imaging parameters, their relative changes after PRRT cycle 1 (C1), and the tumor-absorbed dose at C1 were correlated with lesion morphologic outcome. The average values of the imaging parameters and the minimal, maximal, and mean C1 tumor-absorbed dose in each patient were tested for association with progression-free survival (PFS) and best objective response (RECIST 1.1). Results: In the 37 patients, the median PFS was 28 mo. Eleven of the 37 (30%) achieved a partial response (RECIST 1.1). After a median follow-up of 57 mo, the median time to lesion progression had not been reached in 84 morphologically evaluable lesions, with only 12 (14%) progressing (size increase ≥ 20% from baseline). Patients receiving a minimal C1 dose of 35 Gy in all target lesions exhibited a significantly longer PFS (48.1 vs. 26.2 mo; hazard ratio, 0.37; 95% CI, 0.17-0.82; P = 0.02). Volumetric 68Ga-DOTATATE PET parameters correlated with lesion and patient outcome: patients with an SSTR TV decrease of more than 10% after C1 had a longer PFS (51.3 vs. 22.8 mo; hazard ratio, 0.35; 95% CI, 0.16-0.75; P = 0.003). There was no statistical evidence of an association between other dosimetric or imaging parameters and the lesion or patient outcome. Conclusion: Minimal tumor-absorbed dose at C1 is predictive of outcome in patients with GEP-NETs treated with PRRT, providing a basis for personalized dosimetry-guided treatment strategies. An SSTR TV decrease after C1 could be used for early therapy response assessment as a predictor of PRRT outcome.


Neoadjuvant chemotherapy for early-stage colon cancer
Alessandro Audisio, Roberta Fazio, Valentina Daprà, Irene Assaf, Alain Hendlisz, and Francesco Sclafani
Elsevier BV



Prognostic Value of Circulating Cytokines in Chemorefractory Colorectal Cancer
Irene Assaf, Danai Fimereli, Geraldine Anthoine, Roberta Fazio, Valentina Daprà, Alessandro Audisio, Alina Bardiaux, Tugba Akin Telli, Michele Vanhooren, Rita Saude-Conde,et al.
MDPI AG
Circulating cytokines could be optimal biomarkers for prognostication and management decisions in colorectal cancer (CRC). Chemorefractory CRC patients with available plasma samples were included in this study. In the discovery cohort (n = 85), 182 circulating cytokines were tested with a semi-quantitative multiplex assay, and prognostic cytokines were analyzed in the validation cohort (n = 111) by ELISA. Overall survival (OS) was the primary outcome measure, with the false discovery rate (FDR) method (significance level of <0.01) being used to correct for multiple comparisons. Four cytokines were associated with OS in the discovery cohort: insulin-like growth factor-binding protein 1 (IGFBP-1) (HR 2.1 [95%CI: 1.58–2.79], FDR < 0.001), insulin-like growth factor-binding protein 2 (IGFBP-2) (HR 1.65 [95%CI: 1.28–2.13], FDR = 0.006), serum amyloid A (SAA) (HR 1.84 [95%CI: 1.39–2.43], FDR < 0.001), and angiotensin II (HR 1.65 [95%CI: 1.29–2.1], FDR = 0.006). Of these, IGFBP-1 (HR 2.70 [95%CI: 1.56–4.76], FDR = 0.007) and IGFBP-2 (HR 3.33 [95%CI: 1.64–6.67], FDR = 0.008) were confirmed to be independently associated with OS in the validation cohort. Patients with high concentrations of IGFBP-1 and/or IGFBP-2 had a median OS of 3.0 months as compared with 6.9 months for those with low concentrations of both cytokines (HR 2.44 [95%CI: 1.52–4.0], FDR = 0.002) Validation of circulating IGFBP-1 and IGFBP-2 as independent prognostic biomarkers for chemorefractory CRC in larger, independent series is warranted.


