Publications
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Biello F, Martini V, Branni C, et al., 2021, HEME catabolism in peripheral monocytes and response to immune checkpoint inhibitors in advanced lung cancer, Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: ELSEVIER, Pages: S1218-S1218, ISSN: 0923-7534
Cortellini A, Roldan E, Carmona Garcia MC, et al., 2021, Prevalence and impact of COVID-19 sequelae on treatment pathways and survival of cancer patients who recovered from SARS-CoV-2 infection, Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: ELSEVIER, Pages: S1130-S1130, ISSN: 0923-7534
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- Citations: 1
Pous A, Felip E, Etxaniz Ulazia O, et al., 2021, SERONCOVID: Seroconversion in solid-tumor cancer patients (p) after COVID-19 diagnosis, Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: ELSEVIER, Pages: S1145-S1145, ISSN: 0923-7534
Cortellini A, Mallardo D, Cleary S, et al., 2021, Diabetes therapy burden as proxy of impairment of immune checkpoint inhibitors efficacy, Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: ELSEVIER, Pages: S834-S834, ISSN: 0923-7534
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- Citations: 1
D'Alessio A, Rimassa L, Cortellini A, et al., 2021, PD-1 Blockade for Hepatocellular Carcinoma: Current Research and Future Prospects, JOURNAL OF HEPATOCELLULAR CARCINOMA, Vol: 8, Pages: 887-897
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- Citations: 12
Pinato DJ, Patel M, Lambertini M, et al., 2021, Time-dependent improvement in the clinical outcomes from COVID-19 in cancer patients: An updated analysis of the OnCovid registry, Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: ELSEVIER, Pages: S1132-S1132, ISSN: 0923-7534
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- Citations: 1
Aboagye E, Sharma R, Inglese M, et al., 2020, Monitoring response to transarterial chemoembolization in hepatocellular carcinoma using 18F-Fluorothymidine Positron Emission Tomography, The Journal of Nuclear Medicine, Vol: 61, Pages: 1743-1748, ISSN: 0161-5505
Accurate disease monitoring is essential following transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) due to potential for profound adverse event and large variation in survival outcome. Post-treatment changes on conventional imaging can confound determination of residual/recurrent disease, magnifying the clinical challenge. Based on increased expression of thymidylate synthase (TYMS), thymidine kinase-1 (TK-1) and SLC29A1 (Equilibrative nucleoside transporter 1, ENT1) in HCC compared with liver tissue, we conducted a proof of concept study evaluating the efficacy of 18F-fluorothymidine (18F-FLT)-PET to assess response to TACE. As previous PET studies in HCC have been hampered by high background liver signal, we investigated if a temporal-intensity voxel-clustering (“Kinetic Spatial Filtering”) (KSF) improved lesion detection. Methods: A tissue microarray (TMA) was built from 36 HCC samples and matched surrounding cirrhotic tissue and was stained for thymidine kinase-1 (TK-1). A prospective study was conducted; eighteen patients with a diagnosis of HCC by American Association for the Study of Liver Diseases criteria (AALSD) who were eligible to treatment with TACE were enrolled. Patients underwent baseline conventional imaging and dynamic 18F-FLT-PET/KSF followed by TACE. Repeat imaging was performed 6-8 weeks post TACE. PET parameters were compared with modified-Response Evaluation in Solid Tumours (mRECIST) enhancement-based criteria. Results: Cancer Genome Atlas analysis revealed increased RNA expression of TYMS, TK-1 and SLC29A1 in HCC. TK-1 protein expression was significantly higher in HCC (p<0.05). The sensitivity of 18F-FLT-PET for baseline HCC detection was 73% (SUVmax of 9.7 ± 3.0; tumour to liver ratio of 1.2 ± 0.3). Application of KSF did not improve lesion detection. Lesion response following TACE by mRECIST criteria was 58% (14 patients with 24 lesions). A 30% reduction in mean 18F-FLT-PET uptake was o
Personeni N, Lleo A, Pressiani T, et al., 2020, Biliary tract cancers: molecular heterogeneity and new treatment options, Cancers, Vol: 12, Pages: 1-17, ISSN: 2072-6694
Most patients with biliary tract cancer (BTC) are diagnosed with advanced disease, relapse rates are high in those undergoing surgery and prognosis remains poor, while the incidence is increasing. Treatment options are limited, and chemotherapy is still the standard of care in both adjuvant and advanced disease setting. In recent years, different subtypes of BTC have been defined depending on the anatomical location and genetic and/or epigenetic aberrations. Especially for intrahepatic cholangiocarcinoma (iCCA) novel therapeutic targets have been identified, including fibroblast growth factor receptor 2 gene fusions and isocitrate dehydrogenase 1 and 2 mutations, with molecularly targeted agents having shown evidence of activity in this subgroup of patients. Additionally, other pathways are being evaluated in both iCCA and other subtypes of BTC, alongside targeting of the immune microenvironment. The growing knowledge of BTC biology and molecular heterogeneity has paved the way for the development of new therapeutic approaches that will completely change the treatment paradigm for this disease in the near future. This review provides an overview of the molecular heterogeneity of BTC and summarizes new targets and emerging therapies in development. We also discuss resistance mechanisms, open issues, and future perspectives in the management of BTC.
