150 results found
Pinato DJ, Gramenitskaya D, Altmann DM, et al., 2019, Antibiotic therapy and outcome from immune-checkpoint inhibitors, Journal for ImmunoTherapy of Cancer, Vol: 7, ISSN: 2051-1426
Sensitivity to immune checkpoint inhibitor (ICPI) therapy is governed by a complex interplay of tumor and host-related determinants. Epidemiological studies have highlighted that exposure to antibiotic therapy influences the probability of response to ICPI and predict for shorter patient survival across malignancies. Whilst a number of studies have reproducibly documented the detrimental effect of broad-spectrum antibiotics, the immune-biologic mechanisms underlying the association with outcome are poorly understood. Perturbation of the gut microbiota, an increasingly well-characterized factor capable of influencing ICPI-mediated immune reconstitution, has been indicated as a putative mechanism to explain the adverse effects attributed to antibiotic exposure in the context of ICPI therapy. Prospective studies are required to validate antibiotic-mediated gut perturbations as a mechanism of ICPI refractoriness and guide the development of strategies to overcome this barrier to an effective delivery of anti-cancer immunotherapy.
Sanghera C, Teh JJ, Pinato DJ, 2019, The systemic inflammatory response as a source of biomarkers and therapeutic targets in hepatocellular carcinoma, LIVER INTERNATIONAL, Vol: 39, Pages: 2008-2023, ISSN: 1478-3223
Fessas P, Possamai LA, Clark J, et al., 2019, Immunotoxicity from checkpoint inhibitor therapy: clinical features and underlying mechanisms., Immunology, ISSN: 0019-2805
Immune checkpoint inhibition with monoclonal antibodies is becoming increasingly commonplace in cancer medicine, having contributed to a widening of therapeutic options across oncological indications. Disruption of immune tolerance is the key mechanism of action of checkpoint inhibitors and, whilst immune-related adverse events are a typical class effect of these compounds, the relationship between toxicity and response is not fully understood. Awareness and vigilance are paramount in recognising potentially life-threatening toxicities and managing them in a timely manner. In this review article, we provide an overview of the clinical features, pathologic findings and management principles of common immune-related toxicities, attempting to provide mechanistic insight into an increasingly common complication of cancer therapy.
Pinato DJ, Urus H, Newsom-Davis T, et al., 2019, Applicability of routine targeted next-generation sequencing to estimate Tumor Mutational Burden (TMB) in patients treated with immune checkpoint inhibitor therapy., Journal of Immunotherapy, ISSN: 1524-9557
It remains unclear whether targeted next-generation sequencing (tNGS) conveys a reliable estimate of tumor mutational burden (TMB). We sequenced 79 archival samples of immune checkpoint inhibitors (ICPIs) recipients (57% lung cancer, 43% melanoma) using Ion Ampliseq Cancer Hotspot Panel. Employing multiple cutoff values, we verified that TMB by tNGS did not correlate with response or survival following ICPI. We found enrichment of ATM mutations in ICPI-refractory tumors (P=0.01) to correlate with worse survival (4.2 vs. 10 mo, P=0.03). Limited-coverage tNGS delivers an imprecise estimate of patients' TMB but may aid identification of candidate somatic variants of predictive/prognostic significance.
