Publications by authors named "Nicholas Pavlidis"

174 Publications

Educational contribution of the College of the European School of Oncology to the Latin American Oncologists.

Future Oncol 2021 Jun 8. Epub 2021 Jun 8.

European School of Oncology, Via Turati 29, 20121, Milan, Italy.

The European School of Oncology (ESO) offers a wide range of educational activities in Europe, the Middle East and Latin America. International experts are invited to provide proper education in the diagnosis and treatment of patients with cancer according to a holistic model of care. This activity is currently structured in the ESO College (ESCO) through masterclasses in clinical oncology, international conferences, clinical training centers fellowship programs, certificate of competence and advanced studies, patients' advocacy events, e-learning sessions and medical students' courses in oncology. This institutional profile highlights the ESO-ESCO educational activities dedicated to Latin American oncologists and reports on the experience of the 869 participants that have attended these programs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2021-0421DOI Listing
June 2021

Genomic correlates of response and resistance to immune checkpoint inhibitors in carcinomas of unknown primary.

Eur J Clin Invest 2021 May 10:e13583. Epub 2021 May 10.

University of Ioannina, Ioannina, Greece.

Background: Cancers of unknown primary (CUP) are highly aggressive tumours with limited molecular characterization. These tumours can be particularly sensitive to immune checkpoint inhibitors (ICI) by mounting a seemingly more effective anti-tumour immune response. Unlike other tumour lineages, the biological basis and clinical efficacy of ICI in CUP remain largely unknown.

Materials And Methods: The cBioPortal database was accessed to select eligible cases from the MSK-IMPACT Clinical Sequencing Cohort. The tumour cell genomic correlates of response and resistance to ICI in patients with CUP were compared to those with ICI-eligible tumours: cervical cancer, gastric cancer, renal cell carcinoma, hepatocellular carcinoma, non-small-cell lung cancer, melanoma, Merkel cell carcinoma and urothelial bladder cancer.

Results: Among a total of 234 patients with CUP, the identified genomic alterations were mainly mutation correlates of resistance to ICI, notably mutations in oncogenic signalling pathways including KRAS, STK11 and EGFR (24.7%, 10.9% and 4.2%, respectively). Compared to other tumours considered eligible for ICI, CUP presents a higher prevalence of alterations in the oncogenic signalling pathways KRAS and STK11. CUP patients treated with ICI had similar median overall survival with and without genomic correlates of response and resistance to ICI. An exploratory analysis showed that patients with TMB >10 mutations had a trend for better outcomes.

Conclusions: A tumour mutation burden >10 mutations per megabase can provide a potential genomic correlate of response to ICI in patients with CUP. Further research is warranted to validate these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/eci.13583DOI Listing
May 2021

Immuno-oncology: a narrative review of gastrointestinal and hepatic toxicities.

Ann Transl Med 2021 Mar;9(5):423

Medical School, University of Ioannina, Ioannina, Greece.

Vaccines, cytokines, and adoptive cellular therapies (ACT) represent immuno-therapeutic modalities with great development potential, and they are currently approved for the treatment of a limited number of advanced malignancies. The most up-to-date knowledge on the regulation of the anti-cancer immune response has recently led to the development and approval of inhibitors of immune checkpoints, which have produced unprecedented clinical activity in several hard to treat solid malignancies. However, severe adverse events (AEs) represent a limitation to the use of these drugs. Currently approved checkpoint inhibitors block cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand (PD-L1), resulted in increased survival of patients with several solid and hematologic malignancies. The most common treatment AEs associated with these drugs are fatigue, rash, and auto-immune/inflammatory reactions. Many of the immune-related AEs are reversible and the strategies for their management include supportive care either with or without treatment withdrawal; nevertheless, in severe cases, hospitalization and treatment with immune suppressants, and/or immunomodulators may be required. Steroid therapy is a critical component of the treatment algorithm; nevertheless, the associated immunosuppression may compromise the antitumor response. This article provides a comprehensive and narrative review of luminal gastrointestinal and hepatic complications, including recommendations for their investigation and management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/atm-20-7361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033350PMC
March 2021

Live European School of Oncology e-Sessions (e-ESO).

Crit Rev Oncol Hematol 2021 Mar 16:103301. Epub 2021 Mar 16.

European School of Oncology, Milan, Italy.

The European School of Oncology (ESO) embarked on an online educational project, starting with live sessions in 2008 (e-ESO). Our scholars and young oncologists identified the need to be offered independent high-level online education with contributions from experts around the world, free of charge and available at any moment. We report on various types of e-sessions, such as grand-rounds, highlights, debates, clinical cases and other sessions. Our audience has grown over the last decade, reaching 11,123 users who have viewed a total of 77,041 sessions since the beginning of 2008. Moreover, our activities on social media platforms have enhanced our visibility, reaching more physicians around the globe. Due to the recent events surrounding the COVID-19 pandemic, online education has proven to be of great value in offering long-distance teaching. We have analyzed the growth of our audience and its attendance over the last 12 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.critrevonc.2021.103301DOI Listing
March 2021

Narrative review on serous primary peritoneal carcinoma of unknown primary site: four questions to be answered.