Dettorre G, Diamantis N, Loizidou A, et al., 2020, The systemic pro-inflammatory response identifies cancer patients with adverse outcomes from SARS-CoV-2 infection, ESMO Asia Virtual Congress, Publisher: ELSEVIER, Pages: S1366-S1366, ISSN: 0923-7534
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- Citations: 4
Pinato DJ, Zambelli A, Bertuzzi A, et al., 2020, Clinical portrait of the SARS-CoV-2 epidemic in European cancer patients, ESMO Asia Virtual Congress, Publisher: ELSEVIER, Pages: S1366-S1366, ISSN: 0923-7534
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- Citations: 2
Naqash AR, Cortellini A, Mi E, et al., 2020, C-REACTIVE PROTEIN (CRP) AS A PROGNOSTIC BIOMARKER IN ADVANCED NON-SMALL CELL LUNG CANCER TREATED WITH IMMUNE CHECKPOINT INHIBITORS. RESULTS FROM A MULTI-CENTER INTERNATIONAL OBSERVATIONAL STUDY, Publisher: BMJ PUBLISHING GROUP, Pages: A18-A18
Dalla Pria A, Forni J, Ma WW, et al., 2020, Do immune checkpoint inhibitors deplete HIV reservoirs <i>in vivo</i>?, Publisher: WILEY, Pages: 31-31, ISSN: 1464-2662
Motedayen Aval L, Pease JE, Sharma R, et al., 2020, Challenges and opportunities in the clinical development of STING agonists for cancer immunotherapy, Journal of Clinical Medicine, Vol: 9, ISSN: 2077-0383
Immune checkpoint inhibitors (ICI) have revolutionised cancer therapy. However, they have been effective in only a small subset of patients and a principal mechanism underlying immune-refractoriness is a 'cold' tumour microenvironment, that is, lack of a T-cell-rich, spontaneously inflamed phenotype. As such, there is a demand to develop strategies to transform the tumour milieu of non-responsive patients to one supporting T-cell-based inflammation. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is a fundamental regulator of innate immune sensing of cancer, with potential to enhance tumour rejection through the induction of a pro-inflammatory response dominated by Type I interferons. Recognition of these positive immune-modulatory properties has rapidly elevated the STING pathway as a putative target for immunotherapy, leading to a myriad of preclinical and clinical studies assessing natural and synthetic cyclic dinucleotides and non-nucleotidyl STING agonists. Despite pre-clinical evidence of efficacy, clinical translation has resulted into disappointingly modest efficacy. Poor pharmacokinetic and physiochemical properties of cyclic dinucleotides are key barriers to the development of STING agonists, most of which require intra-tumoral dosing. Development of systemically administered non-nucleotidyl STING agonists, or conjugation with liposomes, polymers and hydrogels may overcome pharmacokinetic limitations and improve drug delivery. In this review, we summarise the body of evidence supporting a synergistic role of STING agonists with currently approved ICI therapies and discuss whether, despite the numerous obstacles encountered to date, the clinical development of STING agonist as novel anti-cancer therapeutics may still hold the promise of broadening the reach of cancer immunotherapy.
