Publications by authors named "Alessandro Rizzo"

130 Publications

Determinants of treatment for first-line immune-based combinations in metastatic renal cell carcinoma: a critical overview of recent evidence.

Immunotherapy 2021 Apr 7. Epub 2021 Apr 7.

Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni - 15, Bologna - Italia.

The last three decades have witnessed a revolution in the therapeutic scenario of metastatic renal cell carcinoma (mRCC), due to the advent of novel agents including tyrosine kinase inhibitors, immune checkpoint inhibitors and the combination of both treatments. These strategies have reported unprecedented response rates, thus improving the clinical outcomes of mRCC patients, and current international guidelines support the use of immune-based combinations as first-line treatment in patients with metastatic disease. However, more data are awaited to help clinicians in the decision-making process. Herein, we provide an overview of recently published results regarding immune-based combinations as first-line treatment in mRCC patients, critically discussing available data that could help in suggesting determinants of treatment in this setting.
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http://dx.doi.org/10.2217/imt-2020-0323DOI Listing
April 2021

Atezolizumab in advanced hepatocellular carcinoma: good things come to those who wait.

Immunotherapy 2021 Apr 6. Epub 2021 Apr 6.

Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni - 15, Bologna, Italia.

Advanced hepatocellular carcinoma (HCC) patients present poor prognosis. However, recent years have seen the advent of several novel treatments in this setting, where the role of immune checkpoint inhibitors has been investigated. Among these, the PD-L1 inhibitor atezolizumab in combination with bevacizumab has reported unprecedented results in treatment-naive patients with unresectable disease, with the recently published IMbrave150 Phase III trial showing the superiority of the combination over sorafenib monotherapy, and after having attended more than a decade of 'stagnation', the HCC medical community has a new standard of care. Herein, we examine the development and the impact of atezolizumab in advanced HCC, summarizing the mechanism of action, pharmacokinetics and recent evidence from Phase I to III clinical trials.
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http://dx.doi.org/10.2217/imt-2021-0026DOI Listing
April 2021

Gene Expression Landscape of SDH-Deficient Gastrointestinal Stromal Tumors.

J Clin Med 2021 Mar 4;10(5). Epub 2021 Mar 4.

Division of Oncology, IRCCS-Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy.

Background: About 20-40% of gastrointestinal stromal tumors (GISTs) lacking KIT/PDGFRA mutations show defects in succinate dehydrogenase (SDH) complex. This study uncovers the gene expression profile (GEP) of SDH-deficient GIST in order to identify new signaling pathways or molecular events actionable for a tailored therapy.

Methods: We analyzed 36 GIST tumor samples, either from formalin-fixed, paraffin-embedded by microarray or from fresh frozen tissue by RNA-seq, retrospectively collected among KIT-mutant and SDH-deficient GISTs. Pathway analysis was performed to highlight enriched and depleted transcriptional signatures. Tumor microenvironment and immune profile were also evaluated.

Results: SDH-deficient GISTs showed a distinct GEP with respect to KIT-mutant GISTs. In particular, SDH-deficient GISTs were characterized by an increased expression of neural markers and by the activation of fibroblast growth factor receptor signaling and several biological pathways related to invasion and tumor progression. Among them, hypoxia and epithelial-to-mesenchymal transition emerged as features shared with SDH-deficient pheochromocytoma/paraganglioma. In addition, the study of immune landscape revealed the depletion of tumor microenvironment and inflammation gene signatures.

Conclusions: This study provides an update of GEP in SDH-deficient GISTs, highlighting differences and similarities compared to KIT-mutant GISTs and to other neoplasm carrying the SDH loss of function. Our findings add a piece of knowledge in SDH-deficient GISTs, shedding light on their putative histology and on the dysregulated biological processes as targets of new therapeutic strategies.
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http://dx.doi.org/10.3390/jcm10051057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961685PMC
March 2021

The evolving landscape of systemic treatment for advanced hepatocellular carcinoma and biliary tract cancer.

Authors:
Alessandro Rizzo

Cancer Treat Res Commun 2021 Mar 23;27:100360. Epub 2021 Mar 23.

Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.ctarc.2021.100360DOI Listing
March 2021

IDH inhibitors in advanced cholangiocarcinoma: Another arrow in the quiver?

Cancer Treat Res Commun 2021 Mar 24;27:100356. Epub 2021 Mar 24.

Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy; Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni, 15, Bologna, Italy.

Cholangiocarcinomas (CCAs) are a heterogenous group of hepatobiliary tumors with poor prognosis and limited therapeutic options. In the last decade, the advent of genomic profiling has led to the identification of several putative actionable aberrations in CCAs, and genomic characterization is playing an increasing role in the management of these malignancies. Thus, a wide number of targetable mutations are currently under investigation, and early studies on this approach in CCAs have been recently presented or published. Among these, isocitrate dehydrogenase (IDH) mutations have been reported in approximately 15-20% of intrahepatic cholangiocarcinoma (iCCA) patients, while these aberrations are considered to be less frequent in perihilar CCA (pCCA), distal CCA (dCCA), and gallbladder cancer. Of note, the recent findings of the ClarIDHy phase III trial add to mounting evidence showing the potential advantages of molecularly targeted therapies in CCA, on the basis of a benefit in previously treated IDH1-mutant patients receiving ivosidenib versus placebo. However, although the results of this trial showed a statistically significant improvement in progression-free survival and overall survival for IDH-mutant CCAs treated with ivosidenib, several questions regarding the real impact of IDH inhibitors in this setting remain open. In this review, we will provide an overview on the biological rationale behind the use of IDH inhibitors in CCA patients and current clinical implications of these molecularly targeted agents. The recently published results of the ClarIDHy - as well as ongoing clinical trials in this setting - are highlighted and critically discussed.
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http://dx.doi.org/10.1016/j.ctarc.2021.100356DOI Listing
March 2021

FGFR inhibitors in elderly patients with advanced biliary tract cancer: an unsolved issue.

Expert Rev Gastroenterol Hepatol 2021 Apr 5:1-8. Epub 2021 Apr 5.

Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy.

Despite recent advances in the understanding of the molecular landscape of biliary tract cancer (BTC), advanced disease continues to carry a poor prognosis, and the benefit from systemic treatments remains modest. However, BTCs have emerged as malignancies harboring specific potentially druggable aberrations, and thus, several molecularly targeted treatments have been recently tested. Among these, fibroblast growth factor receptor (FGFR) inhibitors have shown interesting results in previously treated BTC patients with advanced disease In this review, we aimed to provide an overview of available evidence on FGFR inhibitors in elderly patients with metastatic BTC, especially focusing on subgroup analyses of recently published trials exploring this novel therapeutic approach in these aggressive malignancies. The FGFR1, FGFR2, and FGFR3 inhibitor pemigatinib has been recently approved by the United States Food and Drug Administration (FDA) in metastatic BTCs harboring FGFR2 fusion or other rearrangement. However, few data are available regarding the use of FGFR inhibitors in elderly BTCs, a patient population that remains seriously under-represented in clinical trials.
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http://dx.doi.org/10.1080/17474124.2021.1911646DOI Listing
April 2021

High-Resolution Agent-Based Modeling of COVID-19 Spreading in a Small Town.

Adv Theory Simul 2021 Mar 18;4(3):2000277. Epub 2021 Jan 18.

Department of Mechanical and Aerospace Engineering Tandon School of Engineering New York University Six MetroTech Center Brooklyn NY 11201 USA.

Amid the ongoing COVID-19 pandemic, public health authorities and the general population are striving to achieve a balance between safety and normalcy. Ever changing conditions call for the development of theory and simulation tools to finely describe multiple strata of society while supporting the evaluation of "what-if" scenarios. Particularly important is to assess the effectiveness of potential testing approaches and vaccination strategies. Here, an agent-based modeling platform is proposed to simulate the spreading of COVID-19 in small towns and cities, with a single-individual resolution. The platform is validated on real data from New Rochelle, NY-one of the first outbreaks registered in the United States. Supported by expert knowledge and informed by reported data, the model incorporates detailed elements of the spreading within a statistically realistic population. Along with pertinent functionality such as testing, treatment, and vaccination options, the model accounts for the burden of other illnesses with symptoms similar to COVID-19. Unique to the model is the possibility to explore different testing approaches-in hospitals or drive-through facilities-and vaccination strategies that could prioritize vulnerable groups. Decision-making by public authorities could benefit from the model, for its fine-grain resolution, open-source nature, and wide range of features.
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http://dx.doi.org/10.1002/adts.202000277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995144PMC
March 2021

Impact of HER2 assessment by CISH in urothelial carcinoma: A retrospective single-center experience.

