Publications by authors named "George Zarkavelis"

32 Publications

AGAPP: efficacy of first-line cisplatin, 5-fluorouracil with afatinib in inoperable gastric and gastroesophageal junction carcinomas. A Hellenic Cooperative Oncology Group study.

Acta Oncol 2021 May 18:1-9. Epub 2021 May 18.

Department of Medical Oncology, University of Ioannina, Ioannina, Greece.

Purpose: Gastric cancer is the fifth most common neoplasm worldwide with high rates of mortality. Afatinib, a low molecular, irreversible potent inhibitor of ErbB trans-membrane receptor family, has shown promising results according to preclinical and phase I clinical trial data when combined with chemotherapy. We aimed at evaluating the safety and efficacy of the combination of cisplatin, 5FU with afatinib in molecularly unselected patients with advanced gastric cancer.

Methods: Patients with locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma received first line combination therapy of cisplatin, 5FU and afatinib every 21 days, followed by afatinib maintenance monotherapy. The primary endpoint was the Objective Response Rate (ORR); secondary endpoints included Overall Survival (OS), Progression Free Survival (PFS) and the safety profile. Unplanned exploratory analysis of HER2 and tumor mutational profile was performed.

Results: Among 55 patients (ITT population) enrolled, 19 (34.5%) achieved an objective tumor response; stable disease was observed in 16 patients (29.1%) and progressive disease in 10 patients (18.2%). The ORR in the per protocol population (PP) was 42.9%. Within a median follow-up of 56 months, the median PFS and OS in the ITT population was 5.0 and 8.7 months, respectively. Seven of the 47 HER2 informative cases carried HER2 positive tumors while , and were the most frequently mutated genes. The most common toxicities were neutrophil count and white blood cell decrease occurring in 56.4% of patients, followed by anemia (50.9%), hyperglycemia (40%), and diarrhea (38.2%).

Conclusions: The combination of cisplatin/5FU with afatinib did not surpass the benchmarks of efficacy of the contemporary therapeutic regimens that are being applied for the treatment of patients with advanced gastric cancer. However, the observed efficacy and the improved safety profile support that our administration schedule may be further investigated to overcome toxicity problems when integrating afatinib to cytotoxic chemotherapy.

Clinical Trial Registration: NCT01743365.
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http://dx.doi.org/10.1080/0284186X.2021.1912822DOI Listing
May 2021

Molecular Analysis of an Abdominal Wall Cesarean Section Endometrioid Carcinoma.

Int J Surg Pathol 2021 May 14:10668969211018262. Epub 2021 May 14.

University Hospital of Saint-Etienne, France.

Malignant transformation of endometriosis is rare, and most cases concern the ovaries, while extraovarian cases are mostly found in the rectovaginal septum. Incisional adenocarcinoma is extremely rare, with only few cases reported in the literature, while their molecular profile remains unknown. Thus, we report on an abdominal wall cesarean section scar endometrioid adenocarcinoma studied by next-generation sequencing and microsatellite instability analysis.
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http://dx.doi.org/10.1177/10668969211018262DOI Listing
May 2021

Evaluation of the Role of p95 HER2 Isoform in Trastuzumab Efficacy in Metastatic Breast Cancer.

Anticancer Res 2021 Apr;41(4):1793-1802

Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.

Background/aim: Human epidermal growth factor receptor 2 (HER2) P95-isoform could be involved in trastuzumab resistance in HER2 metastatic breast cancer.

Materials And Methods: A total of 114 metastatic breast cancer patients treated with trastuzumab were evaluated retrospectively. HER2 was centrally reviewed. P95 was evaluated along with other markers possibly affecting trastuzumab efficacy in regards to progression-free survival and overall survival.

Results: HER2 was centrally negative in 54 cases. P95 expression was significantly higher in HER2-positive tumors. High p95 was associated with gain of HER2 copy number variations (CNVs), high pHER2Tyr877, Ki67 and HER2 mRNA. P95 as a continuous variable was positively correlated with mRNA expression of HER2 and negatively correlated with HER4 and IGF1. HER2-negative p95-high patients had a marginally higher risk for death (HR=2.15, p=0.055).

Conclusion: p95 was associated with higher HER2 CNVs and mRNA expression, pHER2Tyr877 expression and high Ki67, indicating a more aggressive phenotype.
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http://dx.doi.org/10.21873/anticanres.14945DOI Listing
April 2021

A Challenging Task: Identifying Patients with Cancer of Unknown Primary (CUP) According to ESMO Guidelines: The CUPISCO Trial Experience.

Oncologist 2021 May 25;26(5):e769-e779. Epub 2021 Mar 25.

Clinical Cooperation Unit Molecular Haematology/Oncology, German Cancer Research Center and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.