Ann Transl Med 2020 Dec;8(24):1709

University of Ioannina, Stavros Niarchou Avenue, Ioannina, Greece.

Serous peritoneal papillary carcinoma (SPPC) represents a particular cancer of unknown primary (CUP) entity that arises in the peritoneal surface lining the abdomen and pelvis without a discriminative primary tumor site. In this review, we discuss the validity of SPPC as a distinct entity. Clinically, patients with SPPC are older, have higher parity and later menarche, are more often obese and probably have poorer survival compared to those with primary ovarian cancer. Pathologically, SPPC is more anaplastic and multifocal, unlike primary ovarian cancer which is commonly unifocal. Biologically, it presents a higher expression of proliferative signals and similar cell cycle and DNA repair protein expression. These differences hint towards SPPC and primary ovarian cancer being as a spectrum of disease. Patients with SPPC are traditionally managed similarly to stage III-IV ovarian cancer. The recommended approach integrates aggressive cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, and systemic chemotherapy to remove the macroscopic tumor, eradicate the microscopic residual disease, and control the microscopic metastasis. However, the available evidence lacks proper randomized or prospective studies on SPPC and is limited to retrospective series. The diligent identification of SPPC is warranted to design specific clinical trials that eventually evaluate the impact of the new therapeutics on this distinct entity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/atm-20-941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812188PMC
December 2020

Development of new poly(ADP-ribose) polymerase (PARP) inhibitors in ovarian cancer: Quo Vadis?

Ann Transl Med 2020 Dec;8(24):1706

Medical School, University of Ioannina, Ioannina, Greece.

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality among women, potentially due to ineffectiveness of screening tests for early detection. Patients typically present with advanced disease at diagnosis, whereas, up to 80% relapse and the estimated median progression-free survival (PFS) is approximately 12-18 months. Increased knowledge on the molecular biology of EOC resulted in the development of several targeted therapies, including poly(ADP-ribose) polymerase (PARP) inhibitors. These agents have changed the therapeutic approach of the EOC and exploit homologous recombination (HR) deficiency through synthetic lethality, especially in breast cancer genes 1 and 2 () mutation carriers. Furthermore, wild-type patients with other defects in the HR repair pathway, or those with platinum-resistant tumors may obtain benefit from this treatment. While PARP inhibitors as a class display many similarities, several differences in structure can translate into differences in tolerability and antitumor activity. Currently, olaparib, rucaparib, and niraparib have been approved by Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) for the treatment of EOC, while veliparib is in the late stage of clinical development. Finally, since October 2018 talazoparib is FDA and EMA approved for carriers with metastatic breast cancers. In this article, we explore the mechanisms of DNA repair, synthetic lethality, efficiency of PARP inhibition, and provide an overview of early and ongoing clinical investigations of the novel PARP inhibitors veliparib and talazoparib.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/atm.2020.03.156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812175PMC
December 2020

Ovarian cancer: state of the art and perspectives of clinical research.

Ann Transl Med 2020 Dec;8(24):1702

Medical School, University of Ioannina, Stavros Niarchou Avenue, 45110, Ioannina, Greece.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/atm-2020-oc-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812238PMC
December 2020

ESO-ESSO-ESTRO Multidisciplinary Course in Oncology for Medical Students: 4 Years of Experience (2016-2019).

J Cancer Educ 2021 Jan 2. Epub 2021 Jan 2.

Oncology, Antwerp University Hospital, Edegem, Belgium.

The ESO-ESSO-ESTRO Multidisciplinary Course in Oncology is intended to fill the gap of the undergraduate fragmented oncology education, to provide insight into all theoretical and practical aspects of oncology, and to encourage future professional choices towards an oncology discipline. Students are exposed to (a) preclinical cancer topics; (b) natural history of the disease; (c) laboratory diagnostic tests; (d) medical, radiation, surgical, and palliative treatment; and (e) direct or through multidisciplinary patients' approach. Students are obliged to attend (i) all theoretical lectures, (ii) clinical case presentations, (iii) laboratories and ward visits, and (iv) to prepare and present a specific project under supervision. Participation is limited to 24 medical students who are selected through a competitive application process. Between 2016 and 2019, 96 students from 29 countries have attended. Data analysis derived from a given questionnaire demonstrates that most of the participants have declared that (1) they have achieved their expectations and objectives, (2) they have highly rated both clinical and non-clinical teaching oncological topics, and (3) they have been stimulated in developing a professional career in the field of oncology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13187-020-01947-3DOI Listing
January 2021

Melanoma of unknown primary: New perspectives for an old story.

Crit Rev Oncol Hematol 2021 Feb 28;158:103208. Epub 2020 Dec 28.

Medical School, University of Ioannina, Stavros Niarchou Avenue, 45110 Ioannina, Greece.