Pathol Res Pract 2021 Apr 18;220:153410. Epub 2021 Mar 18.

Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni - 15, Bologna, Italy. Electronic address:

Background: In recent years, HER2 amplification has been evaluated as a potential prognostic biomarker and therapeutic target in urothelial carcinoma (UC). In this retrospective study, we aimed at exploring the prognostic role of HER2 amplification in UC, measured by chromogenic in situ hybridization (CISH).

Methods: We retrospectively evaluated the presence of HER2 amplification by using CISH in 31 UC patients followed at a single institution between 2018 and 2020. The primary objective was to assess the frequency of HER2 amplification and to compare clinical outcomes of HER2-amplified patients with non-amplified UCs.

Results: HER2 amplification was identified in 4 out of 31 patients (12.9 %). After a median follow-up of 28.1 months (95 % Confidence Intervals [CI] 11.2-45.1), median overall survival (OS) in the whole population was 10.9 months (95 % CI 3.5-22.1). Despite not reaching statistical significance, median OS was shorter in HER2-amplified patients (6.8 months, 95 % CI 3.9-9.7) compared to HER2-negative UCs (15.4 months, 95 % CI 7.5-23.3) (p = 0.45).

Conclusions: Although limited by the small sample size, the results of our study suggest that HER2 amplifications by CISH could represent a prognostic factor for shorter survival in UC patients.
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http://dx.doi.org/10.1016/j.prp.2021.153410DOI Listing
April 2021

Neoadjuvant therapy for cholangiocarcinoma: A comprehensive literature review.

Cancer Treat Res Commun 2021 Mar 16;27:100354. Epub 2021 Mar 16.

Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy; Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni, 15 Bologna, Italy.

Biliary tract cancers (BTCs) comprise a heterogenous group of aggressive and rare malignancies arising in the bile duct outside or within the liver. BTCs include cholangiocarcinoma (CCA), gallbladder cancer (GBC) and ampulla of Vater cancer (AVC); according to the "historical" anatomical classification, CCAs are further subdivided into extrahepatic cholangiocarcinomas (eCCAs) - including distal (dCCA) and perihilar (pCCA) - and intrahepatic cholangiocarcinomas (iCCA). Notably enough, these subtypes reflect distinct features in terms of biology, epidemiology, prognosis and therapeutic strategies. Although surgical resection remains the only potentially curative treatment option for CCA patients, radical surgery is possible for only a small proportion of cases. Moreover, it has been observed that up to 50% of patients deemed resectable at diagnosis are found to be unresectable during exploratory laparotomy. Additionally, even following radical surgery, recurrence rates are high. Neoadjuvant therapy represents an appealing approach in this setting, where this therapeutic strategy has the potential to improve local and distant control, to achieve R0 resection and to prevent distant metastasis. However, few data are currently available supporting neoadjuvant therapy in CCA and several questions remains unanswered, including the activity of systemic therapy in early stages of the disease, the optimal start time of treatment, patient selection and the length of neoadjuvant therapy. In this review, we will discuss available data on neoadjuvant systemic therapy in CCA, highlighting future directions in this setting, with a particular focus on recently published data and ongoing and recruiting trials.
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http://dx.doi.org/10.1016/j.ctarc.2021.100354DOI Listing
March 2021

TRK inhibition in cholangiocarcinoma: Trying to teach an old dog new tricks.

Cancer Treat Res Commun 2021 Mar 13;27:100351. Epub 2021 Mar 13.

Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy; Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, 40128 Bologna, Italy.