Pinato DJ, Howlett S, Ottaviani D, et al., 2019, Association of Prior Antibiotic Treatment With Survival and Response to Immune Checkpoint Inhibitor Therapy in Patients With Cancer., JAMA Oncol
Importance: Gut dysbiosis impairs response to immune checkpoint inhibitors (ICIs) and can be caused by broad-spectrum antibiotic (ATB) therapy. Objective: To evaluate whether there is an association between ATB therapy administered concurrently (cATB) or prior (pATB) to ICI therapy and overall survival (OS) and treatment response to ICI therapy in patients with cancer treated with ICIs in routine clinical practice. Design, Setting, and Participants: This prospective, multicenter, cohort study conducted at 2 tertiary academic referral centers recruited 196 patients with cancer who received ICI therapy between January 1, 2015, and April 1, 2018, in routine clinical practice rather than clinical trials. Main Outcomes and Measures: Overall survival calculated from the time of ICI therapy commencement and radiologic response to ICI treatment defined using the Response Evaluation Criteria in Solid Tumors (version 1.1), with disease refractory to ICI therapy defined as progressive disease 6 to 8 weeks after the first ICI dose without evidence of pseudoprogression. Results: Among 196 patients (137 men and 59 women; median [range] age, 68 [27-93] years) with non-small cell lung cancer (n = 119), melanoma (n = 38), and other tumor types (n = 39), pATB therapy (HR, 7.4; 95% CI, 4.3-12.8; P < .001), but not cATB therapy (HR, 0.9; 95% CI, 0.5-1.4; P = .76), was associated with worse OS (2 vs 26 months for pATB therapy vs no pATB therapy, respectively) (hazard ratio [HR], 7.4; 95% CI, 4.2-12.9) and a higher likelihood of primary disease refractory to ICI therapy (21 of 26 [81%] vs 66 of 151 [44%], P < .001). Overall survival in patients with non-small cell lung cancer (2.5 vs 26 months, P < .001), melanoma (3.9 vs 14 months, P < .001), and other tumor types (1.1 vs 11, P < .001) was consistently worse in those who received pATBs vs those who
Pinato DJ, 2019, Therapeutic hierarchy in hepatocellular carcinoma: A dispute of evidence versus practice, LIVER INTERNATIONAL, Vol: 39, Pages: 1622-1623, ISSN: 1478-3223
Pinato DJ, Howlett S, Ottaviani D, et al., 2019, Antibiotic treatment prior to immune-checkpoint inhibitor therapy is a tumour-agnostic predictive correlate of response in routine clinical practice, British-Pharmacology-Society Meeting (Pharmacology), Publisher: WILEY, Pages: 1636-1637, ISSN: 0306-5251
Howell J, Atkinson SR, Pinato DJ, et al., 2019, Identification of mutations in circulating cell-free tumour DNA as a biomarker in hepatocellular carcinoma, European Journal of Cancer, Vol: 116, Pages: 56-66, ISSN: 0959-8049
BACKGROUND: Hepatocellular carcinoma (HCC) is increasing globally. Prognostic biomarkers are urgently needed to guide treatment and reduce mortality. Tumour-derived circulating cell-free DNA (ctDNA) is a novel, minimally invasive means of determining genetic alterations in cancer. We evaluate the accuracy of ctDNA as a biomarker in HCC. METHODS: Plasma cell-free DNA, matched germline DNA and HCC tissue DNA were isolated from patients with HCC (n = 51) and liver cirrhosis (n = 10). Targeted, multiplex polymerase chain reaction ultra-deep sequencing was performed using a liver cancer-specific primer panel for genes ARID1A, ARID2, AXIN1, ATM, CTNNB1, HNF1A and TP53. Concordance of mutations in plasma ctDNA and HCC tissue DNA was determined, and associations with clinical outcomes were analysed. RESULTS: Plasma cell-free DNA was detected in all samples. Lower plasma cell-free DNA levels were seen in Barcelona Clinic Liver Cancer (BCLC A compared with BCLC stage B/C/D (median concentration 122.89 ng/mL versus 168.21 ng/mL, p = 0.041). 29 mutations in the eight genes (21 unique mutations) were detected in 18/51 patients (35%), median 1.5 mutations per patient (interquartile range 1-2). Mutations were most frequently detected in ARID1A (11.7%), followed by CTNNB1 (7.8%) and TP53 (7.8%). In patients with matched tissue DNA, all mutations detected in plasma ctDNA detected were confirmed in HCC DNA; however, 71% of patients had mutations identified in HCC tissue DNA that were not detected in matched ctDNA. CONCLUSION: ctDNA is quantifiable across all HCC stages and allows detection of mutations in key driver genes of hepatic carcinogenesis. This study demonstrates high specificity but low sensitivity of plasma ctDNA for detecting mutations in matched HCC tissue.