Background: CUPISCO is an ongoing randomized phase II trial (NCT03498521) comparing molecularly guided therapy versus platinum-based chemotherapy in patients newly diagnosed with "unfavorable" cancer of unknown primary (CUP).

Materials And Methods: Patients with an unfavorable CUP diagnosis, as defined by the European Society of Medical Oncology (ESMO), and available cancer tissue for molecular sequencing are generally eligible. Potential patients with CUP entering screening undergo a review involving reference histopathology and clinical work-up by a central eligibility review team (ERT). Patients with "favorable" CUP, a strongly suspected primary site of origin, lack of tissue, or unmet inclusion criteria are excluded.

Results: As of April 30, 2020, 628 patients had entered screening and 346 (55.1%) were screen failed. Screen fails were due to technical reasons (n = 89), failure to meet inclusion and exclusion criteria not directly related to CUP diagnosis (n = 89), and other reasons (n = 33). A total of 124 (35.8%) patients were excluded because unfavorable adeno- or poorly differentiated CUP could not be confirmed by the ERT. These cases were classified into three groups ineligible because of (a) histologic subtype, such as squamous and neuroendocrine, or favorable CUP; (b) evidence of a possible primary tumor; or (c) noncarcinoma histology.

Conclusion: Experience with CUPISCO has highlighted challenges with standardized screening in an international clinical trial and the difficulties in diagnosing unfavorable CUP. Reconfirmation of unfavorable CUP by an ERT in a clinical trial can result in many reasons for screen failures. By sharing this experience, we aim to foster understanding of diagnostic challenges and improve diagnostic pathology and clinical CUP algorithms.

Implications For Practice: A high unmet need exists for improved treatment of cancer of unknown primary (CUP); however, study in a trial setting is faced with the significant challenge of definitively distinguishing CUP from other cancer types. This article reports the authors' experience of this challenge so far in the ongoing CUPISCO trial, which compares treatments guided by patients' unique genetic signatures versus standard chemotherapy. The data presented will aid future decision-making regarding diagnosing true CUP cases; this will have far-reaching implications in the design, execution, and interpretation of not only CUPISCO but also future clinical studies aiming to find much-needed treatment strategies.
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http://dx.doi.org/10.1002/onco.13744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100559PMC
May 2021

Clinical Significance of Germline Cancer Predisposing Variants in Unselected Patients with Pancreatic Adenocarcinoma.

Cancers (Basel) 2021 Jan 8;13(2). Epub 2021 Jan 8.

Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, 14564 Athens, Greece.

Our aim was to determine the prevalence, prognostic and predictive role of germline pathogenic/likely pathogenic variants (P/LPVs) in cancer predisposing genes in patients with pancreatic ductal adenocarcinoma (PDAC). Germline testing of 62 cancer susceptibility genes was performed on unselected patients diagnosed from 02/2003 to 01/2020 with PDAC, treated at Hellenic Cooperative Oncology Group (HeCOG)-affiliated Centers. The main endpoints were prevalence of P/LPVs and overall survival (OS). P/LPVs in PDAC-associated and homologous recombination repair (HRR) genes were identified in 22 (4.0%) and 42 (7.7%) of 549 patients, respectively. P/LPVs were identified in 16 genes, including (11, 2.0%) and (6, 1.1%), while 19 patients (3.5%) were heterozygotes for P/LPVs and 9 (1.6%) carried the low-risk allele, p.(Ile157Thr). Patients carrying P/LPVs had improved OS compared to non-carriers (22.6 vs. 13.9 months, = 0.006). In multivariate analysis, there was a trend for improved OS in P/LPV carriers ( = 0.063). The interaction term between platinum exposure and mutational status of HRR genes was not significant (-value = 0.35). A significant proportion of patients with PDAC carries clinically relevant germline P/LPVs, irrespectively of age, family history or disease stage. The predictive role of these P/LPVs has yet to be defined. ClinicalTrials.gov Identifier: NCT03982446.
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http://dx.doi.org/10.3390/cancers13020198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827324PMC
January 2021

Synthesis of Recommendations From 25 Countries and 31 Oncology Societies: How to Navigate Through Covid-19 Labyrinth.

Front Oncol 2020 19;10:575148. Epub 2020 Nov 19.

Department of Radiotherapy, School of Medicine, University of Crete, Heraklion, Greece.

Introduction: Pandemic COVID-19 is an unexpected challenge for the oncological community, indicating potential detrimental effects on cancer patients. Our aim was to summarize the converging key points providing a general guidance in order to support decision making, pertaining to the oncologic care in the middle of a global outbreak.

Methods: We did an international online search in twenty five countries that have managed a surge in cancer patient numbers. We collected the recommendations from thirty one medical oncology societies.