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http://dx.doi.org/10.1016/j.ctarc.2021.100351DOI Listing
March 2021

Impact of Clinicopathological Features on Survival in Patients Treated with First-line Immune Checkpoint Inhibitors Plus Tyrosine Kinase Inhibitors for Renal Cell Carcinoma: A Meta-analysis of Randomized Clinical Trials.

Eur Urol Focus 2021 Mar 10. Epub 2021 Mar 10.

Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni - 15, Bologna, Italia. Electronic address:

Context: Immune checkpoint inhibitors (ICIs) have reported unprecedented results in the treatment of metastatic renal cell carcinoma (mRCC) patients, as monotherapy or in combination with other anticancer agents. However, little information is available regarding the association between different clinicopathological features and survival in this setting.

Objective: We performed a meta-analysis aimed at exploring the predictive value of routinely collected clinicopathological data in randomized controlled trials (RCTs) evaluating ICIs plus tyrosine kinase inhibitors (TKIs) in treatment-naïve patients with mRCC.

Evidence Acquisition: We retrieved all the relevant RCTs through PubMed/Medline, Cochrane Library, and EMBASE; additionally, proceedings of the main international oncological meetings were also searched for relevant abstracts. Eligible studies included RCTs assessing first-line ICI-TKI versus sunitinib in treatment-naïve mRCC patients; the primary endpoint was overall survival (OS), measured as hazard ratio (HR) with corresponding 95% confidence interval (CI).

Evidence Synthesis: Overall, three phase III RCTs involving 1769 patients with advanced or metastatic RCC were included. Compared with sunitinib, the ICI-TKI combination significantly decreased the risk of death in patients with Eastern Cooperative Oncology Group performance status (ECOG-PS) 0 (HR, 0.66; 95% CI, 0.57-0.76) and ECOG-PS 1 (HR, 0.64; 95% CI, 0.54-0.77). Similarly, the combination was associated with prolonged OS in patients who were <65 yr old (HR, 0.57; 95% CI, 0.49-0.67), in mRCC patients ≥65 yr old (HR, 0.75; 95% CI, 0.61-0.90), as well as in male (HR, 0.66; 95% CI, 0.56-0.78) and female (HR, 0.66; 95% CI, 0.52-0.83) patients.

Conclusions: According to our results, the magnitude of benefit of the ICI-TKI combination over sunitinib monotherapy in treatment-naïve mRCC patients was consistent across the clinicopathological subgroups. Despite the limitations affecting the analysis, we believe that the results of the current meta-analysis could assist clinicians and researchers in the design and interpretation of future clinical trials on combination therapies in this setting.

Patient Summary: First-line combinations of an immune checkpoint inhibitor plus a tyrosine kinase inhibitor improved survival in metastatic renal cell carcinoma (mRCC) patients. This survival benefit was consistent across all subgroups of mRCC patients irrespective of clinicopathological features such as patient performance status, age <65 and ≥65 yr, and male and female gender.
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http://dx.doi.org/10.1016/j.euf.2021.03.001DOI Listing
March 2021

A foreword on biliary tract cancers: emerging treatments, drug targets, and fundamental knowledge gaps.

Expert Opin Investig Drugs 2021 Mar 14. Epub 2021 Mar 14.

Department of Experimental, Diagnostic & Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy.

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http://dx.doi.org/10.1080/13543784.2021.1901192DOI Listing
March 2021

Novel Targeted Therapies for Advanced Cholangiocarcinoma.

Medicina (Kaunas) 2021 Feb 26;57(3). Epub 2021 Feb 26.

Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, 40138 Bologna, Italy.

Cholangiocarcinoma (CCA) includes a group of rare and aggressive hepatobiliary malignancies, including extrahepatic cholangiocarcinoma (eCCA) and intrahepatic cholangiocarcinoma (iCCA), with the former further subdivided into distal (dCCA) and perihilar cholangiocarcinoma (pCCA) [...].
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http://dx.doi.org/10.3390/medicina57030212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996824PMC
February 2021

Durvalumab: an investigational anti-PD-L1 antibody for the treatment of biliary tract cancer.

Expert Opin Investig Drugs 2021 Mar 9:1-8. Epub 2021 Mar 9.

Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy.

: The prognosis of patients with advanced biliary tract cancer (BTC) remains dismal, with a 5-year overall survival rate of less than 10%. Although immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of several hematological and solid tumors, controversial results have been reported in BTC. In this setting, the anti-PD-L1 inhibitor durvalumab is currently under investigation in several clinical trials as monotherapy, or in combination with other pharmacological agents.: We offer an overview of immunotherapies for BTC, discuss recently published or presented data on durvalumab pharmacology, safety, and efficacy in the treatment of BTC and consider future research directions for the agent in this setting.: The promising antitumor activity shown by durvalumab in early trials warrants further investigation because it may provide more effective, much needed treatment options. The results of clinical trials of this PD-L1 inhibitor, as a monotherapy or in combination, are eagerly awaited. Future efforts should focus on the identification and development of reliable biomarkers of response to durvalumab in BTC, clarifying the role of PD-L1 expression, microsatellite instability (MSI), mismatch repair (MMR), tumor mutational burden (TMB) and other emerging predictors.
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http://dx.doi.org/10.1080/13543784.2021.1897102DOI Listing
March 2021

Novel approaches for the management of biliary tract cancer: today and tomorrow.

Authors:
Alessandro Rizzo

Expert Opin Investig Drugs 2021 Mar 17:1-3. Epub 2021 Mar 17.

Department of Experimental, Diagnostic & Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy.

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http://dx.doi.org/10.1080/13543784.2021.1896247DOI Listing
March 2021

Pemigatinib: Hot topics behind the first approval of a targeted therapy in cholangiocarcinoma.

Cancer Treat Res Commun 2021 Feb 18;27:100337. Epub 2021 Feb 18.

Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy; Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni, 15 Bologna, Italy.

Cholangiocarcinoma (CCA) includes a heterogeneous group of malignancies with limited treatment options. Despite recent advances in medical oncology, the prognosis of CCA patients with metastatic disease remains poor, with a median overall survival of less than a year. In the last decade, notable efforts have been made by the CCA medical community in an attempt to improve clinical outcomes of patients, with the development of molecularly targeted therapies in this setting. Among these treatments, the fibroblast growth factor receptor (FGFR) 2 inhibitor pemigatinib has received accelerated approval in April 2020 by the US Food and Drug Administration (FDA) in CCA patients harboring FGFR2 gene fusions or other rearrangements, on the basis of the results of the FIGHT-202 trial, and thus, representing the first molecularly targeted therapy to be approved for the treatment of CCA. However, several issues remain, including the emergence of polyclonal mutations determining resistance to pemigatinib, the identification of biomarkers predictive of response, and the knowledge gaps regarding the role of other FGFR gene aberrations. This review aims to provide an overview of recent development of pemigatinib, especially focusing on the results of the pivotal FIGHT-202 trial, the approval of this FGFR inhibitor, and the future challenges concerning the use of FGFR-directed treatments in CCA patients.
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http://dx.doi.org/10.1016/j.ctarc.2021.100337DOI Listing
February 2021

Adjuvant systemic treatment in resected biliary tract cancer: State of the art, controversies, and future directions.

Cancer Treat Res Commun 2021 Feb 12;27:100334. Epub 2021 Feb 12.

Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy; Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni, 15 Bologna, Italy.

Biliary tract cancer (BTC) includes a heterogeneous group of aggressive malignancies comprising gallbladder cancer (GBC), ampulla of Vater cancer (AVC), intrahepatic cholangiocarcinoma (iCCA), and extrahepatic cholangiocarcinoma (eCCA). Unfortunately, potentially curative resection is possible in approximately the 25% of presenting patients, and relapse rates are high, with a notable proportion of BTCs experiencing disease recurrence. Recent years have seen the publication of several prospective clinical trials evaluating the role of adjuvant systemic treatments, and among these, the phase III BILCAP study provided evidence supporting the use of capecitabine after radical surgery in BTC patients; in fact, although the study failed to meet its primary endpoint, the capecitabine arm showed improved clinical outcomes in terms of overall survival (pre-planned sensitivity analysis in the intention-to-treat population and in the per-protocol analysis) and relapse-free survival. However, the BILCAP has been widely criticized, with several authors that have not accepted adjuvant capecitabine as novel standard of care. In this review, we summarize current state of the art regarding adjuvant systemic treatment in BTC, highlighting advantages and disadvantages of recent clinical trials, and suggesting new research directions in this setting.
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http://dx.doi.org/10.1016/j.ctarc.2021.100334DOI Listing
February 2021

First-line Chemotherapy in Advanced Biliary Tract Cancer Ten Years After the ABC-02 Trial: "And Yet It Moves!"

