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3. Tumor Immune Microenvironment in Intrahepatic Cholangiocarcinoma: Regulatory Mechanisms, Functions, and Therapeutic Implications.

Author

Ricci, Angela Dalia, Rizzo, Alessandro, Schirizzi, Annalisa, D'Alessandro, Rosalba, Frega, Giorgio, Brandi, Giovanni, Shahini, Endrit, Cozzolongo, Raffaele, Lotesoriere, Claudio, and Giannelli, Gianluigi

Subjects
BILE duct tumors, CHOLANGIOCARCINOMA, IMMUNOTHERAPY, TREATMENT effectiveness, TUMOR markers, IMMUNE checkpoint inhibitors, SURVIVAL analysis (Biometry)
Abstract

Simple Summary: Treatment options for intrahepatic cholangiocarcinoma (iCCA), a highly malignant tumor with poor prognosis, are limited. Recent developments in immunotherapy and immune checkpoint inhibitors (ICIs) have offered new hope for treating iCCA. However, several issues remain, including the identification of reliable biomarkers of response to ICIs and immune-based combinations. Tumor immune microenvironment (TIME) of these hepatobiliary tumors has been evaluated and is under assessment in order to boost the efficacy of ICIs and to convert these immunologically "cold" tumors to "hot" tumors. Herein, we examine the role of iCCA TIME, highlighting its mechanisms, current applications and challenges, and future research directions. Treatment options for intrahepatic cholangiocarcinoma (iCCA), a highly malignant tumor with poor prognosis, are limited. Recent developments in immunotherapy and immune checkpoint inhibitors (ICIs) have offered new hope for treating iCCA. However, several issues remain, including the identification of reliable biomarkers of response to ICIs and immune-based combinations. Tumor immune microenvironment (TIME) of these hepatobiliary tumors has been evaluated and is under assessment in this setting in order to boost the efficacy of ICIs and to convert these immunologically "cold" tumors to "hot" tumors. Herein, the review TIME of ICCA and its critical function in immunotherapy. Moreover, this paper also discusses potential avenues for future research, including novel targets for immunotherapy and emerging treatment plans aimed to increase the effectiveness of immunotherapy and survival rates for iCCA patients. [ABSTRACT FROM AUTHOR]

Published
2024
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5. NTRK rearranged sarcoma of the bone. Role for larotrectinib in the neoadjuvant setting of an ultra-rare tumor: a case report

Author

Palmerini, Emanuela, primary, Frega, Giorgio, additional, Gambarotti, Marco, additional, Frisoni, Tommaso, additional, Cesari, Marilena, additional, Bazzocchi, Alberto, additional, Miceli, Marco, additional, Donati, Davide Maria, additional, Fanti, Stefano, additional, Nanni, Cristina, additional, Benini, Stefania, additional, Longhi, Alessandra, additional, Paioli, Anna, additional, Marrari, Andrea, additional, Hakim, Rossella, additional, Righi, Alberto, additional, and Ibrahim, Toni, additional

Published
2023
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7. The Potential Role of Adjuvant Chemoradiotherapy in Patients with Microscopically Positive (R1) Surgical Margins after Resection of Cholangiocarcinoma

Author

Palloni, Andrea, primary, Bisello, Silvia, additional, Maggio, Ilaria, additional, Massucci, Maria, additional, Galuppi, Andrea, additional, Di Federico, Alessandro, additional, Rizzo, Alessandro, additional, Ricci, Angela Dalia, additional, Siepe, Giambattista, additional, Morganti, Alessio Giuseppe, additional, Brandi, Giovanni, additional, and Frega, Giorgio, additional

Published
2023
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8. Lacking Immunotherapy Biomarkers for Biliary Tract Cancer: A Comprehensive Systematic Literature Review and Meta-Analysis

Author

Química orgánica I, Kimika organikoa I, Frega, Giorgio, Cossío Mora, Fernando Pedro, Bañales Asurmendi, Jesús María, Cardinale, Vincenzo, Macias, Rocio I. R., Braconi, Chiara, Lamarca, Angela, Química orgánica I, Kimika organikoa I, Frega, Giorgio, Cossío Mora, Fernando Pedro, Bañales Asurmendi, Jesús María, Cardinale, Vincenzo, Macias, Rocio I. R., Braconi, Chiara, and Lamarca, Angela