Results: By synthesizing guidelines for a) oncology service delivery adjustments, b) general and specific treatment adaptations, and c) discrepancies from guidelines comparison, we present a clinical synopsis with the forty more crucial statements. A Covid-19 risk stratification base was also created in order to obtain a quick, objective patient assessment and a risk-benefit evaluation on a case-by-case basis.

Conclusions: In an attempt to face these complex needs and due to limited understanding of COVID-19, a variability of recommendations based on general epidemiological and infectious disease principles rather than definite cancer-related evidence has evolved. Additionally, the absence of an effective treatment or vaccine requires the development of cancer management guidance, capitalizing on comprehensive COVID-19 oncology experience globally.
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http://dx.doi.org/10.3389/fonc.2020.575148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711151PMC
November 2020

Old Player-New Tricks: Non Angiogenic Effects of the VEGF/VEGFR Pathway in Cancer.

Cancers (Basel) 2020 Oct 27;12(11). Epub 2020 Oct 27.

Department of Medical Oncology, University Hospital of Ioannina, 45500 Ioannina, Greece.

Angiogenesis has long been considered to facilitate and sustain cancer growth, making the introduction of anti-angiogenic agents that disrupt the vascular endothelial growth factor/receptor (VEGF/VEGFR) pathway an important milestone at the beginning of the 21st century. Originally research on VEGF signaling focused on its survival and mitogenic effects towards endothelial cells, with moderate so far success of anti-angiogenic therapy. However, VEGF can have multiple effects on additional cell types including immune and tumor cells, by directly influencing and promoting tumor cell survival, proliferation and invasion and contributing to an immunosuppressive microenvironment. In this review, we summarize the effects of the VEGF/VEGFR pathway on non-endothelial cells and the resulting implications of anti-angiogenic agents that include direct inhibition of tumor cell growth and immunostimulatory functions. Finally, we present how previously unappreciated studies on VEGF biology, that have demonstrated immunomodulatory properties and tumor regression by disrupting the VEGF/VEGFR pathway, now provide the scientific basis for new combinational treatments of immunotherapy with anti-angiogenic agents.
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http://dx.doi.org/10.3390/cancers12113145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692709PMC
October 2020

The cancer immunotherapy environment may confound the utility of anti-TIF-1γ in differentiating between paraneoplastic and treatment-related dermatomyositis. Report of a case and review of the literature.

Contemp Oncol (Pozn) 2020 30;24(1):75-78. Epub 2020 Mar 30.

Department of Medical Oncology, University Hospital of Ioannina, Greece.

With the advent of immunotherapy and with the expanding spectrum of malignancies treated with immunomodulatory agents, a new kind of adverse events has come under the spotlight. Clinicians have to be aware of immune-related adverse events and their clinical manifestations. Immunotherapy has been strongly associated with endocrinopathies, gastrointestinal, pulmonary, cutaneous, and renal toxicities but the incidence of rheumatologic adverse events is lower compared to the aforementioned systems. Dermatomyositis is an autoimmune myopathy which has been correlated to underlying evident or occult malignancies. Apart from its characteristic symptoms and signs, the presence of specific antibodies such as anti-transcriptional intermediary factor 1γ (anti-TIF 1γ) usually supports the diagnosis of paraneoplastic nature of the disease. However, a solid distinction between paraneoplastic syndrome and immune-related adverse event is still missing and remains to be elucidated. We here present a case of dermatomyositis in a male patient who underwent four cycles of combined ipilimumab and nivolumab immunotherapy. This is, to our knowledge, the first case of dermatomyositis following combined immune checkpoint inhibition therapy.
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http://dx.doi.org/10.5114/wo.2020.94727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265958PMC
March 2020

Metabolic consequences of immune checkpoint inhibitors: A new challenge in clinical practice.

Crit Rev Oncol Hematol 2020 Jul 7;151:102979. Epub 2020 May 7.

Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece. Electronic address:

Treatment of oncologic patients has progressed greatly the last few years with the development of immune checkpoint inhibitors (ICPIs). These drugs are associated with the immune system and, thus, may cause side effects of immune origin, the so called immune related adverse events (irAEs). Immune related AEs may actually affect all organs and systems and frequently resemble clinical entities commonly encountered in clinical practice. As ICPIs have improved both quality of life and life expectancy, clinicians of various specialties may need to deal with irAEs in their everyday practice. Therefore, they should be able to recognize them timely and treat them accordingly. Herein, we review the pathophysiology, clinical manifestations and treatment of irAEs.
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http://dx.doi.org/10.1016/j.critrevonc.2020.102979DOI Listing
July 2020

Acquired Hemophilia in an Elderly Patient with Carcinoma of the Ampulla of Vater.