Melanoma of unknown primary site (MUP) comprises 3-4 % of all melanomas. It mostly presents in lymph nodes (LNs), followed by subcutaneous sites, and visceral organs; nevertheless, there is a trend of increase in the relative incidence of visceral counterpart in recent years. Spontaneous regression of the primary lesion is a well-established theory, based on the evidence that melanoma can undergo regression at the primary site. MUP and stage-matched melanoma of known primary site (MKP) share similar prognostic factors. The survival rate of patients with MUP has been compared to those with stage-matched MKP. Multiple studies conducted before the era of novel therapy with immune checkpoint or BRAF/MEK inhibitors found improved survival in favor of MUP, whereas others reported equivalent or poorer outcomes. Here, we discuss the genetic and molecular features, epidemiology, diagnosis, prognostic factors, survival, and treatment of MUP in comparison with MKP, in the pre- and post-novel therapy era.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.critrevonc.2020.103208DOI Listing
February 2021

The management of patients with cancer of unknown primary in middle-income countries: an ESO-AROME survey.

Future Oncol 2021 Jan 11;17(2):151-157. Epub 2020 Dec 11.

Institut Universitaire de Cancerologie APHP-Sorbonne Université, 75006, Paris, France.

To report on the management strategies in patients with cancer of unknown primary (CUP) in middle-income countries. We conceived a survey of 20 items concerning the management of patients with CUP in daily clinical practice. Only participants from lower- and higher-middle-income countries, as per the World Bank Classification, were eligible for this study. The indications for the first-line treatment did not differ between the two economic regions, whereas those for second-line treatment were more prevalent in higher-middle-income countries. The use of targeted therapy based on immunohistochemistry alone was higher in lower-middle-income countries, although the access to CUP classifiers was similar between the two regions. Proper recommendations must ensure that the economic burden is minimized and that other benefits outweigh the limited survival benefit achieved in patients with CUP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2020-0677DOI Listing
January 2021

Synovial Sarcoma: A Complex Disease with Multifaceted Signaling and Epigenetic Landscapes.

Curr Oncol Rep 2020 10 6;22(12):124. Epub 2020 Oct 6.

Department of Orthopaedic Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Purpose Of Review: Aside from a characteristic SS18-SSX translocation identified in almost all cases, no genetic anomalies have been reliably isolated yet to drive the pathogenesis of synovial sarcoma. In the following review, we explore the structural units of wild-type SS18 and SSX, particularly as they relate to the transcriptional alterations and cellular pathway changes imposed by SS18-SSX.

Recent Findings: Native SS18 and SSX contribute recognizable domains to the SS18-SSX chimeric proteins, which inflict transcriptional and epigenetic changes through selective protein interactions involving the SWI/SNF and Polycomb chromatin remodeling complexes. Multiple oncogenic and developmental pathways become altered, collectively reprogramming the cellular origin of synovial sarcoma and promoting its malignant transformation. Synovial sarcoma is characterized by complex epigenetic and signaling landscapes. Identifying the operational pathways and concomitant genetic changes induced by SS18-SSX fusions could help develop tailored therapeutic strategies to ultimately improve disease control and patient survivorship.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11912-020-00985-wDOI Listing
October 2020

The diagnostic challenges of patients with carcinoma of unknown primary.

Expert Rev Anticancer Ther 2020 09 2;20(9):775-783. Epub 2020 Sep 2.

University of Ioannina , Ioannina, Greece.

Introduction: Cancer of unknown primary (CUP) is a disease entity encompassing heterogeneous malignancies without a clinically-detectable anatomical primary. It is usually a poor prognosis malignancy with dismal prognosis where molecular and genetic testing were expected to be a major breakthrough.

Areas Covered: In this review, we provide an overview of the advances in the understanding of the carcinogenesis, biology, diagnosis and treatment of patients with CUP. This review focuses on the advantages and inconveniences of immunohistochemistry and CUP classifiers in assessing the progress in the management of CUP.

Expert Opinion: CUP classifiers were expected to gradually replace the classical multistep approach in identifying the culprit tumors to guide site-specific therapy. Immunohistochemistry staining led to the prediction of a single tissue of origin in 10.8-51%. CUP classifiers identified the primary site in 61-89% of these cases and were concordant with immunohistochemistry in 57.1-100%. Immunohistochemistry is cheap, fast and broadly available whereas CUP classifiers are less widely available and have not been validated in randomized control trials. The diagnostic recommendations consist of a standard pathology evaluation based on morphology and algorithmic immunohistochemistry assessment. Physicians should weigh in the input of the CUP classifier to the clinical picture and pathology investigations before performing additional investigations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14737140.2020.1807948DOI Listing
September 2020

What can we learn from cancer of unknown primary in canine oncology?

J Adv Res 2020 Jul 10;24:495-500. Epub 2020 Jun 10.

Professor Emeritus, University of Ioannina, Ioannina, Greece.