Abstract

Background: Immunotherapy has recently been incorporated into the spectrum of biliary tract cancer (BTC) treatment. The identification of predictive response biomarkers is essential in order to identify those patients who may benefit most from this novel treatment option. Here, we propose a systematic literature review and a meta-analysis of PD-1, PD-L1, and other immune-related biomarker expression levels in patients with BTC. Methods: Prisma guidelines were followed for this systematic review and meta-analysis. Eligible studies were searched on PubMed. Studies published between 2017 and 2022, reporting data on PD-1/PD-L1 expression and other immune-related biomarkers in patients with BTC, were considered eligible. Results: A total of 61 eligible studies were identified. Despite the great heterogeneity between 39 studies reporting data on PD-L1 expression, we found a mean PD-L1 expression percentage (by choosing the lowest cut-off per study) of 25.6% (95% CI 21.0 to 30.3) in BTCs. The mean expression percentages of PD-L1 were 27.3%, 21.3%, and 27.4% in intrahepatic cholangiocarcinomas (iCCAs—15 studies), perihilar–distal CCAs (p/dCCAs—7 studies), and gallbladder cancer (GBC—5 studies), respectively. Furthermore, 4.6% (95% CI 2.38 to 6.97) and 2.5% (95% CI 1.75 to 3.34) of BTCs could be classified as TMB-H and MSI/MMRd tumors, respectively. Conclusion: From our analysis, PD-L1 expression was found to occur approximately in 26% of BTC patients, with minimal differences based on anatomical location. TMB-H and MSI molecular phenotypes occurred less frequently. We still lack a reliable biomarker, especially in patients with mismatch-proficient tumors, and we must need to make an effort to conceive new prospective biomarker discovery studies.

Published
2023

9. Second-Line Chemotherapy in Elderly Patients with Advanced Biliary Tract Cancer: A Multicenter Real-World Study

Author

Rizzo, Alessandro, primary, Salati, Massimiliano, additional, Frega, Giorgio, additional, Merz, Valeria, additional, Caputo, Francesco, additional, Di Federico, Alessandro, additional, Palloni, Andrea, additional, Carloni, Riccardo, additional, Ricci, Angela Dalia, additional, Gadaleta-Caldarola, Gennaro, additional, Messina, Carlo, additional, Spallanzani, Andrea, additional, Gelsomino, Fabio, additional, Benatti, Stefania, additional, Luppi, Gabriele, additional, Melisi, Davide, additional, Dominici, Massimo, additional, and Brandi, Giovanni, additional

Published
2022
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12. Intensive Follow-Up Program and Oncological Outcomes of Biliary Tract Cancer Patients after Curative-Intent Surgery: A Twenty-Year Experience in a Single Tertiary Medical Center

Author

Rizzo, Alessandro, primary, Carloni, Riccardo, additional, Frega, Giorgio, additional, Palloni, Andrea, additional, Di Federico, Alessandro, additional, Ricci, Angela Dalia, additional, De Luca, Raffaele, additional, Tavolari, Simona, additional, and Brandi, Giovanni, additional

Published
2022
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13. Bone Turnover Marker (BTM) Changes after Denosumab in Giant Cell Tumors of Bone (GCTB): A Phase II Trial Correlative Study

Author

Palmerini, Emanuela, primary, Pazzaglia, Laura, additional, Cevolani, Luca, additional, Pratelli, Loredana, additional, Pierini, Michela, additional, Quattrini, Irene, additional, Carretta, Elisa, additional, Manara, Maria Cristina, additional, Pasello, Michela, additional, Frega, Giorgio, additional, Paioli, Anna, additional, Longhi, Alessandra, additional, Cesari, Marilena, additional, Hakim, Rossella, additional, Ibrahim, Toni, additional, Campanacci, Laura, additional, Staals, Eric Lodewijk, additional, Donati, Davide Maria, additional, Benassi, Maria Serena, additional, Scotlandi, Katia, additional, and Ferrari, Stefano, additional

Published
2022
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14. Immunotherapy in Pancreatic Cancer: Why Do We Keep Failing? A Focus on Tumor Immune Microenvironment, Predictive Biomarkers and Treatment Outcomes

Author

Di Federico, Alessandro, primary, Mosca, Mirta, additional, Pagani, Rachele, additional, Carloni, Riccardo, additional, Frega, Giorgio, additional, De Giglio, Andrea, additional, Rizzo, Alessandro, additional, Ricci, Dalia, additional, Tavolari, Simona, additional, Di Marco, Mariacristina, additional, Palloni, Andrea, additional, and Brandi, Giovanni, additional

Published
2022
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18. Hacking Pancreatic Cancer: Present and Future of Personalized Medicine