Bettinger D, Pinato DJ, Schultheiss M, et al., 2019, Stereotactic body radiation therapy as an alternative treatment for patients with hepatocellular carcinoma compared to sorafenib: a propensity score analysis, Liver Cancer, Vol: 8, Pages: 281-294, ISSN: 2235-1795
Background and Aims: Stereotactic body radiation therapy (SBRT) has emerged as a safe and effective treatment for patients with hepatocellular carcinoma (HCC), but its role in patients with advanced HCC is not yet defined. In this study, we aim to assess the efficacy and safety of SBRT in comparison to sorafenib treatment in patients with advanced HCC. Methods: We included 901 patients treated with sorafenib at six tertiary centers in Europe and Asia and 122 patients treated with SBRT from 13 centers in Germany and Switzerland. Medical records were reviewed including laboratory parameters, treatment characteristics and development of adverse events. Propensity score matching was performed to adjust for differences in baseline characteristics. The primary endpoint was overall survival (OS) and progression-free survival. Results: Median OS of SBRT patients was 18.1 (10.3–25.9) months compared to 8.8 (8.2–9.5) in sorafenib patients. After adjusting for different baseline characteristics, the survival benefit for patients treated with SBRT was still preserved with a median OS of 17.0 (10.8–23.2) months compared to 9.6 (8.6–10.7) months in sorafenib patients. SBRT treatment of intrahepatic lesions in patients with extrahepatic metastases was also associated with improved OS compared to patients treated with sorafenib in the same setting (17.0 vs. 10.0 months, p = 0.012), whereas in patients with portal vein thrombosis there was no survival benefit in patients with SBRT. Conclusions: In this retrospective comparative study, SBRT showed superior efficacy in HCC patients compared to patients treated with sorafenib.
Dalla Pria A, Pinato DJ, Bracchi M, et al., 2019, Recent advances in HIV-associated Kaposi sarcoma [version 1; peer review: 2 approved], F1000Research, Vol: 8, ISSN: 2046-1402
Kaposi sarcoma (KS) is a mesenchymal tumour caused by KS-associated herpesvirus and is an AIDS-defining illness. Despite a decline in incidence since the introduction of combination anti-retroviral therapy, KS remains the most common cancer in people living with HIV in sub-Saharan Africa, where it causes significant morbidity and mortality. This review reflects on recent epidemiological data as well as current management, unmet needs and future perspectives in the treatment of HIV-associated KS with particular emphasis on the potential role of immune checkpoint inhibitors.
Pinato DJ, Vallipuram A, Evans J, et al., 2019, Molecular characterization of the tumour microenvironment in neuroendocrine malignancy., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Lachowski D, Cortes E, Rice A, et al., 2019, Matrix stiffness modulates the activity of MMP-9 and TIMP-1 in hepatic stellate cells to perpetuate fibrosis, Scientific Reports, Vol: 9, ISSN: 2045-2322
Liver fibrosis is characterised by a dense and highly cross-linked extracellular matrix (ECM) which promotes progression of diseases such as hepatocellular carcinoma. The fibrotic microenvironment is characterised by an increased stiffness, with rigidity associated with disease progression. External stiffness is known to promote hepatic stellate cell (HSC) activation through mechanotransduction, leading to increased secretion of ECM components. HSCs are key effector cells which maintain the composition of the ECM in health and disease, not only by regulating secretion of ECM proteins such as collagen, but also ECM-degrading enzymes called matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). Uninhibited MMPs degrade ECM proteins to reduce external rigidity. Using fibronectin-coated polyacrylamide gels to alter substrate rigidity without altering ligand density, we show that fibrotic rigidities downregulate MMP-9 expression and secretion, and also upregulate secretion of TIMP-1, though not its expression. Using tissue immunofluorescence studies, we also report that the expression of MMP-9 is significantly decreased in activated HSCs in fibrotic tissues associated with hepatocellular carcinoma. This suggests the presence of a mechanical network that allows HSCs to maintain a fibrotic ECM, with external rigidity providing feedback which affects MMP-9 and TIMP-1 secretion, which may become dysregulated in fibrosis.