Case Rep Oncol 2020 Jan-Apr;13(1):1-6. Epub 2020 Jan 13.

Department of Medical Oncology, University of Ioannina, Ioannina, Greece.

Acquired hemophilia is a rare autoimmune bleeding disorder related to the production of autoantibodies that inhibit clotting factor VIII or IX. The underlying cause can be autoimmune disease, malignancy, pregnancy, or medications, but it is most commonly idiopathic. Here we present the case of an 81-year-old patient with locoregionally relapsed periampullary carcinoma who presented with soft tissue hematoma and an abnormally elevated activated partial thromboplastin time (aPTT) in the presence of a normal prothrombin time. A diagnosis of acquired hemophilia was established. The patient was managed with immunosuppressive prednisone and cyclophosphamide plus immunoglobulin G. He also received a cycle of chemotherapy with gemcitabine and oxaliplatin, because the underlying malignancy was the cause of the bleeding disorder. Care was complicated by neutropenia and nosocomial fever, but the patient eventually showed signs of clinical stability, while the aPTT decreased 2-fold. The patient was successfully discharged from the hospital and continued treatment in outpatient care.
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http://dx.doi.org/10.1159/000504338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036531PMC
January 2020

A case report of psoriasis flare following immunotherapy: Report of an important entity and literature review.

SAGE Open Med Case Rep 2020 13;8:2050313X19897707. Epub 2020 Jan 13.

Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece.

Immune checkpoint inhibitors, such as anti-cytotoxic T-lymphocyte-associated antigen-4 and anti-programmed death-1, are a type of cancer immunotherapy approved for late-stage malignancy treatment. However, such therapies often induce immune-related adverse events. During anti-programmed death-1 blockade therapy, the most commonly reported adverse effects are skin toxicities, such as psoriasis-a chronic immune-mediated inflammatory disorder affecting the skin. We present the clinical characteristics of flared psoriasis in one patient under anti-programmed death-1 therapy who was diagnosed with T2N2M0/IIIB squamous lung carcinoma with a history of psoriasis for the past 5 years, exacerbated after the first cycle of nivolumab. After the third cycle, the extensive skin plaques necessitated treatment cessation. Following the discontinuation of anti-programmed death-1 treatment, skin lesions were treated locally. Possibly, anti-programmed death-1 immunotherapy can trigger immune-mediated diseases, such as psoriasis. Physicians should be alert to immune-related adverse events. Continuation or permanent cessation of treatment depends on the severity and reversibility of immune-related adverse events.
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http://dx.doi.org/10.1177/2050313X19897707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958646PMC
January 2020

Genetic mapping of pancreatic cancer by targeted next-generation sequencing in a cohort of patients managed with nab-paclitaxel-based chemotherapy or agents targeting the EGFR axis: a retrospective analysis of the Hellenic Cooperative Oncology Group (HeCOG).

ESMO Open 2019 18;4(5):e000525. Epub 2019 Sep 18.

Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece.

Pancreatic cancer is one of the most fatal malignancies ranking fourth among the leading causes of cancer death with diagnosis at late stages carrying a dismal prognosis. The aim of our retrospective study was to describe the nature and the incidence of gene mutations and genomic instability in advanced pancreatic adenocarcinomas of a Greek patient population fully annotated with clinicopathological data. We used a targeted next-generation sequencing (NGS) panel encompassing genes commonly mutated in pancreatic tumours in a patient population managed with either nab-paclitaxel regimens or targeted compounds modulating the epidermal growth factor receptor (EGFR)/AKT/mTOR axis. We identified and as being the most prevalent mutations in the study population with the exception of an intriguingly lower incidence regarding KRAS mutants. Homologous recombination gene mutations were found to be mutually exclusive with mutations. The coexistence of both and mutation seems to adversely affect the outcome of the patients whether treated with targeted therapy against EGFR/Akt/mTOR axis or cytotoxic drugs. The poor prognosis observed, correlated to late presentation, specific molecular mutations and to high mutational load warrant prospective validating studies and research into the mechanistic pathophysiology of pancreatic tumours for more effective therapeutic targeting.
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http://dx.doi.org/10.1136/esmoopen-2019-000525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802956PMC
September 2019

Clinical Application of Next-Generation Sequencing as A Liquid Biopsy Technique in Advanced Colorectal Cancer: A Trick or A Treat?

Cancers (Basel) 2019 Oct 16;11(10). Epub 2019 Oct 16.

Laboratory of Clinical Chemistry, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece.