Cancer Treat Res Commun 2021 Feb 11;27:100335. Epub 2021 Feb 11.

Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy; Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni, 15 Bologna, Italy.

Biliary tract cancers (BTCs) include a heterogeneous group of highly aggressive hepatobiliary malignancies, representing the 3% of all gastrointestinal cancers and the second most frequent type of primary liver cancer after hepatocellular carcinoma. Ten years after the publication of the phase III, randomized, ABC-02 trial, the combination of cisplatin plus gemcitabine remains the standard first-line treatment for patients with advanced BTC. In the last decade, a large number of attempts has been made to improve the efficacy of the reference doublet by using novel drugs or adding a third agent to cisplatin-gemcitabine. Unfortunately, despite the addition of different cytotoxic drugs failed to improve clinical outcomes in several studies, recently published clinical trials have provided interesting results, and other first-line chemotherapy options are currently under investigation in randomized phase III studies. Moreover, recent years have witnessed the parallel emergence of molecularly targeted therapies and immune checkpoint inhibitors, with these novel agents having the potential to revolutionize the therapeutic algorithm of advanced BTC. In this review, we will provide an overview on first-line therapeutic opportunities currently available in the management of advanced BTCs, especially focusing on recently published data and ongoing clinical trials in this setting.
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http://dx.doi.org/10.1016/j.ctarc.2021.100335DOI Listing
February 2021

The Identity of PDGFRA D842V-Mutant Gastrointestinal Stromal Tumors (GIST).

Cancers (Basel) 2021 Feb 9;13(4). Epub 2021 Feb 9.

Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.

The majority of gastrointestinal stromal tumors (GIST) carry a sensitive primary KIT mutation, but approximately 5% to 10% of cases harbor activating mutations of platelet-derived growth factor receptor (PDGFRA), mainly involving the A-loop encoded by exon 18 (~5%), or more rarely the JM domain, encoded by exon 12 (~1%), or the ATP binding domain encoded by exon 14 (<1%). The most frequent mutation is the substitution at position 842 in the A-loop of an aspartic acid (D) with a valine (V) in exon 18, widely recognized as D842V. This mutation, as well known, provides primary resistance to imatinib and sunitinib. Thus, until few years ago, no active drugs were available for this subtype of GIST. Conversely, recent years have witnessed the development of a new specific inhibitor-avapritinib-that has been studied in in vitro and clinical setting with promising results. In light of this primary resistance to conventional therapies, the biological background of D842V-mutant GIST has been deeply investigated to better understand what features characterize this peculiar subset of GIST, and some promising insights have emerged. Hereinafter, we present a comprehensive overview on the clinical features and the molecular background of this rare subtype of GIST.
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http://dx.doi.org/10.3390/cancers13040705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916155PMC
February 2021

Pitfalls, challenges, and updates in adjuvant systemic treatment for resected biliary tract cancer.

Expert Rev Gastroenterol Hepatol 2021 Feb 19:1-8. Epub 2021 Feb 19.

Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital , Bologna, Italy.