Pinato DJ, Kaseb A, Wang Y, et al., 2020, Impact of corticosteroid therapy on the outcomes of hepatocellular carcinoma treated with immune checkpoint inhibitor therapy, Journal for ImmunoTherapy of Cancer, Vol: 8, Pages: 1-7, ISSN: 2051-1426
The impact of corticosteroid therapy (CT) on efficacy of immune checkpoint inhibitors (ICI) is undefined in hepatocellular carcinoma (HCC). We evaluated whether CT administered at baseline (bCT) or concurrently with ICI (cCT) influences overall (OS), progression-free survival (PFS) and overall response rates (ORR) in 341 patients collected across 3 continents. Of 304 eligible patients, 78 (26%) received >10 mg prednisone equivalent daily either as bCT (n=14, 5%) or cCT (n=64, 21%). Indications for CT included procedure/prophylaxis (n=37, 47%), management of immune-related adverse event (n=27, 35%), cancer-related symptoms (n=8, 10%) or comorbidities (n=6, 8%). Neither overall CT, bCT nor cCT predicted for worse OS, PFS nor ORR in univariable and multivariable analyses (p>0.05). CT for cancer-related indications predicted for shorter PFS (p<0.001) and was associated with refractoriness to ICI (75% vs 33%, p=0.05) compared with cancer-unrelated indications. This is the first study to demonstrate that neither bCT nor cCT influence response and OS following ICI in HCC. Worse outcomes in CT recipients for cancer-related indications appear driven by the poor prognosis associated with symptomatic HCC.
Pinato DJ, 2020, Shifting paradigms in the systemic management of hepatocellular carcinoma, The Lancet Gastroenterology and Hepatology, Vol: 5, Pages: 883-885, ISSN: 2468-1253
Lythgoe M, Julve M, Pinato D, et al., 2020, "Regorafenib therapy for hepatocellular carcinoma in a HIV-1 infected patient: a case report", Liver Cancer International, Vol: 1, Pages: 51-54, ISSN: 2642-3561
Pinato DJ, Kaneko T, Forner A, et al., 2020, Integrated phenotyping of the anti-cancer immune response in HIV-associated hepatocellular carcinoma, EASL: The Digital International Liver Congress, Publisher: Elsevier, Pages: S375-S375, ISSN: 0168-8278
Pinato DJ, Sng C, Wong YNS, et al., 2020, Determinants of mortality from SARS-CoV-2 infection in European cancer patients, ESMO Virtual Congress, Publisher: ELSEVIER, Pages: S995-S995, ISSN: 0923-7534
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- Citations: 1
Soosaipillai GB, Sureda A, Maluquer Artigal C, et al., 2020, Provision of palliative care for patients with cancer and SARSCoV-2 infection, ESMO Virtual Congress, Publisher: ELSEVIER, Pages: S992-S992, ISSN: 0923-7534
Fessas P, Kaseb A, Wang Y, et al., 2020, Post-registration experience of nivolumab in advanced hepatocellular carcinoma: an international study, Journal for ImmunoTherapy of Cancer, Vol: 8, Pages: 1-9, ISSN: 2051-1426
Background: Nivolumab is FDA-approved in sorafenib-experienced, advanced hepatocellular carcinoma (HCC). Post-registration data of treatment in a real-world setting is lacking. Patients and methods: We performed an international, multi-center observational study to confirm safety and efficacy of nivolumab in 233 patients treated outside clinical trials from 8 centers in North America, Europe and Asia. Results: Patients received nivolumab for Barcelona Clinic Liver Cancer (BCLC) stage C (n=191, 92.0%) and Child-Pugh (CP) A (n=158, 67.8%) or B (n=75, 32.2%) HCC as first (n=85, 36.5%) or second to fourth systemic therapy line (n=148, 63.5%). Objective response rate (ORR) was 22.4% and Disease Control Rate (DCR) was 52.1%. Median overall survival (OS) was 12.2 months (95%CI 8.4-16.0) and median progression-free survival (PFS) was 10.1 months (95%CI 6.1-14.2). Treatment-related adverse events (trAE) of Grade >2 occurred in 26 patients (11.2%). Efficacy and safety were similar across CP classes and therapy line. OS was shorter in CP-B than A (7.3 months versus 16.3 months, P<0.001) and in post-first line use (10.4 versus 16.3 months, p=0.05). Achievement of objective response predicted for improved OS (25.4 months versus 13.2 months, p<0.001). Conclusions: This study confirms safety and efficacy of nivolumab in advanced HCC across various lines of therapy and degrees of liver dysfunction. Despite equal ORR and toxicity to nivolumab, patients with CP-B functional class have shorter survival than CP-A patients.
