Publications by authors named "Stergios Boussios"

44 Publications

Cancer-Associated Thrombosis: A New Light on an Old Story.

Diseases 2021 May 4;9(2). Epub 2021 May 4.

Department of Hematology/Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK.

Cancer-associated thrombosis (CAT) is a rising and significant phenomenon, becoming the second leading cause of death in cancer patients. Pathophysiology of CAT differs from thrombosis in the non-cancer population. There are additional risk factors for thrombosis specific to cancer including cancer type, histology, and treatment, such as chemotherapy. Recently developed scoring systems use these risk factors to stratify the degree of risk and encourage thromboprophylaxis in intermediate- to high-risk patients. Anticoagulation is safely used for prophylaxis and treatment of CAT. Both of these have largely been with low-molecular-weight heparin (LMWH), rather than the vitamin K antagonist (VKA); however, there has been increasing evidence for direct oral anticoagulant (DOAC) use. Consequently, international guidelines have also adapted to recommend the role of DOACs in CAT. Using DOACs is a turning point for CAT, but further research is warranted for their long-term risk profile. This review will discuss mechanisms, risk factors, prophylaxis and management of CAT, including both LMWH and DOACs. There will also be a comparison of current international guidelines and how they reflect the growing evidence base.
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http://dx.doi.org/10.3390/diseases9020034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161803PMC
May 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.
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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.
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http://dx.doi.org/10.21037/atm-20-7361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033350PMC
March 2021

Management of Metastatic Spinal Cord Compression in Secondary Care: A Practice Reflection from Medway Maritime Hospital, Kent, UK.

J Pers Med 2021 Feb 9;11(2). Epub 2021 Feb 9.

Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, Kent, UK.

Introduction: Malignant spinal cord compression (MSCC) is one of the most devastating complications of cancer. This event requires rapid decision-making on the part of several specialists, given the risk of permanent spinal cord injury or death. The goals of treatment in spinal metastases are pain control and improvement of neurological function. There can be challenges in delivering prompt diagnosis and treatment in a secondary care setting. We have reflected on the experience of managing MSCC in a district general setting.

Aim: Our retrospective audit identified 53 patients with suspected MSCC who entered the relevant pathway from April 2017 to March 2018 at Medway, United Kingdom (UK). Our audit standards were set out by Medway Maritime Hospital and Maidstone and Tunbridge Wells NHS Trust MSCC working group members, using a combination of published evidence and best practice.

Results: The patients with suspected MSCC were 53 and 29 of them (54.7%) had confirmed MSCC. The most common malignancies within the confirmed MSCC were lung (11 patients, 37.9%), breast (5 patients 17.2%), and renal (3 patients, 10.3%), followed by prostate, myeloma and carcinoma of unknown primary (2 patients (6.9%) each), as well as pancreatic, colorectal, lymphoma and, bladder (1 patient (3.4%) each). A magnetic resonance imaging (MRI) scan was performed in 48 patients (90.5%); the majority (31 patients, 64.6%) underwent the MRI within the first 24 h, whereas 3 patients had the investigation between 24 and 72 h from the admission. Among the 29 patients with confirmed MSCC, 6 (20.6%) were treated with surgical decompression, while 20 (69%) received radiotherapy (RT) and 3 (10.3%) best supportive care, respectively. Median time to surgery was 5 days (ranged between 2 and 8 days), whereas for RT 44.4 h (ranged between 24 and 72 h). Finally, all 3 patients that decided on symptom control were referred to a palliative care team within the first 24 h following the MRI scan.

Conclusions: MSCC is frequently presented outside tertiary care. This may cause subsequent delays in investigation, diagnosis, and treatment, which can be improved by following a fast track referral pathway.
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http://dx.doi.org/10.3390/jpm11020110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914482PMC
February 2021

Current and future immunotherapy approaches in ovarian cancer.

Ann Transl Med 2020 Dec;8(24):1714

Division of Medical Oncology, Department of Internal Medicine, Bahcesehir University Faculty of Medicine, Istanbul, Turkey.

Ovarian cancer (OC) is the major cause of gynecologic cancer deaths and relapse is common despite advances in surgery and systemic chemotherapy. Therefore, novel treatments are required to improve long-term outcomes of the disease. Efficacy of immunotherapy was demonstrated in many tumors and it has been since incorporated into clinical practice for them. Although early data form preclinical studies imply that OC has an immunogenic microenvironment, immune checkpoint inhibitors (ICIs) did not produce favorable results in clinical trials to date. This review will highlight data from clinical studies regarding immunotherapy in OC and its combination with other agents as well as immunologic prospects which could strengthen the therapeutic armament against the disease in the future.
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http://dx.doi.org/10.21037/atm-20-4499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812210PMC
December 2020

Systemic anti-cancer treatment in malignant ovarian germ cell tumours (MOGCTs): current management and promising approaches.