Author

Di Federico, Alessandro, primary, Tateo, Valentina, additional, Parisi, Claudia, additional, Formica, Francesca, additional, Carloni, Riccardo, additional, Frega, Giorgio, additional, Rizzo, Alessandro, additional, Ricci, Dalia, additional, Di Marco, Mariacristina, additional, Palloni, Andrea, additional, and Brandi, Giovanni, additional

Published
2021
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19. Caloric Restriction Mimetics, Autophagy, and Anticancer Immunosurveillance. ���The bacterial metabolite prodigiosin inhibits autophagy and suppresses antitumor immunity. Results from a fluorescent biosensor-based screening of bacterial metabolites���

Author

Frega, Giorgio <1986> and Brandi, Giovanni

Subjects
MED/06 Oncologia medica
Abstract

Nutrition plays a crucial role in the development and progression of different types of cancer. Dietary components, as well as gut microbiota-derived factors, can exert metabolic and immunomodulatory functions on the host, both locally and systemically. Recent studies highlighted the role of specific gut microbes as predictors of response to immunotherapy. Autophagy has a key function in the elicitation of an immune in response to anticancer therapy. Here, we conducted an automatized fluorescent biosensor-based screening to identify autophagy modulators from a chemical library of host- and bacteria-derived metabolites and found prodigiosin, a red pigment produced by Serratia marcescens, as a potent inducer of LC3 dots in GFP-LC3 biosensor cells. Further autophagic flux analysis in RFP-GFP-LC3 tandem reporter cells and a GFP-Q74 Huntington’s disease model revealed that prodigiosin acts as an inhibitor of autophagic flux. Consistent with the described immunosuppressive role of prodigiosin, our in vivo experiment in BALB/c mice transplanted with syngeneic colon cancers suggest that prodigiosin impairs the activity of anti-PD1 immunotherapy.

Published
2021
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20. Caloric Restriction Mimetics, Autophagy, and Anticancer Immunosurveillance. “The bacterial metabolite prodigiosin inhibits autophagy and suppresses antitumor immunity. Results from a fluorescent biosensor-based screening of bacterial metabolites”

Author

Brandi, Giovanni, Frega, Giorgio <1986>, Brandi, Giovanni, and Frega, Giorgio <1986>

Abstract

Nutrition plays a crucial role in the development and progression of different types of cancer. Dietary components, as well as gut microbiota-derived factors, can exert metabolic and immunomodulatory functions on the host, both locally and systemically. Recent studies highlighted the role of specific gut microbes as predictors of response to immunotherapy. Autophagy has a key function in the elicitation of an immune in response to anticancer therapy. Here, we conducted an automatized fluorescent biosensor-based screening to identify autophagy modulators from a chemical library of host- and bacteria-derived metabolites and found prodigiosin, a red pigment produced by Serratia marcescens, as a potent inducer of LC3 dots in GFP-LC3 biosensor cells. Further autophagic flux analysis in RFP-GFP-LC3 tandem reporter cells and a GFP-Q74 Huntington’s disease model revealed that prodigiosin acts as an inhibitor of autophagic flux. Consistent with the described immunosuppressive role of prodigiosin, our in vivo experiment in BALB/c mice transplanted with syngeneic colon cancers suggest that prodigiosin impairs the activity of anti-PD1 immunotherapy.

Published
2021

23. Second-line Treatment in Advanced Biliary Tract Cancer: Today and Tomorrow

Author

RIZZO, ALESSANDRO, primary, RICCI, ANGELA DALIA, additional, TOBER, NASTASSJA, additional, NIGRO, MARIA CONCETTA, additional, MOSCA, MIRTA, additional, PALLONI, ANDREA, additional, ABBATI, FRANCESCA, additional, FREGA, GIORGIO, additional, DE LORENZO, STEFANIA, additional, TAVOLARI, SIMONA, additional, and BRANDI, GIOVANNI, additional

Published
2020
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24. Percutaneous radiofrequency ablation in intrahepatic cholangiocarcinoma: a retrospective single-center experience

Author

Brandi, Giovanni, primary, Rizzo, Alessandro, additional, Dall’Olio, Filippo Gustavo, additional, Felicani, Cristina, additional, Ercolani, Giorgio, additional, Cescon, Matteo, additional, Frega, Giorgio, additional, Tavolari, Simona, additional, Palloni, Andrea, additional, De Lorenzo, Stefania, additional, Abbati, Francesca, additional, Mollica, Veronica, additional, Ricci, Angela Dalia, additional, and Serra, Carla, additional

Published
2020
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26. The (Eternal) Debate on Microwave Ablation Versus Radiofrequency Ablation in BCLC-A Hepatocellular Carcinoma