Sarker D, Plummer R, Meyer T, et al., 2020, MTL-CEBPA, a small activating RNA therapeutic upregulating C/EBP-α, in patients with advanced liver cancer: a first-in-human, multicenter, open-label, phase I trial, Clinical Cancer Research, Vol: 26, Pages: 3936-3946, ISSN: 1078-0432
PURPOSE: Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α. PATIENTS AND METHODS: We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design). RESULTS: Thirty-eight participants have been treated across six dose levels (28-160 mg/m2) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment-related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD. CONCLUSIONS: MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC.
Sharma R, Pinato DJ, 2020, Management of Hepatocellular CAncer in the time of SARS-CoV-2, Liver International, Vol: 40, Pages: 1823-1825, ISSN: 1478-3223
As COVID-19 the disease caused by SARS-CoV-2 continues to have a profound impact on global health, there have been a number of guidelines recently published addressing the management of patients with liver disease during the COVID-19 pandemic including the recently published EASL-ESCMID Position Paper, guidelines issued by the International Liver Cancer Association and the American Association for the Study of Liver Diseases (1-3). All publications present a sound discussion regarding the challenges face by both patients and clinicians alike in the management of chronic liver disease in the setting of this ongoing pandemic.
Pinato DJ, 2020, Antibiotic-induced Dysbiosis as a Putative Actionable Driver of Cancer Immunity in Renal Cell Carcinoma, EUROPEAN UROLOGY, Vol: 78, Pages: 207-208, ISSN: 0302-2838
Zhang Z, Tauber C, Hess M, et al., 2020, T cell exhaustion dynamics are linked to clinical outcomes in hepatocellular carcinoma, Publisher: ELSEVIER, Pages: S630-S631, ISSN: 0168-8278
Pinato DJ, Wang Y, Marron TU, et al., 2020, Treatment-related toxicity predicts for improved outcome in patients with hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitor therapy, Publisher: ELSEVIER, Pages: S40-S41, ISSN: 0168-8278
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Wong CN, Dominy K, Mauri F, et al., 2020, Optimisation and qualification of tumour mutational burden (TMB) by targeted next-generation sequencing (TNGS) as a clinically applicable biomarker in hepatocellular carcinoma (HCC), Publisher: ELSEVIER, Pages: S374-S375, ISSN: 0168-8278
Pinato D, Zambelli A, Aguilar-Company J, et al., 2020, Clinical portrait of the SARS-Cov-2 epidemic in European cancer patients, Cancer Discovery, Vol: 10, Pages: 1465-1474, ISSN: 2159-8274
The SARS-Cov-2 pandemic significantly impacted on oncology practice across the globe. There is uncertainty as to the contribution of patients' demographics and oncological features on severity and mortality from Covid-19 and little guidance as to the role of anti-cancer and anti-Covid-19 therapy in this population. In a multi-center study of 890 cancer patients with confirmed Covid-19 we demonstrated a worsening gradient of mortality from breast cancer to haematological malignancies and showed that male gender, older age, and number of co-morbidities identifies a subset of patients with significantly worse mortality rates from Covid-19. Provision of chemotherapy, targeted therapy and immunotherapy did not worsen mortality. Exposure to antimalarials was associated with improved mortality rates independent of baseline prognostic factors. This study highlights the clinical utility of demographic factors for individualized risk-stratification of patients and support further research into emerging anti-Covid-19 therapeutics in SARS-Cov-2 infected cancer patients.