Pinato D, Mauri F, Spina P, et al., 2019, Clinical implications of heterogeniety in PD-L1 immuno-histochemical detection in hepatocellular carcinoma: the Blueprint-HCC study, British Journal of Cancer, Vol: 120, Pages: 1033-1036, ISSN: 0007-0920
Programmed cell death ligand-1 immunohistochemical detection (PD-L1 IHC) is a putative predictor of response to PD-1/PD-L1-targeted checkpoint inhibitors. However, there is no gold standard assay in hepatocellular carcinoma (HCC). We evaluated 5 PD-L1 IHC assay platforms (E1LN3, 28-8, 22c3, SP263 and SP142) in 100 HCCs reporting PD-L1 expression in malignant (M) and tumour-infiltrating immune cells (TICs) and non-tumorous cirrhotic tissues (NTICs). We found substantial inter-assay heterogeneity in detecting PD-L1 expression in M (R2 = 0.080–0.921), TICs (Cohen’s κ = 0.175–0.396) and NTICs (κ = 0.004–0.505). Such diversity may impact on the reliability and reproducibility of PD-L1 IHC assays as a predictor of response to immune checkpoint inhibitors.
Flynn MJ, Sayed AA, Sharma R, et al., 2019, Challenges and opportunities in the clinical development of immune checkpoint inhibitors for hepatocellular carcinoma, Hepatology, Vol: 69, Pages: 2258-2270, ISSN: 0270-9139
After a decade of stagnation in drug development, therapeutic reversal of immune-exhaustion with immune checkpoint inhibitors (ICPI) has been shown to be effective in advanced hepatocellular carcinoma (HCC). The clinical development of novel ICPIs continues at a rapid pace, with more than 50 clinical trials of immunotherapeutic agents registered as of May 2018 for this indication. The development of ICPI is particularly challenging in patients with HCC, a population with unique features which impact on safety and efficacy of immune-modulating therapies. In this review, we discuss the biologic foundations supporting the development of ICPI across the advancing stages of HCC, focusing in particular on the proposal of a rational positioning of ICPI across the various Barcelona-Clinic Liver Cancer stages of the disease. Translational studies should guide adequate prioritisation of those therapeutic agents and combination strategies which are most likely to achieve patient benefit based on solid mechanistic and clinical justifications.
Black JRM, Goldin RD, Foxton M, et al., 2019, PD-L1 expressing granulomatous reaction as an on-target mechanism of steroid-refractory immune hepatotoxicity, IMMUNOTHERAPY, Vol: 11, Pages: 585-590, ISSN: 1750-743X
Gkika E, Brunner T, Abbasi-Senger N, et al., 2019, SBRT compared to sorafenib in locally advanced hepatocellular carcinoma: a propensity score analysis, 38th Annual Meeting of the European-Society-for-Radiotherapy-and-Oncology (ESTRO), Publisher: ELSEVIER IRELAND LTD, Pages: S423-S423, ISSN: 0167-8140
Hajiev S, Pinato DJ, Ramaswami R, et al., 2019, Sorafenib starting dose impacts on survival in the elderly population with hepatocellular cancer, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER, Pages: E621-E621, ISSN: 0168-8278
Evans J, Pinato D, Ward C, et al., 2019, Longitudinal monitoring of cell-free DNA predicts for transarterial chemo-embolization failure in hepatocellular carcinoma, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER, Pages: E362-E362, ISSN: 0168-8278
Pinato DJ, Goldin RD, Mineo T, et al., 2019, Trans-arterial chemoembolization as a loco-regional inducer of immunogenic cell death in hepatocellular carcinoma, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER, Pages: E374-E375, ISSN: 0168-8278