Cancer of unknown primary (CUP) represents a heterogeneous group of metastatic tumors that lack an identifiable primary site despite an extensive diagnostic work-up. It is a well-recognized entity that is characterized by early dissemination, aggressive clinical course, unpredictable metastatic pattern, intrinsic treatment resistance, and a dismal prognosis. Despite the molecular diagnostic workup and personalized therapy, the expected improvements in the diagnosis and treatment of CUP have not been achieved. Comparative oncology has a promising role in the exchange of knowledge and practices between humans and canines. Therefore, we intended to review the literature reporting on CUP in dogs in order to identify some interesting parallels and unique results that could be transposed to in-human research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jare.2020.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303049PMC
July 2020

The clinical training centers fellowships: a European School of Oncology career development program (2013-2019).

Future Oncol 2020 Sep 21;16(26):1969-1976. Epub 2020 Jun 21.

European School of Oncology, Milan, Italy.

This article refers to the European School of Oncology Clinical Training Centers (CTCs) program, which is a granted Fellowships program dedicated to young oncologists in training. A total of 74 fellowships were offered by several CTCs during the last 7 years. Candidates were enrolled for 3-6 months of training rotations as fellows or observers in more than 30 training programs in well known Cancer Centers around Europe. Fellowships were covering medical, surgical, radiation and pediatric oncology specialties, laboratory diagnostic training and experimental, translational and clinical research. Fellows originated from Europe, Latin America and Mediterranean Africa. Analysis of the questionnaire assessment showed that 95.5% of the fellows evaluated CTC programs with an 'excellent' or 'very good' score, while 100% declare that they had reached their objectives. The European School of Oncology CTC program designed for an additional practical education abroad meets the needs of young oncologists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2020-0193DOI Listing
September 2020

Wise Management of Ovarian Cancer: On the Cutting Edge.

J Pers Med 2020 May 21;10(2). Epub 2020 May 21.

Medical School, University of Ioannina, Stavros Niarchou Avenue, 45110 Ioannina, Greece.

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality among women. Two-thirds of patients present at advanced stage at diagnosis, and the estimated 5 year survival rate is 20-40%. This heterogeneous group of malignancies has distinguishable etiology and molecular biology. Initially, single-gene sequencing was performed to identify germline DNA variations associated with EOC. However, hereditary EOC syndrome can be explained by germline pathogenic variants (gPVs) in several genes. In this regard, next-generation sequencing (NGS) changed clinical diagnostic testing, allowing assessment of multiple genes simultaneously in a faster and cheaper manner than sequential single gene analysis. As we move into the era of personalized medicine, there is evidence that poly (ADP-ribose) polymerase (PARP) inhibitors exploit homologous recombination (HR) deficiency, especially in breast cancer gene 1 and 2 () mutation carriers. Furthermore, extensive preclinical data supported the development of aurora kinase (AURK) inhibitors in specific tumor types, including EOC. Their efficacy may be optimized in combination with chemotherapeutic or other molecular agents. The efficacy of metformin in ovarian cancer prevention is under investigation. Certain mutations, such as ARID1A mutations, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which are specific in ovarian clear cell carcinoma (OCCC) and endometrioid ovarian carcinoma (EnOC), may offer additional therapeutic targets in these clinical entities. Malignant ovarian germ cell tumors (MOGCTs) are rare and randomized trials are extremely challenging for the improvement of the existing management and development of novel strategies. This review attempts to offer an overview of the main aspects of ovarian cancer, catapulted from the molecular mechanisms to therapeutic considerations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jpm10020041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354604PMC
May 2020

The impact of the European School of Oncology masterclass in clinical oncology on self-professional development.

Crit Rev Oncol Hematol 2020 Jul 28;151:102976. Epub 2020 Apr 28.

European School of Oncology, Milan, Italy.

We investigated the impact of the European School of Oncology's (ESO) Masterclass (MCO) in Clinical Oncology on the career development of young participants. MCO represents the flagship educational activity of ESO and is organized annually, mostly in collaboration with the European Society for Medical Oncology (ESMO) in five different geographical regions. A questionnaire consisting of 21 questions was sent to all doctors who attended the ESO MCOs from 2009 to 2016. The 228 responders were mostly from European countries and hold the specialty of Medical Oncology. Ninety-five percent of them evaluated ESO MCOs as "extremely useful" or "useful" for their professional career. Around 60% were trained at University Hospitals or Cancer Institutes and currently, one-third of them are employed in Academic Centers. Eighty percent have performed translational or clinical research and 77.5% were able to publish in pertinent international journals. The contribution of ESO MCOs to trainees' career development in different oncology disciplines around the world is discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.critrevonc.2020.102976DOI Listing
July 2020

Progress in refining the clinical management of cancer of unknown primary in the molecular era.

Nat Rev Clin Oncol 2020 09 29;17(9):541-554. Epub 2020 Apr 29.

Medical School, University of Ioannina, Ioannina, Greece.