Owing to its advantages over prior relevant technologies, massive parallel or next-generation sequencing (NGS) is rapidly evolving, with growing applications in a wide range of human diseases. The burst in actionable molecular alterations in many cancer types advocates for the practicality of using NGS in the clinical setting, as it permits the parallel characterization of multiple genes in a cost- and time-effective way, starting from low-input DNA. In advanced clinical practice, the oncological management of colorectal cancer requires prior knowledge of , , and status, for the design of appropriate therapeutic strategies, with more gene mutations still surfacing as potential biomarkers. Tumor heterogeneity, as well as the need for serial gene profiling due to tumor evolution and the emergence of novel genetic alterations, have promoted the use of liquid biopsies-especially in the form of circulating tumor DNA (ctDNA)-as a promising alternative to tissue molecular analysis. This review discusses recent studies that have used plasma NGS in advanced colorectal cancer and summarizes the clinical applications, as well as the technical challenges involved in adopting this technique in a clinically beneficial oncological practice.
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http://dx.doi.org/10.3390/cancers11101573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826585PMC
October 2019

How I treat cancers of unknown primary.

ESMO Open 2019 10;4(Suppl 2):e000502. Epub 2019 May 10.

Medical Oncology, University of Ioannina, Ioannina, Greece.

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http://dx.doi.org/10.1136/esmoopen-2019-000502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555599PMC
May 2019

TAILORing targeted therapies to the right patient at the right time: how close are we?

Ann Transl Med 2018 Nov;6(Suppl 1):S87

Department of Medical Oncology, University of Ioannina, Ioannina, Greece.

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http://dx.doi.org/10.21037/atm.2018.10.75DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291566PMC
November 2018

Postoperative chemotherapy with single-agent after resection of colorectal cancer liver metastases: a meta-analysis of randomised trials.

ESMO Open 2018 23;3(4):e000343. Epub 2018 Jun 23.

Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece.

Surgical resection is the only option of cure for patients with metastatic colorectal cancer. Risk of recurrence after metastasectomy is around 75%. Use of adjuvant chemotherapy after metastasectomy is controversial.

Aim: To address whether adjuvant systemic therapy after colorectal cancer metastasectomy offers any survival benefit compared with surgery alone.

Methods: Systematic review of literature and meta-analysis of all available randomised evidence. Relative hazards (RHs) were summarised across trials and heterogeneity was assessed with the Q and I2 statistics.

Results: Five trials were eligible. Three trials, all using single-agent fluoropyrimidine chemotherapy, presented data valuable for analyses. 482 patients were included in the meta-analysis: 238 randomly assigned to receive postoperative chemotherapy and 244 to metastasectomy only. We found no overall survival (OS) benefit with the use of postoperative single-agent fluoropyrimidines compared with surgery alone, even if a trend for benefit was observed (relative hazard (RH)=0.781, 95% CI 0.593 to 1.030, p=0.080). Significant disease-free survival benefit with the use of postoperative chemotherapy was observed (RH=0.645, 95% CI 0.509 to 0.818, p=0.001). No quality of life (QL) data were available. All trials showed accrual delay, two stopped and one recruiting after 10 years. Long follow-up needs were evidenced since OS curves split only after 3.5 years.

Conclusions: No OS benefit was documented from the use of postoperative monochemotherapy. Metastasectomy alone continues to be the standard of care. Combination chemotherapy regimens should be evaluated along with QL assessment in future trials appropriately designed for long-term accrual and follow-up.
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http://dx.doi.org/10.1136/esmoopen-2018-000343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045754PMC
June 2018

Clonal evolution of colorectal cancer in a patient with serially resected metastases and liquid biopsies: a case report and discussion of the literature.

ESMO Open 2018 9;3(4):e000329. Epub 2018 Jun 9.

Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece.

Background: Metastatic colorectal cancer represents a striking example of clonal heterogeneity and tumour evolution, which generates acquired resistance to therapy. Once hard to perform, the study of clonal heterogeneity is now significantly aided by the use of liquid biopsies.

Method: We herein report a case of a patient with colorectal cancer and serial development of multiple metastases which were all resected and genotyped. A rare point mutation was identified in the primary tumour (but not in any of the organ metastatic sites), as well as in the first and the last out of three consecutive liquid biopsies. The review of the literature offered some insight in the evolution of the patient's tumour and general directions on how to interpret liquid biopsy results.

Conclusions: This patient case emphasises the need for large prospective studies designed to bridge liquid biopsy data with useful clinical endpoints, in order to optimally integrate this revolutionary tool in everyday practice.
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http://dx.doi.org/10.1136/esmoopen-2018-000329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6012565PMC
June 2018

Comprehensive molecular screening by next generation sequencing reveals a distinctive mutational profile of / genes and novel genomic alterations: results from a 20-year cohort of patients with GIST from north-western Greece.

ESMO Open 2018 6;3(3):e000335. Epub 2018 Apr 6.