Gudd CLC, Liu T, Triantafyllou E, et al., 2019, Elevated tissue homing of monocytes and increased cytotoxic activity of CD8+T-cells in immune checkpoint inhibitor-induced hepatitis, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER, Pages: E19-E20, ISSN: 0168-8278
Samani A, Pinato DJ, Bettinger D, et al., 2019, Sorafenib use in patients with HCC on a background of non-alcoholic fatty liver disease, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER, Pages: E621-E621, ISSN: 0168-8278
Pinato D, Brown MW, Trousil S, et al., 2019, Integrated analysis of multiple receptor tyrosine kinases identifies Axl as a therapeutic target and mediator of resistance to sorafenib in hepatocellular carcinoma., British Journal of Cancer, Vol: 120, Pages: 512-521, ISSN: 0007-0920
Background: Aberrant activation of Axl is implicated in the progression of HCC. We explored biologic significance and preclinical efficacy of Axl inhibition as a therapeutic strategy in sorafenib-naïve and resistant HCC.Methods: We evaluated Axl expression in sorafenib-naïve and resistant (SR) clones of epithelial (HuH7) and mesenchymal origin (SKHep-1) using antibody arrays and confirmed tissue expression. We tested the effect of Axl inhibition with RNA-interference and pharmacologically with R428 on a number of phenotypic assays. Results: Axl mRNA overexpression in cell lines (n=28) and RNA-seq tissue datasets (n=373) correlated with epithelial-to-mesenchymal transition (EMT). Axl was overexpressed in HCC compared to cirrhosis and normal liver. We confirmed sorafenib-resistance to be associated with EMT and enhanced motility in both HuH7-SR and SKHep-1-SR cells documenting a 4-fold increase in Axl phosphorylation as an adaptive feature of chronic sorafenib treatment in SKHep-1-SR cells. Axl inhibition reduced motility and enhanced sensitivity to sorafenib in SKHep-1SR cells. In patients treated with sorafenib (n=40) circulating Axl levels correlated with shorter survival.Conclusions: Suppression of Axl-dependent signaling influences the transformed phenotype in HCC cells and contributes to adaptive resistance to sorafenib, providing a pre-clinical rationale for the development of Axl inhibitors as a measure to overcome sorafenib resistance.
Pinato DJ, Allara E, Chen T-Y, et al., 2019, Influence of HIV Infection on the natural history of hepatocellular carcinoma: results from a global multicohort study, Journal of Clinical Oncology, Vol: 37, Pages: 296-304, ISSN: 0732-183X
PURPOSEConflicting evidence indicates that HIV seropositivity may influence the outcome of patients with hepatocellular carcinoma (HCC), a leading cause of mortality in people with HIV. We aimed to verify whether HIV affected the overall survival (OS) of patients with HCC, independent of treatment and geographic origin.PATIENTS AND METHODSWe designed an international multicohort study of patients with HCC accrued from four continents who did not receive any anticancer treatment. We estimated the effect of HIV seropositivity on patients’ OS while accounting for common prognostic factors and demographic characteristics in uni- and multivariable models.RESULTSA total of 1,588 patients were recruited, 132 of whom were HIV positive. Most patients clustered within Barcelona Clinic Liver Cancer (BCLC) C or D criteria (n = 1,168 [74%]) and Child-Turcotte-Pugh (CTP) class B (median score, 7; interquartile range [IQR], 3). At HCC diagnosis, the majority of patients who were HIV-positive (n = 65 [64%]) had been on antiretrovirals for a median duration of 8.3 years (IQR, 8.59 years) and had median CD4+ cell counts of 256 (IQR, 284) with undetectable HIV RNA (n = 68 [52%]). OS decreased significantly throughout BCLC stages 0 to D (16, 12, 7.5, 3.1, and 3 months, respectively; P < .001). Median OS of patients