: Unfortunately, potentially curative surgical resection is possible in approximately the 25% of biliary tract cancer (BTC) patients at diagnosis, and even following radical surgery, relapse rates remain high. Thus, the role of adjuvant systemic treatment has been widely explored in this setting over the last decades, with the hope of lowering recurrence rates and improving outcomes of BTC patients. : In this review, we provide an overview of available evidence regarding adjuvant systemic therapy in resected BTC, critically discussing the pros and cons of recently published clinical trials such as the BILCAP, the BCAT, and the PRODIGE-12/ACCORD-18 phase III studies. : Although the BILCAP trial has established adjuvant capecitabine for 6 months following radical resection as a novel standard of care, the role of adjuvant systemic chemotherapy is the object of debate and controversy in the BTC medical community. Although most of the international guidelines on BTC management have not yet been updated, the recently published ASCO guidelines support the use of capecitabine in this setting. Several phase I to III clinical trials are currently evaluating the role of novel therapeutic approaches in patients with resected BTC, and the results of these studies are highly awaited.
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http://dx.doi.org/10.1080/17474124.2021.1890031DOI Listing
February 2021

Modelling and predicting the effect of social distancing and travel restrictions on COVID-19 spreading.

J R Soc Interface 2021 02 10;18(175):20200875. Epub 2021 Feb 10.

Department of Electronics and Telecommunications, Politecnico di Torino, 10129 Turin, Italy.

To date, the only effective means to respond to the spreading of the COVID-19 pandemic are non-pharmaceutical interventions (NPIs), which entail policies to reduce social activity and mobility restrictions. Quantifying their effect is difficult, but it is key to reducing their social and economic consequences. Here, we introduce a meta-population model based on temporal networks, calibrated on the COVID-19 outbreak data in Italy and applied to evaluate the outcomes of these two types of NPIs. Our approach combines the advantages of granular spatial modelling of meta-population models with the ability to realistically describe social contacts via activity-driven networks. We focus on disentangling the impact of these two different types of NPIs: those aiming at reducing individuals' social activity, for instance through lockdowns, and those that enforce mobility restrictions. We provide a valuable framework to assess the effectiveness of different NPIs, varying with respect to their timing and severity. Results suggest that the effects of mobility restrictions largely depend on the possibility of implementing timely NPIs in the early phases of the outbreak, whereas activity reduction policies should be prioritized afterwards.
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http://dx.doi.org/10.1098/rsif.2020.0875DOI Listing
February 2021

Treating Prostate Cancer by Antibody-Drug Conjugates.

Int J Mol Sci 2021 Feb 4;22(4). Epub 2021 Feb 4.

Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.

Prostate cancer is the most frequent malignancy in the worldwide male population; it is also one of the most common among all the leading cancer-related death causes. In the last two decades, the therapeutic scenario of metastatic castration-resistant prostate cancer has been enriched by the use of chemotherapy and androgen receptor signaling inhibitors (ARSI) and, more recently, by immunotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors. At the same time, several trials have shown the survival benefits related to the administration of novel ARSIs among patients with non-castration-resistant metastatic disease along with nonmetastatic castration-resistant cancer too. Consequently, the therapeutic course of this malignancy has been radically expanded, ensuring survival benefits never seen before. Among the more recently emerging agents, the so-called "antibody-drug conjugates" (ADCs) are noteworthy because of their clinical practice changing outcomes obtained in the management of other malignancies (including breast cancer). The ADCs are novel compounds consisting of cytotoxic agents (also known as the payload) linked to specific antibodies able to recognize antigens expressed over cancer cells' surfaces. As for prostate cancer, researchers are focusing on STEAP1, TROP2, PSMA, CD46 and B7-H3 as optimal antigens which may be targeted by ADCs. In this paper, we review the pivotal trials that have currently changed the therapeutic approach to prostate cancer, both in the nonmetastatic castration-resistant and metastatic settings. Therefore, we focus on recently published and ongoing trials designed to investigate the clinical activity of ADCs against prostate malignancy, characterizing these agents. Lastly, we briefly discuss some ADCs-related issues with corresponding strategies to overwhelm them, along with future perspectives for these promising novel compounds.
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http://dx.doi.org/10.3390/ijms22041551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913806PMC
February 2021

Broad spectrum mutational analysis of chromophobe renal cell carcinoma using next-generation sequencing.

Pathol Res Pract 2021 Mar 1;219:153350. Epub 2021 Feb 1.

Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni - 15, Bologna, Italy. Electronic address:

Background: Chromophobe renal cell carcinoma (ChRCC) is a rare subtype of non-clear cell renal cell carcinoma. Due to its rarity, its molecular characterization as well as therapeutic targets are still not fully understood.