Association between primary tumor characteristics and histopathological growth pattern of liver metastases in colorectal cancer
Ali Bohlok, Camille Tonneau, Sophie Vankerckhove, Ligia Craciun, Valerio Lucidi, Fikri Bouazza, Alain Hendlisz, Jean Luc Van Laethem, Denis Larsimont, Peter Vermeulen,et al.
Springer Science and Business Media LLC



Neoadjuvant chemotherapy for resectable colon cancer in the era of precision oncology: a step forward or a step back?
Alessandro Audisio, Roberta Fazio, Alain Hendlisz, and Francesco Sclafani
Ovid Technologies (Wolters Kluwer Health)



Editorial introductions
Ovid Technologies (Wolters Kluwer Health)



Immunotherapies in non-metastatic gastrointestinal cancers
Rita Saúde-Conde, Dan Nguyen, and Alain Hendlisz
Ovid Technologies (Wolters Kluwer Health)
Purpose Over the last decade, immune checkpoint inhibitors (ICI) have emerged as cornerstone in the treatment of many metastatic tumour types, including gastrointestinal cancers. In many solid tumours, the effective therapies in the metastatic field are progressively brought into the curative setting. Consequently, earlier tumoural settings have become a field of experiment for immunotherapies. In melanoma, lung, and bladder cancers, excellent results were recorded, possibly explained by differences in the tumour microenvironment between metastatic and non-metastatic settings. In gastrointestinal (GI) Oncology, nivolumab is the first immune checkpoint inhibitor to become a standard-of-care adjuvant treatment after curative surgery for oesophagal or gastroesophageal junction cancer. Recent findings We herein discuss the results of a selection of the most relevant studies presented/published over the last 18 months testing immunotherapies in non-metastatic GI cancers. Among immunotherapies, ICI have been investigated in pre-, peri- and postoperative setting across tumour types, alone or in combination with chemo- and/or radiotherapy. Vaccines are also a new field of investigation. Summary Promising results from two studies (NCT04165772 and NICHE-2 study) demonstrating never-seen-before responses to neoadjuvant immunotherapy in MMR deficient (dMMR) colorectal cancers raise hope for improving the patients’ outcome and developing organ-sparing strategies in this situation.


The Prognostic Value of Distinct Histological Growth Patterns of Colorectal Peritoneal Metastases: A Pilot Study
Antoine El Asmar, Pieter Demetter, Fahd Fares, Francesco Sclafani, Alain Hendlisz, Vincent Donckier, Peter Vermeulen, and Gabriel Liberale
Springer Science and Business Media LLC
Abstract Background Different histological growth patterns (HGP) describing the tumor-to-liver interface have been described in colorectal liver metastases and have been associated with a strong prognostic value. However, HGP of peritoneal metastases (PM) of colorectal cancer (CRC) have not yet been described. Our objective was to determine whether distinct HGP can be identified in PMCRC and to evaluate their potential prognostic value in these patients. Methods This retrospective study included 38 patients who underwent curative-intent surgery for PMCRC between July 2012 and March 2019, with PCI≤6, and who had not received preoperative chemotherapy. In each patient, the tumor-to-peritoneum interface was evaluated in the excised peritoneal nodules. The association between HGP and postoperative survival was analyzed by using the Kaplan–Meier method. Results Two distinct HGP were identified: a pushing-type (P-HGP), characterized by a fibrous rim separating the PM and peritoneum, and an infiltrating-type (I-HGP), characterized by focal penetration of tumor cells into the surrounding peritoneal lining without a fibrous rim. Fifteen patients had dominant P-HGP, and 23 patients had dominant I-HGP. Patients with dominant P-HGP (>50% tumor-peritoneum interface) had a significantly better DFS (30 months) than those with P-HGP <50% (9 months; p = 0.029). Patients with a P-HGP dominance >60% had better OS (131 months) than those with P-HGP <60% (41 months; p = 0.044). Conclusions This is the first description of two distinct, reproducible HGP in PMCRC. The dominant P-HGP is associated with a favorable prognosis in patients with PMCRC, compared with I-HGP, suggesting that this parameter could ultimately represent a new prognostic biomarker.