Department of Medical Oncology, School of Medicine, Ioannina, Greece.

Introduction: Gastrointestinal stromal tumours (GIST) are mesenchymal neoplasms that usually carry an activating mutation in or platelet-derived growth factor receptor alpha () genes with predictive and prognostic significance. We investigated the extended mutational status of GIST in a patient population of north-western Greece in order to look at geopraphic/genotypic distinctive traits.

Patient And Methods: Clinicopathological and molecular data of 38 patients diagnosed from 1996 to 2016 with GIST in the region of Epirus in Greece were retrospectively assessed. Formalin-fixed paraffin-embedded tumours were successfully analysed for mutations in 54 genes with oncogenic potential. Next generation sequencing was conducted by using the Ion AmpliSeqCancer Hotspot Panel V.2 for DNA analysis (Thermofisher Scientific).

Results: Among 38 tumours, 24 (63.16%) and seven (18.42%) of the tumours harboured mutations in the and genes, respectively, while seven (18.42%) tumours were negative for either or mutation. No mutations were detected in five (13.16%) cases. Concomitant mutations of and fibroblast growth factor receptor 3 () genes were observed in two patients with gene mutation. Two patients with / wild-type GIST had mutations in either or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha () genes. There was no significant survival difference regarding the exonic site of mutation in either or gene. The presence of a mutation in pathway effectors downstream of or , such as , or , was associated with poor prognosis. Adverse prognosticators were also high mitotic index and the advanced disease status at diagnosis.

Conclusions: We report comparable incidence of and mutation in patients with GIST from north-western Greece as compared with cohorts from other regions. Interestingly, we identified rare mutations on , and genes in patients with poor prognosis.
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http://dx.doi.org/10.1136/esmoopen-2018-000335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890860PMC
April 2018

Ovarian sex-cord stromal tumours and small cell tumours: Pathological, genetic and management aspects.

Crit Rev Oncol Hematol 2017 Dec 16;120:43-51. Epub 2017 Oct 16.

Gynaecology Unit, General Hospital "G. Hatzikosta", Makrigianni Avenue, 45001, Ioannina, Greece.

Non-epithelial ovarian cancers (NEOC) constitute a group of uncommon malignancies and their treatment is still a challenging task. Collectively, these tumours account for about 10% of all ovarian cancers and occur in all age groups from childhood to old-age. They include malignancies of germ cell origin, sex cord-stromal cell origin, and a variety of extremely rare ovarian cancers, such as small-cell carcinomas and sarcomas. Each of these classifications encompasses multiple histologic subtypes. It is imperative that these rare tumours are managed with accurate diagnosis, staging, and treatment, to optimise the outcome. The aetiology and molecular origins of each sub-group of NEOC remain largely unresolved, and international cooperation to promote high quality translational research is crucial. Much effort has been made into researching the molecular mechanisms underlying epithelial ovarian cancers, but far less is known about the genetic changes in NEOC. In this article, it is provided an overview of the current knowledge on the incidence, clinical presentation, pathology, genetics, therapeutic interventions, survival and prognostic factors of adult and juvenile granulosa cell tumours (GrCT), Sertoli-Leydig Cell tumours (SLCT) and small cell carcinoma of the ovary. We also consider future potential therapeutic targets in these rare cancers.
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http://dx.doi.org/10.1016/j.critrevonc.2017.10.007DOI Listing
December 2017

Current and future biomarkers in colorectal cancer.

Ann Gastroenterol 2017 22;30(6):613-621. Epub 2017 Sep 22.

Department of Medical Oncology, Medical School, University of Ioannina (George Zarkavelis, Stergios Boussios, Alexandra Papadaki, George Pentheroudakis), Greece.

Colorectal cancer (CRC), one of the leading causes of death among cancer patients, is a heterogeneous disease and is characterized by diversions in multiple molecular pathways throughout its evolutionary process. To date, specific mutations in RAS and RAF genes are tested in everyday clinical practice along with mismatch repair gene deficiency, serving either as prognostic or predictive biomarkers, providing information for patient risk stratification and the choice of appropriate therapy. However, ongoing studies are focusing on the potential role of recently discovered genetic and epigenetic alterations in the management of CRC patients and their potential prognostic or predictive value. To overcome the problem of tumor heterogeneity as well as the practical obstacles of access to tumor tissue, and to achieve real-time monitoring of disease and therapy efficacy, liquid biopsies constitute a novel technology worth exploring. CRC screening and management is entering a new era where molecular testing will be applied to genomic material extracted from easily accessible bodily fluids.
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http://dx.doi.org/10.20524/aog.2017.0191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5670280PMC
September 2017

Nivolumab-induced hypothyroidism and selective pituitary insufficiency in a patient with lung adenocarcinoma: a case report and review of the literature.