Cancer of unknown primary (CUP) is an enigmatic disease entity encompassing heterogeneous malignancies without a detectable primary tumour, despite a thorough diagnostic workup. A minority of patients with CUP (15-20%) can be assigned a putative primary tissue of origin according to clinical and histopathological findings and typically have a more favourable prognosis with the use of corresponding tumour type-specific therapies. Thus, the majority of patients with CUP have disease that cannot be assigned to a culprit primary tumour, are treated with empirical chemotherapy and have a poor prognosis. In the molecular era, the use of (epi)genomic or transcriptomic CUP classifiers and DNA or RNA sequencing offers two, sometimes overlapping, therapeutic strategies: tumour type-specific therapy and biomarker-guided therapy. Published data reveal that the accuracy of site-of-origin predictions made using CUP classifiers ranges between 54% and 98% when compared with the assignment made according to the recommended clinicopathological criteria. These advances have led to promising results in non-randomized prospective studies evaluating the efficacy of tumour type-specific therapy; however, the favourable outcomes were not confirmed in randomized controlled studies comparing this approach with standard empirical chemotherapy. Currently, the evidence supporting the use of biomarker-guided therapies is limited to case reports and small case series. In this Review, we discuss the clinical management of CUP in the era of precision medicine. We focus on the advances in understanding the biology of CUP, the implications for the diagnosis and classification of CUP according to the tissue of origin and the shift away from empirical therapy towards tailored therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41571-020-0359-1DOI Listing
September 2020

Clinical Case Presentation and Discussion During ESO-ESMO Masterclass: a 10-Year Interactive Educational Experience.

J Cancer Educ 2020 Apr 17. Epub 2020 Apr 17.

European School of Oncology, Milan, Italy.

In this article, we report on the clinical case presentations that have been delivered during the ESO or ESO-ESMO Masterclasses in Clinical Oncology in the last 10 years. Masterclasses have been held in three different geographical continents including Europe, Middle East, and Latin America, in which participants had to submit a clinical case and present it either in front of a tumor board (multidisciplinary-like sessions) or in small groups. Clinical case presentation is a unique part of the educational program preparing young oncologists to present and discuss their own patients with distinguished experts. In each Masterclass, between 40 and 55 clinical cases-depending on the number of participants-are presented. All presentations are assessed and evaluated by faculty members as well as by the rest of the participants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13187-020-01744-yDOI Listing
April 2020

Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond.

Drugs R D 2020 Jun;20(2):55-73

Medical School, University of Ioannina, Stavros Niarchou Avenue, 45110, Ioannina, Greece.

Genetic complexity and DNA damage repair defects are common in different cancer types and can induce tumor-specific vulnerabilities. Poly(ADP-ribose) polymerase (PARP) inhibitors exploit defects in the DNA repair pathway through synthetic lethality and have emerged as promising anticancer therapies, especially in tumors harboring deleterious germline or somatic breast cancer susceptibility gene (BRCA) mutations. However, the utility of PARP inhibitors could be expanded beyond germline BRCA1/2 mutated cancers by causing DNA damage with cytotoxic agents in the presence of a DNA repair inhibitor. US Food and Drug Administration (FDA)-approved PARP inhibitors include olaparib, rucaparib, and niraparib, while veliparib is in the late stage of clinical development. Talazoparib inhibits PARP catalytic activity, trapping PARP1/2 on damaged DNA, and it has been approved by the US FDA for the treatment of metastatic germline BRCA1/2 mutated breast cancers in October 2018. The talazoparib side effect profile more closely resembles traditional chemotherapeutics rather than other clinically approved PARP inhibitors. In this review, we discuss the scientific evidence that has emerged from both experimental and clinical studies in the development of talazoparib. Future directions will include optimizing combination therapy with chemotherapy, immunotherapies and targeted therapies, and in developing and validating biomarkers for patient selection and stratification, particularly in malignancies with 'BRCAness'.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40268-020-00301-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221042PMC
June 2020

New rising entities in cancer of unknown primary: Is there a real therapeutic benefit?

Crit Rev Oncol Hematol 2020 Mar 23;147:102882. Epub 2020 Jan 23.

University of Ioannina, Ioannina, Greece.

Cancers of Unknown Primary Site (CUP) account for approximately 1-3 % of all malignant neoplasms. It represents a heterogeneous group of malignancies without a detectable primary and is characterized by aggressive clinical behavior. Patients with CUP are presumably categorized into prognostic subsets according to their clinical and pathological characteristics. The majority of these patients are chemoresistant and treated with empiric chemotherapy regimens which yield limited survival. Recent diagnostic advances have led to the identification of a higher percentage of culprit primaries among which colorectal, lung and renal tumors. The empiric CUP regimens may be suboptimal in these patients which explain in part their poor prognosis. In the absence of prospective randomized studies to prove the benefit of site-specific therapy in these subsets, we reviewed the literature to assess whether CUP with colorectal, lung and renal - profiles should be treated similarly to the correspondent primary tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.critrevonc.2020.102882DOI Listing
March 2020

Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?

Br J Cancer 2020 04 11;122(8):1124-1132. Epub 2020 Feb 11.

University of Ioannina, Ioannina, Greece.