Preexisting evidence and outcome of phase III trials in gastrointestinal oncology: a systematic review
Giacomo Bregni, Elena Trevisi, Rita Saúde Conde, Michele Vanhooren, Tugba Akin Telli, Irene Assaf, Alain Hendlisz, Massimo Di Maio, and Francesco Sclafani
Oxford University Press (OUP)
Abstract Background A minority of phase III trials in gastrointestinal oncology are positive. We assessed the association between their outcome and the level and characteristics of preexisting evidence. Methods EMBASE, PubMed, and proceedings from international meetings were searched for phase III gastrointestinal cancer trials (gastroesophageal, hepatocellular, biliary tract, pancreatic, small bowel, colorectal, anal, stromal, and neuroendocrine) between January 2000 and June 2020. Trials investigating anticancer drugs for advanced disease, with superiority design and standard treatments as control were eligible. The highest level of preexisting evidence was retrieved from the main study report. Results A total of 193 phase III trials were included, and 69 (35.8%) met their primary endpoint. Positivity rates were as follows: gastroesophageal 37%, colorectal 48%, pancreatic 17.1%, hepatocellular 20%, neuroendocrine 75%, and both biliary tract and GIST 60%. No information about preexisting evidence was found for 44 trials (22.8%). For the remaining 149, preexisting evidence consisted of phase II studies in 123 cases (82.6%) and phase I studies in 26 cases (17.4%). The probability of success was 34.1%, 35.8%, and 35.7%, respectively (P = .934). No parameter from prior studies predicted the outcome of phase III trials except β < .2 (P = .048). A numerically increased success rate was observed for phase III trials preceded by positive phase II studies (41.9% vs 18.5%, P = .2). Conclusions There does not appear to be an association between level of prior evidence and success of phase III gastrointestinal cancer trials. These data, along with the high phase III failure rate, highlight the need to improve the drug development process in this setting.


Histopathological growth pattern of liver metastases as an independent marker of metastatic behavior in different primary cancers
Ali Bohlok, François Richard, Valerio Lucidi, Antoine El Asmar, Pieter Demetter, Ligia Craciun, Denis Larsimont, Alain Hendlisz, Jean Luc Van Laethem, Luc Dirix,et al.
Frontiers Media SA
Surgical resection can lead to prolonged survival in patients with isolated liver metastases (LM) from various primary cancers. However, there are currently no validated predictive markers to discriminate between these oligo/argometastatic patients, who will benefit from surgery, and those with diffuse metastatic behavior in whom surgery will be futile. To evaluate whether the tumor microenvironment, or histopathological growth pattern (HGP), of LM reflects the type of metastatic progression independently of the origin of the primary cancer, we analyzed a combined series of patients who underwent surgery for colorectal LM (N=263) or non-colorectal LM (N=66). HGPs of LM were scored in each patient to distinguish between desmoplastic HGP (all LM showing a complete encapsulated pattern) and non-desmoplastic HGP (at least one LM with some infiltrating-replacement component). In the entire series, 5-year overall and progression-free survival were, 44.5% and 15.5%, respectively, with no significant differences between colorectal and non-colorectal LM. In patients with desmoplastic HGP, 5-year overall and progression-free survival were 57% and 32%, respectively, as compared to 41% and 12%, respectively, in patients with non-desmoplastic-HGP (p=0.03 and 0.005). Irrespective of cancer origin and compared to traditional risk factors, desmoplastic HGP was the most significant predictor for better post-operative overall survival (adjusted HR: 0.62; 95% CI: [0.49-0.97]; p=0.035) and progression-free survival (adjusted HR: 0.61; 95% CI: [0.42-0.87], p=0.006). This suggests that the HGP of LM may represent an accurate marker that reflects the mode of metastatic behavior, independently of primary cancer type.


Tumor biology reflected by histological growth pattern is more important than surgical margin for the prognosis of patients undergoing resection of colorectal liver metastases
Ali Bohlok, Lisa Inchiostro, Valerio Lucidi, Sophie Vankerckhove, Alain Hendlisz, Jean Luc Van Laethem, Ligia Craciun, Pieter Demetter, Denis Larsimont, Luc Dirix,et al.
Elsevier BV



Regorafenib Induces Senescence and Epithelial-Mesenchymal Transition in Colorectal Cancer to Promote Drug Resistance
Pashalina Kehagias, Nadège Kindt, Mohammad Krayem, Ahmad Najem, Giulia Agostini, Elena Acedo Reina, Giacomo Bregni, Francesco Sclafani, Fabrice Journe, Ahmad Awada,et al.
MDPI AG
Potential intrinsic resistance mechanisms to regorafenib were explored after short exposure (3 days) on five CRC cell lines (HCT-116, SW1116, LS-1034, SW480, Caco-2). The observation of senescence-like features led to the investigation of a drug-initiated phenotype switch. Following long-term exposure (12 months) of HCT-116 and SW480 cell lines to regorafenib, we developed resistant models to explore acquired resistance. SW480 cells demonstrated senescent-like properties, including a cell arrest in the late G2/prophase cell cycle stage and a statistically significant decrease in the expression of G1 Cyclin-Dependent Kinase inhibitors and key cell cycle regulators. A specific senescence-associated secretome was also observed. In contrast, HCT-116 treated cells presented early senescent features and developed acquired resistance triggering EMT and a more aggressive phenotype over time. The gained migration and invasion ability by long-exposed cells was associated with the increased expression level of key cellular and extracellular EMT-related factors. The PI3K/AKT pathway was a significant player in the acquired resistance of HCT-116 cells, possibly related to a PI3KCA mutation in this cell line. Our findings provide new insights into the phenotypic plasticity of CRC cells able, under treatment pressure, to acquire a stable TIS or to use an early senescence state to undergo EMT.