Author

RICCI, ANGELA DALIA, primary, RIZZO, ALESSANDRO, additional, BONUCCI, CHIARA, additional, TAVOLARI, SIMONA, additional, PALLONI, ANDREA, additional, FREGA, GIORGIO, additional, MOLLICA, VERONICA, additional, TOBER, NASTASSJA, additional, MAZZOTTA, ELENA, additional, FELICANI, CRISTINA, additional, SERRA, CARLA, additional, and BRANDI, GIOVANNI, additional

Published
2020
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29. How to Choose Between Percutaneous Transhepatic and Endoscopic Biliary Drainage in Malignant Obstructive Jaundice: An Updated Systematic Review and Meta-analysis

Author

RIZZO, ALESSANDRO, primary, RICCI, ANGELA DALIA, additional, FREGA, GIORGIO, additional, PALLONI, ANDREA, additional, DE LORENZO, STEFANIA, additional, ABBATI, FRANCESCA, additional, MOLLICA, VERONICA, additional, TAVOLARI, SIMONA, additional, DI MARCO, MARIACRISTINA, additional, and BRANDI, GIOVANNI, additional

Published
2020
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30. BAP1 in solid tumors

Author

Di Nunno, Vincenzo, primary, Frega, Giorgio, additional, Santoni, Matteo, additional, Gatto, Lidia, additional, Fiorentino, Michelangelo, additional, Montironi, Rodolfo, additional, Battelli, Nicola, additional, Brandi, Giovanni, additional, and Massari, Francesco, additional

Published
2019
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32. Adjuvant treatment in biliary tract cancer

Author

Palloni, Andrea, primary, Frega, Giorgio, additional, De Lorenzo, Stefania, additional, Rizzo, Alessandro, additional, Abbati, Francesca, additional, Deserti, Marzia, additional, Tavolari, Simona, additional, and Brandi, Giovanni, additional

Published
2019
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34. The role of metronomic capecitabine for treatment of recurrent hepatocellular carcinoma after liver transplantation

Author

Ravaioli, Matteo, primary, Cucchetti, Alessandro, additional, Pinna, Antonio Daniele, additional, De Pace, Vanessa, additional, Neri, Flavia, additional, Barbera, Maria Aurelia, additional, Maroni, Lorenzo, additional, Frega, Giorgio, additional, Palloni, Andrea, additional, De Lorenzo, Stefania, additional, Ripoli, Maria Cristina, additional, Pantaleo, Maria Abbondanza, additional, Cescon, Matteo, additional, Del Gaudio, Massimo, additional, and Brandi, Giovanni, additional

Published
2017
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39. In Reply

Author

Brandi, Giovanni, primary, Deserti, Marzia, additional, Vasuri, Francesco, additional, Farioli, Andrea, additional, Degiovanni, Alessio, additional, Palloni, Andrea, additional, Frega, Giorgio, additional, Barbera, Maria A., additional, Lorenzo, Stefania, additional, Garajova, Ingrid, additional, Di Marco, Mariacristina, additional, Pinna, Antonio D., additional, Cescon, Matteo, additional, Cucchetti, Alessandro, additional, Ercolani, Giorgio, additional, D'Errico‐Grigioni, Antonietta, additional, Pantaleo, Maria A., additional, Biasco, Guido, additional, Tavolari, Simona, additional, Brandi, Giovanni, additional, Aprile, Giuseppe, additional, Cereda, Stefano, additional, Fornaro, Lorenzo, additional, Leone, Francesco, additional, Lonardi, Sara, additional, Santini, Daniele, additional, Silvestris, Nicola, additional, and Vasile, Enrico, additional

Published
2016
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40. Role of MicroRNA in IPMN Lesions.

Author

Palloni, Andrea, Mollica, Veronica, Ferracin, Manuela, Frega, Giorgio, Maggio, Ilaria, Giovannetti, Elisa, Caparello, Chiara, Biasco, Guido, and Garajová, Ingrid

Published
2017

41. Membrane Localization of Human Equilibrative Nucleoside Transporter 1 in Tumor Cells May Predict Response to Adjuvant Gemcitabine in Resected Cholangiocarcinoma Patients.