ESMO Open 2017 5;2(4):e000217. Epub 2017 Oct 5.

Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece.

Immune checkpoint blockade including programmed cell death 1 pathway inhibition with agents such as nivolumab is gaining ground in a wide array of malignancies, so far demonstrating significantly improved survival rates even in metastatic, often multiply pretreated settings. Although targeted in nature and generally well-tolerated compared with conventional anticancer treatments, these agents are often linked to a newly emerged group of adverse reactions, referred to as immune-related adverse events, which can also affect endocrine organs. This is a case report of a patient who received nivolumab for the treatment of recurrent metastatic non-small cell lung cancer and developed primary hypothyroidism and secondary adrenal insufficiency caused by selective pituitary dysfunction (with preservation of all other endocrine functions). After hormone replacement with daily administration of T4, T3 and hydrocortisone, the patient achieved complete recovery. Adequate characterisation of these rare yet potentially severe entities is essential for prompt diagnostic and therapeutic interventions that will permit us to fully benefit from these new agents' therapeutic potential.
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http://dx.doi.org/10.1136/esmoopen-2017-000217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640091PMC
October 2017

Primary Pulmonary Malignant Melanoma: Report of an Important Entity and Literature Review.

Case Rep Oncol Med 2017 2;2017:8654326. Epub 2017 Mar 2.

Department of Medical Oncology, Medical School, University of Ioannina, Stavros Niarchos Avenue, 45110 Ioannina, Greece; Society for Study of the Clonal Heterogeneity of Neoplasia, Ioannina, Greece.

Malignant melanoma involving the respiratory tract is nearly always metastatic in origin, and primary tumors are extremely rare. Published data on primary pulmonary malignant melanomas are limited. Up to now 40 relevant cases have been reported in the English literature. Herein, we report a case of a 56-year-old female patient who presented with intracranial metastases due to primary pulmonary melanoma. She underwent bronchoscopy and died 5 months after the initial diagnosis despite the administered biochemotherapy and subsequent immunotherapy. To establish the diagnosis of primary pulmonary malignant melanoma, any extrapulmonary origin was excluded by detailed examination and radiographic imaging. Moreover, an extensive review of the literature regarding this rare entity has been performed.
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http://dx.doi.org/10.1155/2017/8654326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352873PMC
March 2017

Aromatase inhibitors induced autoimmune disorders in patients with breast cancer: A review.

J Adv Res 2016 Sep 23;7(5):719-726. Epub 2016 Apr 23.

Department of Medical Oncology, Ioannina University Hospital, S. Niarchos Avenue, 45500 Ioannina, Greece.

Subacute cutaneous lupus erythematosus (SCLE) is characterized by particular cutaneous manifestations such as non-scaring plaques mainly in sunlight exposed parts of the body along with specific serum autoantibodies (i.e. antinuclear antibodies (ANA), Ro/SSa, La/SSb). It is considered either idiopathic or drug induced. The role of chemotherapeutic agents in causing SCLE has been investigated with the taxanes being the most common anticancer agents. However, recent data emerging point toward antiestrogen therapies as a causative factor not only for SCLE but also for a variety of autoimmune disorders. This is a report of a case of a 42 year old woman who developed clinical manifestations of SCLE after letrozole treatment in whom remission of the cutaneous manifestations was noticed upon discontinuation of the drug. In addition, an extensive review of the English literature has been performed regarding the association of antiestrogen therapy with autoimmune disorders. In conclusion, Oncologists should be aware of the potential development of autoimmune reactions in breast cancer patients treated with aromatase inhibitors.
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http://dx.doi.org/10.1016/j.jare.2016.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328027PMC
September 2016

Management of patients with recurrent/advanced cervical cancer beyond first line platinum regimens: Where do we stand? A literature review.

Crit Rev Oncol Hematol 2016 Dec 15;108:164-174. Epub 2016 Nov 15.

Department of Medical Oncology, Medical School, University of Ioannina, Stavros Niarchos Avenue, 45500, Ioannina, Greece.

Background: Cervical cancer is the fourth most common cancer affecting women worldwide. Despite advances in screening and human papillomavirus (HPV) vaccination, a significant number of women present with or develop advanced disease. Palliative platinum-based chemotherapy (CT) is the standard first-line treatment for metastatic/recurrent cervical cancer. The prognosis remains poor and effective second line options are urgently needed.

Methods: We searched the English-language medical literature as well as relevant guideline databases, published from January 1981 to December 2015 and identified publications related to cervical cancer and its therapies. Our effort was to highlight the available treatment options in the setting of recurrent/metastatic disease.