Ann Transl Med 2020 Dec;8(24):1713

Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

Malignant ovarian germ cell tumours (MOGCTs) are rare. Unlike epithelial ovarian cancer, MOGCTs typically occur in girls and young women. Fertility-sparing surgery and platinum-based chemotherapy remain the standard of care, providing high chance of cure at all stages. Given the lack of high-quality studies in this field, current practice guidelines recommend chemotherapy regimens adopted in testicular germ cell tumours. However, platinum-resistant/refractory MOGCTs retain a worse prognosis in comparison with their male counterpart. Herein, we focus on current systemic anti-cancer treatment options in MOGCTs and promising approaches. Future studies enrolling exclusively female participants or germ cell tumour trials allowing participation of MOGCT patients are strongly recommended in order to improve evidence on existing management and develop novel strategies.
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http://dx.doi.org/10.21037/atm.2020.04.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812190PMC
December 2020

Endometriosis-associated ovarian carcinomas: insights into pathogenesis, diagnostics, and therapeutic targets-a narrative review.

Ann Transl Med 2020 Dec;8(24):1712

Department of Medical Oncology, Medway NHS Foundation Trust, Gillingham, Kent, UK.

Endometriosis is a benign gynecologic condition affecting up to one woman out of ten of reproductive age. It is defined by the presence of endometrial-like tissue in localizations outside of the uterine cavity. It often causes symptoms such as chronic pain, most frequently associated with the menstrual cycle, and infertility, but may also be oligo- or asymptomatic. There is evidence that some ovarian carcinoma (OC) histotypes, mainly the ovarian clear cell (OCCC) and endometrioid (EnOC) carcinoma, may arise from endometriosis. The most frequent genomic alterations in these carcinomas are mutations in the AT-rich interacting domain containing protein 1A () gene, a subunit of the SWI/SNF chromatin remodeling complex, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which frequently co-occur. In ARID1A deficient cancers preclinical experimental data suggest different targetable mechanisms including epigenetic regulation, cell cycle, genomic instability, the PI3K/AKT/mTOR pathway, inflammatory pathways, immune modulation, or metabolic alterations as potential precision oncology approaches. Most of these strategies are relying on the concept of synthetic lethality in which tumors deficient in ARID1A are more sensitive to the different compounds. Some of these approaches are currently being or have recently been investigated in early clinical trials. The remarkably frequent occurrence of these mutations in endometriosis-associated ovarian cancer, the occurrence in a relatively young population, and the high proportion of platinum-resistant disease certainly warrants further investigation of precision oncology opportunities in this population. Furthermore, advanced knowledge about oncogenic mutations involved in endometriosis-associated ovarian carcinomas may be potentially useful for early cancer detection. However, this approach may be complicated by the frequent occurrence of somatic mutations in benign endometriotic tissue as recent studies suggest. In this narrative review of the current literature, we will discuss the data available on endometriosis-associated ovarian carcinoma, with special emphasis on epidemiology, diagnosis and molecular changes that could have therapeutic implications and clinical applicability in the future.
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http://dx.doi.org/10.21037/atm-20-3022aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812165PMC
December 2020

Metformin and ovarian cancer: the evidence.

Ann Transl Med 2020 Dec;8(24):1711

Department of Oncology and Radiotherapy, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.

In recent decades, great interest in the off-label use of metformin has arisen as a result of its broad effects on different signaling pathways, with only a few side effects, and low cost. Metformin has been shown to have multiple, dose-dependent preclinical anticancer effects, which can be roughly divided into either direct effects via inhibition of mitochondrial respiratory chain complex I, or indirect effects through lowered glucose, insulin and insulin-like growth factor levels. Further details on and anticancer effects specifically in ovarian cancer are continuously reported. Preclinically metformin has clear chemosensitizing effects in ovarian cancer and it is an effective negative regulator of angiogenesis. There are also some epidemiological studies on metformin use in ovarian cancer, but the results of these studies are not as promising as those preclinical studies would indicate. Most preclinical studies have involved metformin concentrations that are many times higher than the pharmacological doses used in patients, which might confound the clinical use of metformin as regards the above-mentioned aspects. In this review we evaluate preclinical and clinical evidence concerning metformin in ovarian cancer treatment.
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http://dx.doi.org/10.21037/atm-20-1060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812201PMC
December 2020

Neoadjuvant treatment for newly diagnosed advanced ovarian cancer: where do we stand and where are we going?