who were HIV-positive was one half that of their HIV-uninfected counterparts (2.2 months [bootstrap 95% CI, 1.2 to 3.1 months] v 4.1 months [95% CI, 3.6 to 4.4 months]). In adjusted analyses, HIV seropositivity increased the hazard of death by 24% (P = .0333) independent of BCLC (P < .0001), CTP (P < .0001), α-fetoprotein (P < .0001), geographical origin (P < .0001), and male sex (P = .0016). Predictors of worse OS in patients who were HIV-positive included CTP (P = .0071) and α-fetoprotein (P < .0001).CONCLUSIONDespite adequate antiretroviral treatment, HIV seropositivity is associated with decreased survival in HCC, independent of stage
Cortes E, Lachowski D, Rice A, et al., 2019, Retinoic acid receptor-β is downregulated in hepatocellular carcinoma and cirrhosis and its expression inhibits myosin-driven activation and durotaxis in hepatic stellate cells, Hepatology, Vol: 69, Pages: 785-802, ISSN: 0270-9139
Hepatic stellate cells (HSCs) are essential perisinusoidal cells in the healthy and diseased liver. HSCs modulate extracellular matrix (ECM) homeostasis when quiescent, but in liver fibrosis, HSCs become activated and promote excess deposition of ECM molecules and tissue stiffening via force generation and mechanosensing. In hepatocellular carcinoma (HCC), activated HSCs infiltrate the stroma and migrate to the tumor core to facilitate paracrine signalling with cancer cells. Since the function of HSCs is known to be modulated by retinoids, we investigated the expression profile of retinoic acid receptor beta (RAR-β) in cirrhotic and HCC patients, as well as the effects of RAR-β activation in HSCs. We found that RAR-β expression is significantly reduced in cirrhotic and HCC tissues. Using a comprehensive set of biophysical methods combined with cellular and molecular biology, we have elucidated the biomechanical mechanism by which all trans-retinoic acid (ATRA) promotes HSC deactivation via RAR-β-dependent transcriptional downregulation of myosin light chain 2 (MLC-2) expression. Furthermore, this also abrogated mechanically driven migration towards stiffer substrates. CONCLUSION: Targeting mechanotransduction in HSCs at the transcriptional level may offer new therapeutic options for a range of liver diseases. This article is protected by copyright. All rights reserved.
Bettinger D, Pinato DJ, Schultheiss M, 2019, Stereotactic Body Radiation Therapy as an Alternative Treatment for Patients with Hepatocellular Carcinoma Compared to Sorafenib: A Propensity Score Analysis (vol 8, pg 281, 2019), LIVER CANCER, Vol: 8, Pages: 295-295, ISSN: 2235-1795
Tan T, Shen L, Hajiev S, et al., 2018, Development and external international validation of a therapy-independent HCC survival prediction score from a cohort of 1270 patients, Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) / Liver Meeting, Publisher: Wiley, Pages: 551A-551A, ISSN: 0270-9139
Pinato DJ, Kythreotou A, Mauri FA, et al., 2018, Functional immune characterization of HIV-associated non-small-cell lung cancer, Annals of Oncology, Vol: 29, Pages: 1486-1488, ISSN: 0923-7534
Pinato DJ, 2018, Circulating-free tumour DNA and the promise of disease phenotyping in hepatocellular carcinoma, Oncogene, Vol: 37, Pages: 4635-4638, ISSN: 0950-9232
Pinato DJ, 2018, Breaking Kuhn's paradigm in advanced hepatocellular carcinoma, Hepatology, Vol: 67, Pages: 1663-1665, ISSN: 0270-9139
Pinato DJ, Kaplan DE, Yen C, et al., 2018, Risk-stratified management of advanced hepatocellular carcinoma (HCC), International Liver Congress (ILC), Publisher: ELSEVIER SCIENCE BV, Pages: S196-S196, ISSN: 0168-8278
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