Pinato DJ, Kaneko T, Saeed A, et al., 2020, Immunotherapy in Hepatocellular Cancer Patients with Mild to Severe Liver Dysfunction: Adjunctive Role of the ALBI Grade., Cancers, Vol: 12, ISSN: 2072-6694
Immune checkpoint inhibitors (ICI) have shown positive results in patients with hepatocellular carcinoma (HCC). As liver function contributes to prognosis, its precise assessment is necessary for the safe prescribing and clinical development of ICI in HCC. We tested the accuracy of the albumin-bilirubin (ALBI) grade as an alternative prognostic biomarker to the Child-Turcotte-Pugh (CTP). In a prospectively maintained multi-centre dataset of HCC patients, we assessed safety and efficacy of ICI across varying levels of liver dysfunction described by CTP (A to C) and ALBI grade and evaluated uni- and multi-variable predictors of overall (OS) and post-immunotherapy survival (PIOS). We studied 341 patients treated with programmed-death pathway inhibitors (n = 290, 85%). Pre-treatment ALBI independently predicted for OS, with median OS of 22.5, 9.6, and 4.6 months across grades (p < 0.001). ALBI was superior to CTP in predicting 90-days mortality with area under the curve values of 0.65 (95% CI 0.57-0.74) versus 0.63 (95% CI 0.54-0.72). ALBI grade at ICI cessation independently predicted for PIOS (p < 0.001). Following adjustment for ICI regimen, neither ALBI nor CTP predicted for overall response rates or treatment-emerging adverse events (p > 0.05). ALBI grade identifies a subset of patients with prolonged survival prior to and after ICI therapy, lending itself as an optimal stratifying biomarker to optimise sequencing of systemic therapies in advanced HCC.
Pinato DJ, Lee AJX, Biello F, et al., 2020, Presenting features and early mortality from SARS-CoV-2 infection in cancer patients during the initial stage of the COVID-19 pandemic in Europe, Cancers, Vol: 12, ISSN: 2072-6694
We describe the outcomes in cancer patients during the initial outbreak of the COVID-19 in Europe from the retrospective, multi-center observational OnCovid study. We identified 204 cancer patients from eight centers in the United Kingdom, Italy, and Spain aged > 18 (mean = 69) and diagnosed with COVID-19 between February 26th and April 1st, 2020. A total of 127 (62%) were male, 184 (91%) had a diagnosis of solid malignancy, and 103 (51%) had non-metastatic disease. A total of 161 (79%) had > 1 co-morbidity. A total of 141 (69%) patients had > 1 COVID-19 complication. A total of 36 (19%) were escalated to high-dependency or intensive care. A total of 59 (29%) died, 53 (26%) were discharged, and 92 (45%) were in-hospital survivors. Mortality was higher in patients aged > 65 (36% versus 16%), in those with > 2 co-morbidities (40% versus 18%) and developing > 1 complication from COVID-19 (38% versus 4%, p = 0.004). Multi-variable analyses confirmed age > 65 and > 2 co-morbidities to predict for patient mortality independent of tumor stage, active malignancy, or anticancer therapy. During the early outbreak of SARS-CoV-2 infection in Europe co-morbid burden and advancing age predicted for adverse disease course in cancer patients. The ongoing OnCovid study will allow us to compare risks and outcomes in cancer patients between the initial and later stages of the COVID-19 pandemic.
Han G, Berhane S, Toyoda H, et al., 2020, Prediction of survival among patients receiving transarterial chemoembolization for hepatocellular carcinoma: a response-based approach, Hepatology, Vol: 72, Pages: 198-212, ISSN: 0270-9139
The heterogeneity of intermediate-stage hepatocellular carcinoma (HCC) and the widespread use of transarterial chemoembolization (TACE) outside recommended guidelines have encouraged the development of scoring systems that predict patient survival. The aim of this study was to build and validate statistical models that offer individualized patient survival prediction using response to TACE as a variable. Clinically relevant baseline parameters were collected for 4,621 patients with HCC treated with TACE at 19 centers in 11 countries. In some of the centers, radiological response (as assessed by modified Response Evaluation Criteria in Solid Tumors [mRECIST]) was also accrued. The data set was divided into a training set, an internal validation set, and two external validation sets. A new pre-TACE model ("Pre-TACE-Predict") and a post-TACE model ("Post-TACE-Predict") that included response were built. The performance of the models in predicting overall survival (OS) was compared with existing ones. Median OS was 19.9 months. The factors influencing survival were tumor number and size, alpha-fetoprotein, albumin, bilirubin, vascular invasion, etiology, and response as assessed by mRECIST. The proposed models showed superior predictive accuracy compared to existing models (the HAP score and its various modifications) and allowed for patient stratification into four distinct risk categories whose median OS ranged from 7 months to more than 4 years. Conclusion: A TACE-specific and extensively validated model based on routinely available clinical features and response after first TACE permitted patient-level prognostication.
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