Cancer of unknown primary (CUP) affects a small percentage of the general population. Nonetheless, a substantial number of these patients have a poor prognosis and consequently succumb to their illness within a year of diagnosis. The natural history of CUP is characterised by early metastasis from the unknown primary site, aggressive course and resistance to conventional chemotherapy. Unfortunately, the processes by which this orphan disease originates and progresses have not been fully elucidated and its biology remain unclear. Despite the conceptual progress in genetic and molecular profiling made over the past decade, recognition of the genetic and molecular abnormalities involved in CUP, as well as the identification of the tissue of origin remain unresolved issues. This review will outline the biology of CUP by exploring the hallmarks of cancer in order to rationalise the complexities of this enigmatic syndrome. This approach will help the reader to understand where research efforts currently stand and the pitfalls of this quest.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-019-0723-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156745PMC
April 2020

The role of site-specific therapy for cancers of unknown of primary: A meta-analysis.

Eur J Cancer 2020 03 30;127:118-122. Epub 2020 Jan 30.

University of Ioannina, Ioannina, Greece.

Cancers of unknown primary (CUP) are among the most common causes of death due to cancer, are associated with a poor prognosis and have few therapeutic options available. Molecularly-guided site-specific treatments were explored based on the assumption that CUP are similar in their response to treatment of predicted primary tumours. Given the discordant results between these studies, a meta-analysis using a random-effects model and the inverse variance method was performed. MEDLINE and conference abstracts of American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) meetings were searched from inception until November 2019. A trend towards improved OS was noted with site-specific versus empiric treatment for CUP (HR = 0.73; 95% confidence interval (CI) 0.52-1.02). There was significant heterogeneity across the four studies (I [2] = 79%; p = 0.002) but no significant difference was noted between the treatment effect in the two subgroups (randomised vs. non-randomised; p = 0.07). The test for overall effect for progression free survival, which had only been reported for the two randomised studies, was not statistically significant (HR = 0.93; 95% CI 0.74-1.17), with little heterogeneity between studies (I [2] = 0%; p = 0.77). The results of this meta-analysis highlight the significant heterogeneity between the prospective studies comparing molecularly tailored to empiric therapy for CUP and the need for other randomised studies including only primary tumors with available effective therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2019.12.016DOI Listing
March 2020

Changing the education paradigm in oncology: ESO masterclass, 17 years of continuous success.

Crit Rev Oncol Hematol 2020 Feb 1;146:102798. Epub 2019 Aug 1.

European School of Oncology, Milan, Italy.

In this review, we summarize the history of the 41 Masterclasses in Clinical Oncology (MCO) organized by ESO or ESO-ESMO during the last 17 years. MCOs have been held in five different geographical regions including: a) Central Europe, b) Eastern Europe and Balkans, c) Baltic and Euroasia, d) Arab World and Southern European Countries and e) Latin America. More than 2.000 young oncologists have attended and more than 250 distinguished faculty members have actively participated. The program exposes students to sessions covering all major tumors ("big killers") and to spotlights updating information on various important cancers and related topics. Participants are able to present their own clinical case in front of a tumor board or in parallel group sessions and are evaluated by a Learning Assessment Test (LAT) at the end of the event. They are asked to discuss the programme, using a questionnaire on the goals, quality and organization of the MCOs, which has been very highly scored by most of the participants. The Masterclass in Clinical Oncology has become the major educational event of ESO, intending to educate young oncologists from various countries within or outside Europe, providing an up-to-date interactive program based on solid evidence for all presented topics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.critrevonc.2019.07.022DOI Listing
February 2020

ESO-ESMO Masterclass in Clinical Oncology: Analysis and Evaluation of the Learning Self-Assessment Test.

J Cancer Educ 2021 Jun;36(3):556-560

European School of Oncology, Milan, Italy.

Masterclass in Clinical Oncology (MCO) represents the "key educational event" of European School of Oncology's (ESO) teaching program. MCO in collaboration with European Society for Medical Oncology (ESMO) is a multidisciplinary and clinical oriented educational event offered mainly to young oncologists worldwide. It provides full immersion in oncology with clinical case presentations and a Learning Self-Assessment Test (LSAT).LSAT is consisting of 45 multiple choice questions on an electronic platform referring to the material taught during the MCO. Three questions related to their topics are requested in advance from each faculty member. The major intentions of LSAT are the following: (a) the learning reflection of the massive information given during 4-5 days of intensive teaching and (b) to offer the opportunity to the participants to prepare themselves for their National Boards or for ESMO examination.In this article, we are analyzing and evaluating the results of LSAT from the ESO-ESMO Central European MCOs. We used the information of Central European MCOs for analysis due to the homogeneity of the available data. We assessed the level of participants' knowledge in relation to their oncology specialty or to their country of origin and the level of the quality of faculty teaching.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13187-019-01664-6DOI Listing
June 2021

AROME-ESO Oncology Consensus Conference: access to cancer care innovations in countries with limited resources. Association of Radiotherapy and Oncology of the Mediterranean Area (AROME-Paris) and European School of Oncology (ESO - Milan).

J BUON 2019 Sep-Oct;24(5):2180-2197

Clinical Center of Montenegro, University of Montenegro, Podgorica, Montenegro.