Ann Transl Med 2020 Dec;8(24):1710

Northampton General Hospital NHS Trust, Cliftonville, Northampton, UK.

Newly diagnosed high grade serous epithelial ovarian cancer (EOC) patients are treated with radical surgery followed by adjuvant platinum and taxane combination chemotherapy. In EOC patients where upfront surgery is contraindicated for medical reasons (e.g., comorbidities or poor performance status), or where complete cytoreduction cannot be achieved, neoadjuvant chemotherapy (NACT) prior to interval debulking surgery (IDS), and adjuvant chemotherapy is an alternative therapeutic option. There is currently a lack of consensus about who are the best candidates to receive NACT, and some authors have even suggested that this approach could be harmful in a subset of patients via promotion of early chemoresistance. Standard and novel imaging techniques together with a better molecular characterization of the disease have the potential to improve selection of patients, but ultimately well designed randomised clinical trials are needed to guide treatment decisions in this setting. The advent of new and effective treatment options (antiangiogenics and PARP inhibitors), now approved for use in the first line and relapse settings has opened the way to clinical trials aiming to investigate these agents as substitute or in addition to chemotherapy in the neoadjuvant setting in molecularly selected EOC patients. Here, we will review the evidence supporting the use of NACT in newly diagnosed EOCs, data highlighting the importance of its use in selected patients, new imaging methodologies and biomarkers that can guide patient selection.
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http://dx.doi.org/10.21037/atm-20-1683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812234PMC
December 2020

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

Upfront debulking surgery for high-grade serous ovarian carcinoma: current evidence.

Ann Transl Med 2020 Dec;8(24):1707

Department of General Surgery, University Hospital of Ioannina, Ioannina, Greece.

High-grade serous ovarian carcinoma (HGSOC) is a leading cause of mortality among women worldwide. Currently, there is no clear consensus over the regime these patients should receive. The main two options are upfront debulking surgery with adjuvant chemotherapy or neoadjuvant chemotherapy followed by interval debulking surgery (IDS). The former approach is proposed to be accompanied by lower chemoresistance rates but could lead to severe surgical comorbidities and lower quality of life (QoL). Optimizing patient's selection for upfront debulking surgery might offer higher progression-free and overall survival rates. Further studies need to be conducted in order to elucidate the predictive factors, which are favorable for patients undergoing upfront debulking surgery in cases of high-grade serous ovarian cancer.
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http://dx.doi.org/10.21037/atm-20-1620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812243PMC
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.
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http://dx.doi.org/10.21037/atm.2020.03.156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812175PMC
December 2020

NOTCH signalling in ovarian cancer angiogenesis.

Ann Transl Med 2020 Dec;8(24):1705

King's College London, School of Medicine, Guy's Campus, London, UK.

The Notch signalling pathway is involved in the new vessel formation process by regulating tip and stalk cells, which are key cells in the sprout formation. This process is essential in both normal ovary and cancer angiogenesis and is regulated by Notch-VEGF crosstalk. Furthermore, Notch has been linked in ovary with stem cell maintenance and epithelial mesenchymal transition processes. Dysregulation of the Notch pathway is frequent in ovarian cancer (OC) and it has been associated with impaired survival and advanced stages or lymph node involvement. Notch also plays a role in chemoresistance to platinum. In this context, this pathway has emerged as an attractive target for precision medicine in OC. Two main targets of this pathway concentrate the clinical development of compounds blocking Notch: gamma secretase and Delta-like ligand 4. Most of the clinical trials including OC patients have been developed in phase I or phase Ib. Despite being in an early phase, both of these compounds, navicixizumab or demcizumab, two monoclonal antibodies targeting Dll4, showed promising efficacy data in platinum-resistant OC patients in recent studies. This review will focus on the mechanisms of the Notch pathway with special interest in angiogenesis regulation and the implication of Notch as a potential therapeutic target in OC.
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http://dx.doi.org/10.21037/atm-20-4497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812236PMC
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.

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

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

An Update on the Prognostic and Predictive Serum Biomarkers in Metastatic Prostate Cancer.

Diagnostics (Basel) 2020 Jul 31;10(8). Epub 2020 Jul 31.