Author

Brandi, Giovanni, Deserti, Marzia, Vasuri, Francesco, Farioli, Andrea, Degiovanni, Alessio, Palloni, Andrea, Frega, Giorgio, Barbera, Maria A., Lorenzo, Stefania, Garajova, Ingrid, Di Marco, Mariacristina, Pinna, Antonio D., Cescon, Matteo, Cucchetti, Alessandro, Ercolani, Giorgio, D'Errico‐Grigioni, Antonietta, Pantaleo, Maria A., Biasco, Guido, Tavolari, Simona, and Aprile, Guiseppe

Subjects
ANTIMETABOLITES, BIOMARKERS, CONFIDENCE intervals, STATISTICAL correlation, FISHER exact test, IMMUNOHISTOCHEMISTRY, RESEARCH funding, STATISTICAL hypothesis testing, T-test (Statistics), CHOLANGIOCARCINOMA, PROPORTIONAL hazards models, RETROSPECTIVE studies, DATA analysis software, DESCRIPTIVE statistics, KAPLAN-Meier estimator, MANN Whitney U Test
Abstract

Background. The use of gemcitabine as an adjuvant modality for cholangiocarcinoma (CC) is increasing, but limited data are available on predictive biomarkers of response. Human equilibrative nucleoside transporter 1 (hENT-1) is the major transporter involved in gemcitabine intracellular uptake. This study investigated the putative predictive role of hENT-1 localization in tumor cells of CC patients undergoing treatment with adjuvant gemcitabine. Methods. Seventy-one consecutive patients with resected CC receiving adjuvant gemcitabine at our center were retrospectively analyzed by immunohistochemistry for hENT-1 localization in tumor cells. The main outcome measure was disease-free survival (DFS). Hazard ratios (HRs) of relapse and associated 95% confidence intervals (CIs) were obtained from proportional hazards regression models stratified on quintiles of propensity score. Results. Twenty-three (32.4%) cases were negative for hENT-1, 22 (31.0%) were positive in the cytoplasm only, and 26 (36.6%) showed concomitant cytoplasm/membrane staining. Patients with membrane hENT-1 had a longer DFS (HR 0.49, 95% CI 0.24-0.99, p = .046) than those who were negative or positive only in the cytoplasm of tumor cells. Notably, the association between DFS and membrane hENT-1 was dependent on the number of gemcitabine cycles (one to two cycles: HR 0.96, 95% CI0.34-2.68; three to four cycles: HR 0.99,95% CI 0.34-2.90; five to six cycles: HR 0.27, 95% CI 0.10-0.77). Conclusion. hENT-1 localization on tumor cell membrane may predict response to adjuvant gemcitabine in CC patients receiving more than four cycles of chemotherapy. Further prospective randomized trials on larger populations are required to confirm these preliminary results, so that optimal gemcitabine-based chemotherapy may be tailored for CC patients in the adjuvant setting. [ABSTRACT FROM AUTHOR]

Published
2016
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43. Sustained complete response of advanced hepatocellular carcinoma with metronomic capecitabine: a report of three cases

Author

Ingrid Garajová, Michela Venturi, Giovanni Brandi, Rita Golfieri, Andrea Palloni, Francesca Garuti, Francesca Abbati, Maria Abbondanza Pantaleo, Gioconda Saccoccio, Giorgio Frega, Stefania De Lorenzo, Maria Aurelia Barbera, Brandi, Giovanni, Venturi, Michela, De Lorenzo, Stefania, Garuti, Francesca, Frega, Giorgio, Palloni, Andrea, Garajovà, Ingrid, Abbati, Francesca, Saccoccio, Gioconda, Golfieri, Rita, Pantaleo, Maria Abbondanza, and Barbera, Maria Aurelia

Subjects
Oncology, Sorafenib, Male, medicine.medical_specialty, Antimetabolites, Antineoplastic, Cancer Research, Carcinoma, Hepatocellular, Hepatocellular carcinoma, Case Report, lcsh:RC254-282, Metronomic capecitabine, Capecitabine, 03 medical and health sciences, 0302 clinical medicine, First line therapy, Internal medicine, medicine, Humans, Protein Kinase Inhibitors, neoplasms, Complete response, Aged, Aged, 80 and over, business.industry, Liver Neoplasms, Remission Induction, Treatment options, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, digestive system diseases, Angiogenesis inhibitor, Treatment Outcome, Liver, 030220 oncology & carcinogenesis, Administration, Metronomic, 030211 gastroenterology & hepatology, Previously treated, business, medicine.drug
Abstract

Background Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related death. Sorafenib, a multitarget angiogenesis inhibitor, is an approved frontline treatment for advanced HCC in Western countries, although a complete response (CR) to treatment is infrequently reported. Capecitabine, an oral fluoropyrimidine, has been shown to be effect in both treatment-naïve patients and those previously treated with sorafenib. To date, however, only one case of sustained CR to metronomic capecitabine has been reported. Case presentation We describe three cases of advanced HCC treated with metronomic capecitabine where a CR was obtained. In the first case, capecitabine was administered as first line therapy; in the second case, capecitabine was used after intolerance to sorafenib; while in the third case, capecitabine was administered after sorafenib failure. Conclusion Capecitabine is a potentially important treatment option for patients with advanced HCC and may even represent a cure in certain cases.