Purpose: Cancer is a leading cause of mortality worldwide. Its incidence is still increasing, particularly in developing countries. Recent progresses further strengthen the differences between low/middle and high-income countries. This situation calls for joint action to reduce inequities in cancer outcomes among the patients. The Association of Radiotherapy and Oncology of the Mediterranean Area (AROME) and the European School of Oncology (ESO), have initiated joint conferences devoted to access to innovations in oncology in the Mediterranean area. The heterogeneity of the economic, political and cultural situations of the different participating countries, offers the opportunity to develop consensus conference.

Methods: Cancer prevention and treatment strategies were discussed according to existing international guidelines. The Scientific committee prepared 111 questions with an objective to prioritize the access to treatments and innovations in low/middle-income Mediterranean countries. The results from the votes of 65 oncology experts, coming from 16 countries and 33 institutions have been analysed and access priorities classified accordingly.

Results: Ninety six percent of the proposed general recommendations concerning national health care strategies, oncology education, and treatment organization were considered to be high priorities. Regarding access to systemic treatments, 41% of the drugs without validated predictive markers and 53% of those with validated predictive markers were considered to be 1st level priority. Only 4 biological tests were considered to be 1st level priority to access to innovation.

Conclusions: AROME-ESO consensus offers to cancer specialists from developing countries a basis for discussion with health authorities and payers on the prioritization of access to innovations in cancer care.
View Article and Find Full Text PDF

Download full-text PDF

Source
April 2020

Veliparib in ovarian cancer: a new synthetically lethal therapeutic approach.

Invest New Drugs 2020 02 24;38(1):181-193. Epub 2019 Oct 24.

Medical School, University of Ioannina, Stavros Niarchou Avenue, 45110, Ioannina, Greece.

Epithelial ovarian cancer (EOC) accounts for nearly 90% of all ovarian malignancies. The standard therapeutic strategy includes cytoreductive surgery and neo (adjuvant) platinum-based chemotherapy. Relapse of advanced high grade serous ovarian cancer (HGSOC) is related to the development of drug resistance. A defective DNA damage response is a defining hallmark of HGSOC. Poly (ADP-ribose) polymerase (PARP) inhibitors exploit this deficiency through synthetic lethality and have emerged as promising anticancer therapies, especially in breast cancer gene (BRCA1 or BRCA2) mutation carriers. Apart from inducing synthetic lethality, PARP inhibitors have also been shown to trap PARP1 and PARP2 on DNA, leading to PARP-DNA complexes. This "PARP trapping" potentiates synergism between PARP inhibition and both alkylating agents and platinum-based chemotherapy. However, there are remarkable differences in the ability of PARP inhibitors to trap PARP, based on the size and structure of each separate molecule. Since monotherapy with PARP inhibitors is unlikely to induce cancer cell death in BRCA-proficient tumors, the efficacy of PARP inhibitors could be potentially optimized when combined with DNA-damaging agents, or with molecular targeted agents that also impair mechanisms of DNA repair. Olaparib, rucaparib, and niraparib have all obtained US Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) approval in ovarian cancer in different settings. Veliparib does not yet have an approved label; nevertheless, there are currently promising results available in preclinical and early clinical settings. This comprehensive review summarizes the mechanism of action of veliparib and provides an overview of its early and ongoing clinical investigations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10637-019-00867-4DOI Listing
February 2020

Advances in the management of brain metastases from cancer of unknown primary.

Future Oncol 2019 Aug 6;15(23):2759-2768. Epub 2019 Aug 6.

University of Ioannina, Ioannina, Greece.

Cancer of unknown primary accounts for 3-5% of all cancers for which an adequate investigation does not identify the primary tumor. The particular subset of brain metastasis in cancer of unknown primary (BMCUP) is a clinical challenge that lacks standardized diagnostic and therapeutic options. It is diagnosed predominantly in male patients in the sixth decade of age with complaints of headache, neurological dysfunction, cognitive and behavioral disturbances and seizures. The therapeutic approach to patients with BMCUP relies on local control and systemic treatment. Surgery or stereotactic radiosurgery and/or whole brain radiation therapy seems to be the cornerstone of the treatment approach to BMCUP. Systemic therapy remains essential as cancers of unknown primary are conceptually metastatic tumors. The benefits of chemotherapy were disappointing whereas those of targeted therapies and immune checkpoint inhibitors remain to be evaluated. In this Review, we address the advances in the diagnosis and treatment of BMCUP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2019-0108DOI Listing
August 2019

Combined Strategies with Poly (ADP-Ribose) Polymerase (PARP) Inhibitors for the Treatment of Ovarian Cancer: A Literature Review.

Diagnostics (Basel) 2019 Aug 1;9(3). Epub 2019 Aug 1.

Medical School, University of Ioannina, Stavros Niarchou Avenue, 45110 Ioannina, Greece.