Results: Although there have been important advances in the management of women with cervical cancer, the optimal treatment for patients with locally recurrent and metastatic disease after platinum failure is still problematic. Overall, there is a trend in terms of longer overall survival (OS) and better quality of life for the combination of cisplatin/paclitaxel (PC) as compared to the doublets of cisplatin/topotecan (TC), cisplatin/vinorelbine (VC), and cisplatin/gemcitabine (GC). Currently available single agents beyond first-line platinum-based therapy have limited efficacy in this setting and include topoisomerase inhibitors, vinca alkaloids, taxanes, alkylating agents and antimetabolites. Several targeted therapies have demonstrated activity in advanced cervical cancer. Bevacizumab has been evaluated in a phase III trial using doublets of cisplatin with paclitaxel or topotecan and has been approved in the first-line setting by the U. S. Food and Drug Administration. Selective targeting of angiogenic kinases by tyrosine kinase inhibitors (TKIs) may represent a novel therapeutic tool in this setting, but its use alone or in combination with CT is still investigational. Early reports have implicated PI3KCA somatic mutations suggesting that mTOR-targeted agents should be explored in this disease. Development of the immune checkpoint programmed cell death 1 (PD-1) and T-lymphocyte-associated molecule-4 (CTLA-4) inhibitors have been of considerable interest, leading to ongoing phase II studies in patients with advanced cervical cancer.

Conclusions: Progress in the management of recurrent and advanced cervical cancer patients has been slow and restricted to palliative intent. These patients should be considered for clinical trials of novel targeted agents and/or immunotherapy.
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http://dx.doi.org/10.1016/j.critrevonc.2016.11.006DOI Listing
December 2016

Non-epithelial Ovarian Cancer: Elucidating Uncommon Gynaecological Malignancies.

Anticancer Res 2016 10;36(10):5031-5042

Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece.

Non-epithelial ovarian cancers (NEOC) are a group of fascinating but uncommon malignancies which can be extremely challenging to treat. Collectively, these tumours only represent 10-15% of all ovarian cancers and occur in all age groups from childhood to old age. This broad term includes diverse tumours of germ cell origin, sex cord-stromal cell origin, as well as extremely rare types of ovarian cancer, such as small-cell carcinomas and sarcomas, each of which require specialist management. It is imperative that these rare tumours are managed with accurate diagnosis, staging and treatment in order to optimize patient outcomes. The aetiology and molecular origins of each sub-group of NEOC remain poorly understood and international cooperation to facilitate high quality translational research is needed. This review summarizes the published literature on the incidence, clinical presentation, pathology, therapeutic interventions, survival and prognostic factors of each sub-type of NEOC.
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http://dx.doi.org/10.21873/anticanres.11072DOI Listing
October 2016

Testicular Signet-Ring Cell Metastasis from a Carcinoma of Unknown Primary Site: A Case Report and Literature Review.

Case Rep Oncol Med 2016 18;2016:7010173. Epub 2016 Jul 18.

Department of Medical Oncology, University Hospital of Ioannina, 45500 Ioannina, Greece.

Signet-ring cell carcinoma is a highly malignant adenocarcinoma consisting of cells characterized as cytoplasmic vacuoles filled with mucin. The most common primary location of this type of cancer is the stomach, but it may also be found in other organs such as prostate, testis, bladder, ovaries, or colon. To date, metastatic signet-ring cell carcinoma of unknown primary (CUP) site to the testis is an extremely rare entity in daily practice. Reviewing the literature, we have been able to detect only three cases of testicular metastases from CUP, two with histological diagnosis of a signet-ring cell carcinoma and one with an adenocarcinoma. In this short paper, we report a case of a 56-year-old man who presented to our Department with testicular mass and ascites. Following a standard diagnostic approach no primary tumor could be identified. CUP was the final clinical diagnosis, histologically characterized as poorly differentiated adenocarcinoma with signet-ring cells involving the peritoneum and the testicular structures.
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http://dx.doi.org/10.1155/2016/7010173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967671PMC
August 2016

Bone and soft tissue sarcomas during pregnancy: A narrative review of the literature.

J Adv Res 2016 Jul 2;7(4):581-7. Epub 2016 Feb 2.

Department of Medical Oncology, Ioannina University Hospital, 45110 Ioannina, Greece.

Bone or soft tissue sarcomas are rarely diagnosed during pregnancy. Until today 137 well documented cases have been reported in the English literature between 1963 and 2014. Thirty-eight pregnant mothers were diagnosed with osteosarcoma, Ewing's sarcoma or chondrosarcoma, whereas 95 other cases of soft tissue sarcomas of various types have been documented. We present the clinical picture and therapeutic management of this coexistence.
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http://dx.doi.org/10.1016/j.jare.2016.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4921935PMC
July 2016