Medway NHS Foundation Trust, Windmill Road, Gillingham, Kent ME7 5NY, UK.

Serum biomarkers are molecules produced by normal and abnormal cells. Prostate specific antigen (PSA) is an example of a serum biomarker used widely in the diagnosis and prognostication of prostate cancer. PSA has its limitations as it is organ- but not cancer-specific. The aim of this review is to summarize the current published data on the potential prognostic and predictive biomarkers in metastatic prostate cancer (mPC) that can be used in conjunction with PSA. These biomarkers include microRNAs, androgen receptor variants, bone metabolism, neuroendocrine and metabolite biomarkers, and could guide treatment selection and sequence in an era where we strive to personalized therapy.
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http://dx.doi.org/10.3390/diagnostics10080549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459446PMC
July 2020

Langerhans cell histiocytosis with spinal, pulmonary and pituitary involvement: What about ACTH deficiency without diabetes insipidus? A propos of a case.

J BUON 2020 Mar-Apr;25(2):612-617

Medway NHS Foundation Trust, Windmill Road, ME7 5NY, Gillingham, Kent, UK.

Langerhans cell histiocytosis (LCH) is disease process characterized by clonal proliferation of CD1a+ dendritic cells within an inflammatory infiltrate of hematopoietic derived cells. LCH can manifest with a broad spectrum of symptoms and can involve single organs or have a multisystem distribution. Central nervous system (CNS) involvement of LCH can manifest as granulomatous parenchymal or pituitary mass lesions. Focal, space-occupying lesions, such as masses in the meninges, choroid plexus, and brain parenchyma may contain CD1a+ LCH cells, lymphocytes, and macrophages with histology similar to that of extracranial lesions. Here, we describe a rare case of multisystem LCH in an adult patient presenting with spinal lesions and isolated adrenocorticotropic (ACTH) deficiency without diabetes insipidus (DI). In addition, we review the literature summarizing the few reports of hypopituitarism in LCH in the absence of DI.
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January 2021

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.
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http://dx.doi.org/10.3390/jpm10020041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354604PMC
May 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'.
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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.
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http://dx.doi.org/10.1016/j.critrevonc.2020.102882DOI Listing
March 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.
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http://dx.doi.org/10.1007/s10637-019-00867-4DOI Listing
February 2020

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

PARP Inhibitors in Ovarian Cancer: The Route to "Ithaca".

Diagnostics (Basel) 2019 May 18;9(2). Epub 2019 May 18.

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

Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Genomic instability characterizes high-grade serous ovarian cancer (HGSOC), with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Early studies have shown significant efficacy for PARP inhibitors in patients with germline breast related cancer antigens 1 and 2 (BRCA1/2) mutations. It has also become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this treatment. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The choice of which PARP inhibitor is mainly based upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of patients most likely to benefit from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The aim of this review is to describe the current evidence for PARP inhibitors in ovarian cancer, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolution of resistance.
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http://dx.doi.org/10.3390/diagnostics9020055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627688PMC
May 2019

Ovarian carcinosarcoma: Current developments and future perspectives.

Crit Rev Oncol Hematol 2019 Feb 24;134:46-55. Epub 2018 Dec 24.

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

Ovarian carcinosarcoma (OCS) constitute uncommon malignancies accounting for only 1-4% of ovarian cancers. Patients more often present with advanced stage disease and symptoms similar to those of epithelial ovarian cancers (EOC). Optimal tumor cytoreduction appears to be an important determinant of survival. Platinum-based chemotherapy remains the most commonly employed adjuvant treatment. The uncertain origin and poor prognosis of OCS motivate determination of the molecular basis of carcinosarcomas aggressive behavior in the hope of developing novel and effective treatment modalities. The present review summarizes the current knowledge on the epidemiology, pathology, prognostic factors, clinical presentation, and therapeutic interventions including future potential therapeutic targets.
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http://dx.doi.org/10.1016/j.critrevonc.2018.12.006DOI Listing
February 2019

The Developing Story of Predictive Biomarkers in Colorectal Cancer.

J Pers Med 2019 Feb 7;9(1). Epub 2019 Feb 7.