Published
2018
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44. The role of metronomic capecitabine for treatment of recurrent hepatocellular carcinoma after liver transplantation

Author

Matteo Cescon, Stefania De Lorenzo, Andrea Palloni, Vanessa De Pace, Giovanni Brandi, Flavia Neri, Maria Abbondanza Pantaleo, Alessandro Cucchetti, Massimo Del Gaudio, Lorenzo Maroni, Maria Cristina Ripoli, Matteo Ravaioli, Antonio Daniele Pinna, Maria Aurelia Barbera, Giorgio Frega, Ravaioli, Matteo, Cucchetti, Alessandro, Pinna, Antonio Daniele, De Pace, Vanessa, Neri, Flavia, Barbera, Maria Aurelia, Maroni, Lorenzo, Frega, Giorgio, Palloni, Andrea, De Lorenzo, Stefania, Ripoli, Maria Cristina, Pantaleo, Maria Abbondanza, Cescon, Matteo, Del Gaudio, Massimo, and Brandi, Giovanni

Subjects
Adult, Male, Oncology, Sorafenib, Antimetabolites, Antineoplastic, medicine.medical_specialty, Carcinoma, Hepatocellular, medicine.medical_treatment, lcsh:Medicine, Liver transplantation, Article, Capecitabine, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Carcinoma, Humans, Neoplasm Invasiveness, hepatocellular carcinoma,liver transplantation, capecitabine, lcsh:Science, Survival analysis, Aged, Neoplasm Staging, Univariate analysis, Multidisciplinary, business.industry, Liver Neoplasms, lcsh:R, Middle Aged, medicine.disease, Survival Analysis, Recurrent Hepatocellular Carcinoma, digestive system diseases, Liver Transplantation, Treatment Outcome, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Administration, Metronomic, Female, 030211 gastroenterology & hepatology, lcsh:Q, Neoplasm Recurrence, Local, business, medicine.drug
Abstract

The management of recurrent hepatocellular carcinoma untreatable with surgical options is based on systemic therapy with sorafenib. Due to the high rates of adverse events connected to the therapy with sorafenib, metronomic capecitabine seems a promising strategy for these patients. We analyzed the data of 38 patients with hepatocellular carcinoma recurrent after liver transplantation performed at our center. We compared the outcome of 17 patients receiving metronomic capecitabine versus 20 patients experiencing best supportive care and versus the data of the literature about treatment with sorafenib. In the group treated with metronomic capecitabine we observed an increased survival after tumor recurrence at the univariate and multivariate analysis compared to the group of best supportive care (median 22 months vs. 7 months, p

Published
2017
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45. Antitumoral Efficacy of Two Turmeric Extracts According to Different Extraction Methods in Hepatocellular Carcinoma Cell Lines

Author

Marzia Deserti, Giorgio Frega, Marina Naldi, Giovanni Brandi, Simona Tavolari, Deserti, Marzia, Tavolari, Simona, Naldi, Marina, Frega, Giorgio, and Brandi, Giovanni

Subjects
Traditional medicine, Hepatocellular carcinoma, Curcuminoid, Cytotoxicity, 010401 analytical chemistry, Extraction (chemistry), Ethyl acetate, Cancer, Turmeric, Extraction, Hepatic carcinoma, medicine.disease, 030226 pharmacology & pharmacy, 01 natural sciences, 0104 chemical sciences, Rhizome, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, medicine, Extraction methods
Abstract

Curcuminoids, bioactive molecules contained in turmeric, have been reported to exert anticancer effects in several human cancers, including hepatocellular carcinoma (HCC). However, the extraction method can significantly affect the structural characteristics of curcuminoids and their biological properties. On this basis, in the present study we investigated the content of curcuminoids and the anticancer activity of two turmeric powders extracted according two different methodologies: solvent extraction with ethyl acetate vs an ancient Indian extraction method of boiling of rhizomes in water followed by dehydration at the sun. Results obtained showed that extraction with ethyl acetate resulted in a significant recovery of curcuminoids and anticancer activity both in terms of cell cytotoxicity and migration/invasiveness inhibition in HCC cell lines, compared to common Indian practice. Overall these findings suggest that turmeric powders could have different efficacy, depending on the extraction method. This aspect should be taken into account when choosing the best product to be employed in the prevention and treatment of human diseases, including cancer.