Regorafenib in combination with immune checkpoint inhibitors for mismatch repair proficient (pMMR)/microsatellite stable (MSS) colorectal cancer
Tugba Akin Telli, Giacomo Bregni, Michele Vanhooren, Rita Saude Conde, Alain Hendlisz, and Francesco Sclafani
Elsevier BV



Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142
T. André, S. Lonardi, K.Y.M. Wong, H.-J. Lenz, F. Gelsomino, M. Aglietta, M.A. Morse, E. Van Cutsem, R. McDermott, A. Hill,et al.
Elsevier BV



Mind the target: Human epidermal growth factor receptor 2 in colorectal cancer
Rita Saúde-Conde, Gertjan Rasschaert, Giacomo Bregni, Alain Hendlisz, and Francesco Sclafani
Ovid Technologies (Wolters Kluwer Health)
Purpose of review In this article, we briefly summarise the current knowledge about human epidermal growth factor receptor 2 (HER2) alterations in colorectal cancer (CRC) and provide an overview of the latest published evidence especially regarding standardisation of detection methods/diagnostic criteria, prognostication, prediction and targeted treatments. Recent findings Over the last 18 months, the results of many studies have been presented confirming the therapeutic potential of established anti-HER2 agents either as a monotherapy or in combination, as well as new anti-HER2 agents like antibody-drug-conjugates and tyrosine kinase inhibitors. Also, we have seen confirmation of the utility of liquid biopsy and ctDNA analyses as tool for HER2 detection and patient selection. Summary Despite concerning only 5% of metastatic CRC, HER2 represents a valuable target for emerging anti-HER2 therapies that might significantly improve the outcome of these patients. Standardising HER2 detection methods/diagnostic criteria, and producing high-quality, randomised evidence are the next challenges to meet the standards of regulatory authorities and ultimately have anti-HER2 agents available for use in routine practice.

RECENT SCHOLAR PUBLICATIONS

Management of high-grade neuroendocrine neoplasms: impact of functional imaging
O Islam, K Sarti, L Verbruggen, V Vandersmissen, KV Bulcke, L Annys, ...
Endocrine-Related Cancer 32 (4) 2025



Rationale and Design of the COPERNIC Trial: A Study of On-treatment ctDNA Changes in Chemo-refractory Colorectal Cancer Patients
I Assaf, G Bregni, G Anthoine, T Aparicio, P Artru, MB Abdelghani, ...
Clinical colorectal cancer 24 (1), 101-105 2025



Deep epigastric lymph node involvement in patients with ovarian and colorectal peritoneal metastasis: A prospective pilot study
A El Asmar, C Khaled, I Veys, MG Galdon, L Verset, A Hendlisz, ...
European Journal of Surgical Oncology 50 2024



Evolution of dosimetric parameters through PRRT and potential impact on clinical practice: data from the prospective phase II LUMEN study
R Danieli, M Mileva, G Marin, P Kristanto, W Delbart, B Vanderlinden, ...
EJNMMI research 14 (1), 110 2024



[⁶⁸Ga]FAPI-46PET/CT for preoperative assessment of peritoneal carcinomatosis- Preliminary analysis of FAPeCa trial
AA Ozturk, G Liberale, A Hendlisz, L Polastro, AV Sanchez, A Deleu, ...
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 51, S264-S264 2024



PD-L1 Expression in Paired Samples of Rectal Cancer
M Coussement, R Fazio, A Audisio, R El Khoury, FZ Abbassi, I Assaf, ...
Cancers 16 (14), 2606 2024