Methods: We performed a next-generation sequencing analysis using the platform Ion PGM System on 20 retrospectively collected ChRCC cases with the aim of identify molecular biomarkers with potential prognostic value or that could have therapeutic implications.

Results: We identified mutation onTP53, SMARCB1, RB1 and JAK3. The most frequently altered gene was TP53 (6/20, 30 % of cases). SMARCB1 mutation was found in 3 (15 %) patients and in all cases the mutational variant was p.T72 K, with known pathogenenic meaning. One (5%) patient presented a pathogenetic mutation of RB1. JAK3 was mutated in 1 (5%) patient and this mutation resulted to have uncertain pathogenetic significance.

Conclusion: ChRCC is a rare disease still not fully molecularly characterized. Next-generation sequencing analysis could be useful to identify potential mutation with prognostic value or that could be potential therapeutic targets.
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http://dx.doi.org/10.1016/j.prp.2021.153350DOI Listing
March 2021

Biochemical predictors of response to immune checkpoint inhibitors in unresectable hepatocellular carcinoma.

Cancer Treat Res Commun 2021 Feb 2;27:100328. Epub 2021 Feb 2.

Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy; Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni, 15 Bologna, Italy.

Hepatocellular carcinoma (HCC) represents the most commonly diagnosed liver cancer worldwide, and the overall survival of patients with unresectable disease is poor. In the last five years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment scenario of several hematological and solid tumors, and these agents have been actively explored in unresectable HCC. Firstly, promising findings of phase I and II clinical studies reporting durable responses and a tolerable safety profile have led to the assessment of ICIs as single agents in phase III clinical studies; however, the latter have provided controversial results, and the activity of ICI monotherapy seems limited to a small subgroup of patients. Conversely, the IMbrave150 trial recently showed that, among patients with previously untreated unresectable HCC, treatment with atezolizumab plus bevacizumab resulted in significantly longer overall survival and progression-free survival compared to sorafenib monotherapy. In addition, the activity of several other ICIs is under investigation, as combination immunotherapy as well as combinations of immunotherapy with antiangiogenic agents. Nonetheless, there are currently no validated predictive biomarkers able to guide treatment choice in this setting, where the identification of specific predictors of response to ICIs represents a major challenge. In this review, we aim to provide a critical overview of recent evidence on biochemical predictors of response to ICIs in patients with unresectable HCC, especially focusing on PD-L1, TMB, MSI, and other emerging biomarkers.
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http://dx.doi.org/10.1016/j.ctarc.2021.100328DOI Listing
February 2021

In Regard to "A Phase Ib Study of NUC-1031 in Combination with Cisplatin for the First-Line Treatment of Patients with Advanced Biliary Tract Cancer (ABC-08)".

Oncologist 2021 Feb 4. Epub 2021 Feb 4.

Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy.

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http://dx.doi.org/10.1002/onco.13703DOI Listing
February 2021

PD-L1, TMB, MSI, and Other Predictors of Response to Immune Checkpoint Inhibitors in Biliary Tract Cancer.

Cancers (Basel) 2021 Feb 1;13(3). Epub 2021 Feb 1.

Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.

Biliary tract cancer (BTC) represents the second most frequently diagnosed primary liver cancer worldwide following hepatocellular carcinoma, and the overall survival of patients with unresectable disease remains poor. In recent years, the advent of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic landscape of several malignancies with these agents, which have also been explored in advanced BTC, as monotherapy or in combination with other anticancer agents. However, clinical trials evaluating ICIs in BTC have shown conflicting results, and the clinical benefit provided by immunotherapy seems limited to a small subgroup of BTC patients. Thus, the identification of reliable predictors of the response to immunotherapy represents a significant challenge in this setting. This review provides an overview of the available evidence on the biomarkers predictive of the response to ICIs in patients with advanced BTC, especially focusing on programmed death-ligand 1 (PD-L1), tumor mutational burden (TMB), microsatellite instability (MSI), and other emerging biomarkers.
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http://dx.doi.org/10.3390/cancers13030558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867133PMC
February 2021