Published
2018
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46. Metronomic capecitabine vs. best supportive care in Child-Pugh B hepatocellular carcinoma: A proof of concept

Author

Francesco Tovoli, Ingrid Garajová, Maria Aurelia Barbera, Andrea Palloni, Francesca Garuti, Stefania De Lorenzo, Giovanni Brandi, Giorgio Frega, Alessandro Rizzo, Franco Trevisani, De Lorenzo, Stefania, Tovoli, Francesco, Barbera, Maria Aurelia, Garuti, Francesca, Palloni, Andrea, Frega, Giorgio, Garajovà, Ingrid, Rizzo, Alessandro, Trevisani, Franco, and Brandi, Giovanni

Subjects
0301 basic medicine, Adult, Liver Cirrhosis, Male, medicine.medical_specialty, Carcinoma, Hepatocellular, lcsh:Medicine, Neutropenia, Gastroenterology, Proof of Concept Study, Article, Capecitabine, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Prospective Studies, Adverse effect, lcsh:Science, Propensity Score, Aged, Retrospective Studies, Aged, 80 and over, Multidisciplinary, Performance status, Proportional hazards model, business.industry, Liver Diseases, Confounding, lcsh:R, Liver Neoplasms, Middle Aged, medicine.disease, Survival Rate, 030104 developmental biology, Treatment Outcome, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Propensity score matching, Administration, Metronomic, lcsh:Q, Female, business, medicine.drug
Abstract

There is a relative lack of evidence about systemic treatments in patients with hepatocellular carcinoma (HCC) and moderate liver dysfunction (Child-Pugh B). In this multicenter study we retrospectively analyzed data from Child-Pugh B-HCC patients naïve to systemic therapies, treated with MC or best supportive care (BSC). To reduce the risk of selection bias, an inverse probability of treatment weighting approach was adopted. Propensity score was generated including: extrahepatic spread; macrovascular invasion; performance status, alphafetoprotein > 400 ng/ml, Child- Pugh score [B7 vs. B8–9]. We identified 35 MC-treated patients and 70 controls. Median overall survival was 7.5 [95% CI: 3.733–11.267]in MC-patients and 5.1 months [95% CI: 4.098–6.102] in the BSC group (p = 0.013). In patients treated with MC, median progression-free survival was 4.5 months (95% CI: 2.5–6.5). The univariate unweighted Cox regression showed a 42% reduction in death risk for patients on MC (95%CI: 0.370–0.906; p = 0.017). After weighting for potential confounders, death risk remained essentially unaltered. In the MC group, 12 patients (34.3%) experienced at least one adverse event, the most common of which were: fatigue (17.1%), hand-foot syndrome (8.5%), thrombocytopenia (8.5%), and neutropenia (5.7%). MC seems a safe option for Child-Pugh B-HCC patients. Its potential antitumour activity warrants prospective evaluations.

Published
2018

47. Membrane localization of human equilibrative nucleoside transporter 1 in tumor cells may predict response to adjuvant gemcitabine in resected cholangiocarcinoma patients

Author

Francesco Vasuri, Antonietta D'Errico-Grigioni, Alessandro Cucchetti, Simona Tavolari, Andrea Farioli, Marzia Deserti, Matteo Cescon, G.I.Co. (Gruppo Italiano Colangiocarcinoma), Andrea Palloni, Stefania De Lorenzo, Maria Aurelia Barbera, Guido Biasco, Maria Abbondanza Pantaleo, Antonio Daniele Pinna, Mariacristina Di Marco, Giorgio Ercolani, Giovanni Brandi, Alessio Degiovanni, Giorgio Frega, Ingrid Garajová, Brandi, Giovanni, Deserti, Marzia, Vasuri, Francesco, Farioli, Andrea, Degiovanni, Alessio, Palloni, Andrea, Frega, Giorgio, Barbera, Maria A., De Lorenzo, Stefania, Garajova, Ingrid, Di Marco, Mariacristina, Pinna, Antonio D., Cescon, Matteo, Cucchetti, Alessandro, Ercolani, Giorgio, D’errico-Grigioni, Antonietta, Pantaleo, Maria A., Biasco, Guido, and Tavolari, Simona