Beyond ‘the good, the bad and the ugly’: let us put rectal cancer patients at the centre of the decision making
F Sclafani, C Conti, C Gallio, A Hendlisz
Current Opinion in Oncology 36 (4), 305-307 2024



State-of-the-art and trends in fibroblast growth factor receptor-directed therapies in gastro-intestinal malignancies
C Hanssens, O Mouna, M Meyers, A Hendlisz
Current Opinion in Oncology 36 (4), 320-325 2024



Ectopic ACTH-Dependent Cushing’s Syndrome Emerging at a Late Stage of a Mixed Histology Neuroendocrine Neoplasm: A Case Report
M Meyers, A Awada, I Karfis, D t'Kint de Roodenbeke, H Couvert, ...
Case Reports in Oncology 17 (1), 1146-1156 2024



LBA2 Interim efficacy analysis of REGINA, a phase II trial of neoadjuvant regorafenib (Rego), nivolumab (Nivo), and short-course radiotherapy (SCRT) in stage II-III rectal
F Sclafani, G Bregni, I Assaf, F Puleo, P Vergauwe, H Prenen, M Diaz, ...
Annals of Oncology 35, S212-S213 2024



505P State of the art of gastrointestinal (GI) cancer trials for older patients (pts): A systematic review (SR)
R Fazio, A Audisio, ED Saad, G Bregni, D Sur, V Dapr, C Conti, ...
Annals of Oncology 35, S201-S202 2024



Current trends of clinical trials for older patients with cancer: A systematic review.
R Fazio, A Audisio, ED Saad, G Bregni, DG Sur, V Dapr, C Conti, ...
Journal of Clinical Oncology 42 (16_suppl), 1621-1621 2024



Non-operative management after immune checkpoint inhibitors for early-stage, dMMR/MSI-H gastrointestinal cancers
R Fazio, A Audisio, V Dapr, C Conti, N Benhima, FZ Abbassi, I Assaf, ...
Cancer Treatment Reviews, 102752 2024



Development of Clinical Radiomics-Based Models to Predict Survival Outcome in Pancreatic Ductal Adenocarcinoma: A Multicenter Retrospective Study
A Mokhtari, R Casale, Z Salahuddin, Z Paquier, T Guiot, HC Woodruff, ...
Diagnostics 14 (7), 712 2024



Neoadjuvant chemotherapy for early-stage colon cancer
A Audisio, R Fazio, V Dapr, I Assaf, A Hendlisz, F Sclafani
Cancer Treatment Reviews 123, 102676 2024



Prediction of 177Lu-DOTATATE PRRT outcome using multimodality imaging in patients with gastroenteropancreatic neuroendocrine tumors: results from a prospective phase II LUMEN study
M Mileva, G Marin, H Levillain, C Artigas, C Van Bogaert, C Marin, ...
Journal of Nuclear Medicine 65 (2), 236-244 2024



159TiP COPERNIC: A study of on-treatment circulating tumour (ct) DNA changes in chemo-refractory colorectal cancer (CRC) patients
I Assaf, G Bregni, G Anthoine, T Aparicio, P Artru, M Ben Abdelghani, ...
Annals of Oncology 35, S70 2024



Prognostic Value of Circulating Cytokines in Chemorefractory Colorectal Cancer
I Assaf, D Fimereli, G Anthoine, R Fazio, V Dapr, A Audisio, A Bardiaux, ...
Cancers 15 (24), 5823 2023



Histopathological growth pattern of liver metastases as an independent marker of metastatic behavior in different primary cancers
A Bohlok, F Richard, V Lucidi, AE Asmar, P Demetter, L Craciun, ...
Frontiers in Oncology 13, 1260880 2023



599P R-IMMUNE: A phase Ib/II study to evaluate safety and efficacy of atezolizumab combined with radio-chemotherapy in a preoperative setting for patients with locally advanced
J Carrasco, G Beniuga, A Jouret-Mourin, P Baldin, I Sinapi, D Schroeder, ...
Annals of Oncology 34, S432 2023

MOST CITED SCHOLAR PUBLICATIONS

Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer
E Van Cutsem, M Peeters, S Siena, Y Humblet, A Hendlisz, B Neyns, ...
Journal of clinical oncology 25 (13), 1658-1664 2007
Citations: 2471



Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair–deficient/microsatellite instability–high metastatic colorectal cancer
MJ Overman, S Lonardi, KYM Wong, HJ Lenz, F Gelsomino, M Aglietta, ...
Journal of clinical oncology 36 (8), 773-779 2018
Citations: 2103



First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study
HJ Lenz, E Van Cutsem, M Luisa Limon, KYM Wong, A Hendlisz, ...
Journal of Clinical Oncology 40 (2), 161-170 2022
Citations: 542



Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal
A Hendlisz, MV Eynde, M Peeters, G Maleux, B Lambert, J Vannoote, ...
Journal of clinical oncology 28 (23), 3687-3694 2010
Citations: 517



Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors
D Strumberg, JW Clark, A Awada, MJ Moore, H Richly, A Hendlisz, ...
The oncologist 12 (4), 426-437 2007
Citations: 495



Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours
A Awada, A Hendlisz, T Gil, S Bartholomeus, M Mano, D de Valeriola, ...
British journal of cancer 92 (10), 1855-1861 2005
Citations: 420



First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE
HS Wasan, P Gibbs, NK Sharma, J Taieb, V Heinemann, J Ricke, ...
The Lancet Oncology 18 (9), 1159-1171 2017
Citations: 414



Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study
R Marechal, B Vos, M Polus, T Delaunoit, M Peeters, P Demetter, ...
Annals of oncology 23 (6), 1525-1530 2012
Citations: 201



Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up
T Andr, S Lonardi, KYM Wong, HJ Lenz, F Gelsomino, M Aglietta, ...
Annals of Oncology 33 (10), 1052-1060 2022
Citations: 195



Multimodality imaging can predict the metabolic response of unresectable colorectal liver metastases to radioembolization therapy with Yttrium-90 labeled resin microspheres
P Flamen, B Vanderlinden, P Delatte, G Ghanem, L Ameye, ...
Physics in Medicine & Biology 53 (22), 6591 2008
Citations: 176



Gemcitabine and oxaliplatin (GEMOX) in gemcitabine refractory advanced pancreatic adenocarcinoma: a phase II study
A Demols, M Peeters, M Polus, R Marechal, F Gay, E Monsaert, ...
British journal of cancer 94 (4), 481-485 2006
Citations: 170



Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study
E Van Cutsem, S Tejpar, D Vanbeckevoort, M Peeters, Y Humblet, ...
Journal of clinical oncology 30 (23), 2861-2868 2012
Citations: 159



Association of progression‐free survival, overall survival, and patient‐reported outcomes by skin toxicity and KRAS status in patients receiving panitumumab
M Peeters, S Siena, E Van Cutsem, A Sobrero, A Hendlisz, S Cascinu, ...
Cancer: Interdisciplinary International Journal of the American Cancer 2009
Citations: 153



Prognostic values of galectin-3 and the macrophage migration inhibitory factor (MIF) in human colorectal cancers
H Legendre, C Decaestecker, N Nagy, A Hendlisz, MP Schring, I Salmon, ...
Modern pathology 16 (5), 491-504 2003
Citations: 152



Treatment of colorectal liver metastases: a review
MV Eynde, A Hendlisz
Reviews on recent clinical trials 4 (1), 56-62 2009
Citations: 137



Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset
H Blons, JF Emile, K Le Malicot, C Juli, A Zaanan, J Tabernero, E Mini, ...
Annals of oncology 25 (12), 2378-2385 2014
Citations: 135



Tumour-educated circulating monocytes are powerful candidate biomarkers for diagnosis and disease follow-up of colorectal cancer
A Hamm, H Prenen, W Van Delm, M Di Matteo, M Wenes, E Delamarre, ...
Gut 65 (6), 990-1000 2016
Citations: 109



Durable clinical benefit with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR
HJJ Lenz, E Van Cutsem, ML Limon, KY Wong, A Hendlisz, M Aglietta, ...
Annals of oncology 29, viii714 2018
Citations: 101



Prognostic value of adipose tissue and muscle mass in advanced colorectal cancer: a post hoc analysis of two non-randomized phase II trials
N Charette, C Vandeputte, L Ameye, CV Bogaert, J Krygier, T Guiot, ...
BMC cancer 19, 1-9 2019
Citations: 100



New strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel
JL Van Laethem, C Verslype, JL Iovanna, P Michl, T Conroy, C Louvet, ...
Annals of oncology 23 (3), 570-576 2012
Citations: 98