Poly (ADP-ribose) polymerase (PARP) inhibitors are the first clinically approved drugs designed to exploit synthetic lethality, and were first introduced as a cancer-targeting strategy in 2005. They have led to a major change in the treatment of advanced ovarian cancer, and altered the natural history of a disease with extreme genetic complexity and defective DNA repair via homologous recombination (HR) pathway. Furthermore, additional mechanisms apart from breast related cancer antigens 1 and 2 () mutations can also result in HR pathway alterations and consequently lead to a clinical benefit from PARP inhibitors. Novel combinations of PARP inhibitors with other anticancer therapies are challenging, and better understanding of PARP biology, DNA repair mechanisms, and PARP inhibitor mechanisms of action is crucial. It seems that PARP inhibitor and biologic agent combinations appear well tolerated and clinically effective in both -mutated and wild-type cancers. They target differing aberrant and exploitable pathways in ovarian cancer, and may induce greater DNA damage and HR deficiency. The input of immunotherapy in ovarian cancer is based on the observation that immunosuppressive microenvironments can affect tumour growth, metastasis, and even treatment resistance. Several biologic agents have been studied in combination with PARP inhibitors, including inhibitors of vascular endothelial growth factor (VEGF; bevacizumab, cediranib), and PD-1 or PD-L1 (durvalumab, pembrolizumab, nivolumab), anti-CTLA4 monoclonal antibodies (tremelimumab), mTOR-(vistusertib), AKT-(capivasertib), and PI3K inhibitors (buparlisib, alpelisib), as well as MEK 1/2, and WEE1 inhibitors (selumetinib and adavosertib, respectively). Olaparib and veliparib have also been combined with chemotherapy with the rationale of disrupting base excision repair via PARP inhibition. Olaparib has been investigated with carboplatin and paclitaxel, whereas veliparib has been tested additionally in combination with temozolomide vs. pegylated liposomal doxorubicin, as well as with oral cyclophosphamide, and topoisomerase inhibitors. However, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations requires further investigation with dose escalation studies. In this review, we discuss multiple clinical trials that are underway examining the antitumor activity of such combination strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/diagnostics9030087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787707PMC
August 2019

Comprehensive management of HPV-related squamous cell carcinoma of the head and neck of unknown primary.

Head Neck 2019 10 13;41(10):3700-3711. Epub 2019 Jul 13.

University of Ioannina, Ioannina, Greece.

Background: Human papillomavirus (HPV)-related squamous cell carcinoma of unknown primary (SCCUP) is currently rising in incidence but lacks a validated management approach.

Aims: This paper reviews the clinical presentation, diagnosis, and treatment of HPV-related SCCUP.

Materials And Methods: The Medline/Pubmed database was searched by using the following keywords "CUP", "cancer of unknown primary", "HPV", "human papilloma virus", and "head and neck". The references of the publications of interest were also screened for relevant papers.

Results: The clinical assessment of HPV-related SCCUP includes a complete clinical examination, an endoscopic evaluation with white-light and narrow band imaging, and radiologic assessment using morphologic and metabolic imaging. If the diagnosis remains unconfirmed, endoscopic examination under anesthesia with tonsillectomy ± base of tongue mucosectomy is performed. The therapeutic rationale aims to eradicate the involved lymph nodes and potential primary tumor with a sequence of chemoradiotherapy and neck dissection.

Discussion: As a general approach, p16-negative SCCUP are truly HPV negative, whereas p16-positive specimens require confirmation with HPV in situ hybridization or polymerase chain reaction to confirm HPV infection. If a cervical metastasis is considered HPV positive, the primary lesion is likely in the oropharynx, and further diagnostic interventions such as tonsillectomy seems to be mandatory. Whether the optimal treatment is neck dissection followed by adjuvant radiotherapy or concomitant chemoradiotherapy (CRT) (in case of extranodal extension or advanced lymph node stages) or definitive CRT followed by neck dissection (in case of positive F-FDG-PET/CT) remains a matter of debate. Solid scientific evidence supporting treatment de-escalation in HPV-related SCCUP is lacking, and the results of ongoing trials are at the brink of reporting.

Conclusion: Currently, the treatment of patients with HPV-related SCCUP should not differ from the standard treatment of other SCCUP patients and is similarly based on the staging of the disease and general condition of the patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hed.25858DOI Listing
October 2019

The currently declining incidence of cancer of unknown primary.

Cancer Epidemiol 2019 08 26;61:139-141. Epub 2019 Jun 26.

University of Ioannina, Ioannina, Greece.

Cancer of unknown primary (CUP) is a heterogeneous group of metastatic cancers for which a primary tumor cannot be identified after a standardized work-up. The biology of CUP has not been fully elucidated and epidemiologic data may be helpful in this regard. The variations in the incidence-rate over time and between countries reflect changes in the risk factors for CUP, incidence trends of the primary tumors that potentially contribute to the burden of CUP and changes in the diagnostic technologies and practice. CUP accounted for 3-5% of cancers in the historical series but its incidence seems to decline in the recent publications. This paper reviews the published cancer-registry studies in order to identify and understand the variations in the incidence-rates of CUP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canep.2019.06.006DOI Listing
August 2019