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Pathology, Cancer Research, Human equilibrative nucleoside transporter 1, medicine.medical_treatment, Population, Equilibrative nucleoside transporter 1, Cholangiocarcinoma, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, education, Chemotherapy, education.field_of_study, biology, business.industry, Hazard ratio, Gemcitabine, Adjuvant gemcitabine, Predictive biomarkers of response to chemotherapy, 030104 developmental biology, 030220 oncology & carcinogenesis, Concomitant, biology.protein, Immunohistochemistry, Hepatobiliary, business, Adjuvant, medicine.drug
Abstract

Background The use of gemcitabine as an adjuvant modality for cholangiocarcinoma (CC) is increasing, but limited data are available on predictive biomarkers of response. Human equilibrative nucleoside transporter 1 (hENT-1) is the major transporter involved in gemcitabine intracellular uptake. This study investigated the putative predictive role of hENT-1 localization in tumor cells of CC patients undergoing treatment with adjuvant gemcitabine. Methods Seventy-one consecutive patients with resected CC receiving adjuvant gemcitabine at our center were retrospectively analyzed by immunohistochemistry for hENT-1 localization in tumor cells. The main outcome measure was disease-free survival (DFS). Hazard ratios (HRs) of relapse and associated 95% confidence intervals (CIs) were obtained from proportional hazards regression models stratified on quintiles of propensity score. Results Twenty-three (32.4%) cases were negative for hENT-1, 22 (31.0%) were positive in the cytoplasm only, and 26 (36.6%) showed concomitant cytoplasm/membrane staining. Patients with membrane hENT-1 had a longer DFS (HR 0.49, 95% CI 0.24-0.99, p = .046) than those who were negative or positive only in the cytoplasm of tumor cells. Notably, the association between DFS and membrane hENT-1 was dependent on the number of gemcitabine cycles (one to two cycles: HR 0.96, 95% CI 0.34-2.68; three to four cycles: HR 0.99, 95% CI 0.34-2.90; five to six cycles: HR 0.27, 95% CI 0.10-0.77). Conclusion hENT-1 localization on tumor cell membrane may predict response to adjuvant gemcitabine in CC patients receiving more than four cycles of chemotherapy. Further prospective randomized trials on larger populations are required to confirm these preliminary results, so that optimal gemcitabine-based chemotherapy may be tailored for CC patients in the adjuvant setting. Implications for practice Gemcitabine is becoming an increasingly used adjuvant modality in cholangiocarcinoma (CC), but limited data are available on predictive biomarkers of response. In this study, patients receiving more than four cycles of adjuvant gemcitabine and harboring Human equilibrative nucleoside transporter 1 (hENT-1, the major transporter involved in gemcitabine intracellular uptake) on tumor cell membrane had a longer disease-free survival compared with patients negative or positive for hENT-1 only in the cytoplasm of tumor cells. Overall these results may lay the basis for further prospective randomized trials based on a larger population of patients and may prove useful for tailoring appropriate gemcitabine-based chemotherapy for CC patients in the adjuvant setting.

Published
2016

48. In Reply

Author

Giovanni Brandi, Marzia Deserti, Francesco Vasuri, Andrea Farioli, Alessio Degiovanni, Andrea Palloni, Giorgio Frega, Maria A. Barbera, Stefania de Lorenzo, Ingrid Garajova, Mariacristina Di Marco, Antonio D. Pinna, Matteo Cescon, Alessandro Cucchetti, Giorgio Ercolani, Antonietta D’Errico-Grigioni, Maria A. Pantaleo, Guido Biasco, Simona Tavolari, Brandi, Giovanni, Deserti, Marzia, Vasuri, Francesco, Farioli, Andrea, Degiovanni, Alessio, Palloni, Andrea, Frega, Giorgio, Barbera, Maria A, de Lorenzo, Stefania, Garajova, Ingrid, Di Marco, Mariacristina, Pinna, Antonio D, Cescon, Matteo, Cucchetti, Alessandro, Ercolani, Giorgio, D'Errico-Grigioni, Antonietta, Pantaleo, Maria A, Biasco, Guido, and Tavolari, Simona

Subjects
Cholangiocarcinoma, Cancer Research, Bile Ducts, Intrahepatic, Treatment Outcome, Bile Duct Neoplasms, Oncology, Chemotherapy, Adjuvant, Humans, h-ENT 1, Letters to the Editor, Deoxycytidine, Gemcitabine
Abstract

Brandi et al. clarify data about the localization of human equilibrative nucleoside transporter 1 in cancer patients receiving gemcitabine-based chemotherapy. They discuss methodology, differences between antibodies, and recommendations for further study.

Published
2016
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