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

Colorectal cancer (CRC) is the third most common malignancy worldwide. Surgery remains the most important treatment for non-metastatic CRC, and the administration of adjuvant chemotherapy depends mainly on the disease stage, which is still the strongest prognostic factor. A refined understanding of the genomics of CRC has recently been achieved thanks to the widespread use of next generation sequencing with potential future therapeutic implications. Microsatellite instability (MSI) has been suggested as a predictive marker for response to anti-programmed-cell-death protein 1 (PD-1) therapy in solid tumors, including CRC. It should be noted that not all cancers with MSI phenotype respond to anti-PD-1 immunotherapy, highlighting the urgent need for even better predictive biomarkers. Mitogen-Activated Protein Kinase () pathway genes , , and represent important molecular targets and could serve as independent prognostic biomarkers in CRC, and identify those who potentially benefit from anti-epidermal growth factor receptor (EGFR) treatment. Emerging evidence has attributed a significant role to inflammatory markers including blood cell ratios in the prognosis and survival of CRC patients; these biomarkers can be easily assessed in routine blood exams and be used to identify high-risk patients or those more likely to benefit from chemotherapy, targeted therapies and potentially immunotherapy. Analysis of cell-free DNA (cfDNA), circulating tumor cells (CTC) and/or micro RNAs (miRNAs) could provide useful information for the early diagnosis of CRC, the identification of minimal residual disease and, the evaluation of the risk of recurrence in early CRC patients. Even the selection of patients suitable for the new targeted therapy is becoming possible with the use of predictive miRNA biomarkers. Finally, the development of treatment resistance with the emergence of chemo-resistance clones after treatment remains the most important challenge in the clinical practice. In this context it is crucial to identify potential biomarkers and therapeutic targets which could lead to development of new and more effective treatments.
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http://dx.doi.org/10.3390/jpm9010012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463186PMC
February 2019

Malignant peritoneal mesothelioma: clinical aspects, and therapeutic perspectives.

Ann Gastroenterol 2018 Nov-Dec;31(6):659-669. Epub 2018 Sep 14.

Department of Gastroenterology, University Hospital of Ioannina, Faculty of Medicine, School of Health Sciences, University of Ioannina, Greece (Konstantinos H. Katsanos, Dimitrios K. Christodoulou).

Malignant peritoneal mesothelioma (MPM) is a rare disease with a wide clinical spectrum. It arises from the peritoneal lining and commonly presents with diffuse, extensive spread throughout the abdomen and, more rarely, metastatic spread beyond the abdominal cavity. Computed tomography, magnetic resonance imaging and positron-emission tomography are important diagnostic tools used for the preoperative staging of MPM. The definitive diagnosis is based on histopathological analysis, mainly via immunohistochemistry. In this regard, negativity represents a useful diagnostic biomarker for differentiating MPM from ovarian carcinoma. In addition, loss is specific to MPM and allows it to be distinguished from both benign mesothelial lesions and ovarian serous tumors. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has become an increasingly important therapeutic approach, while systemic therapies are still being developed. Histology, Ki-67, completeness of cytoreduction, age, sex, and baseline thrombocytosis are commonly used to optimize patient selection for CRS with HIPEC. Additionally, it is well recognized that, compared to other subtypes, an epithelial morphology is associated with a favorable prognosis, whereas baseline thrombocytosis predicts an aggressive biologicalbehavior. Platelets and other immunologic cytokines have been evaluated as potential novel therapeutic targets. Epigenetic modifiers, including BAP1, SETD2 and DDX3X, are crucial in mesothelial tumorigenesis and provide opportunities for targeted treatment. Overexpression of the closely interacting phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathways appears crucial in regulation of the malignant phenotype. The use of targeted therapies with PI3K-mTOR-based inhibitors requires further clinical assessment as a novel approach.
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http://dx.doi.org/10.20524/aog.2018.0305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191875PMC
September 2018

Spinal Ewing Sarcoma Debuting with Cord Compression: Have We Discovered the Thread of Ariadne?

Anticancer Res 2018 Oct;38(10):5589-5597

Acute Oncology Assessment Unit, Medway NHS Foundation Trust, Kent, U.K.

Ewing's sarcoma (ES) of the spine with cord or radicular compression as an initial sign is infrequent. It is unclear, in alleviating a neurological deficit, whether decompressive laminectomy is preferred over chemotherapy. Herein, a literature review of the treatment approaches to the primary or metastatic ES of the spine has been performed. Collected data included clinical features of the patients, treatment, and outcome. There are reported 69 cases with initial presentation of cord or radicular compression of spinal cord, arising from primary or metastatic ES, treated either with initial chemotherapy and/or radiotherapy (RT) (33.33%, n=23), or decompressive surgery (66.66%, n=46). The median age at diagnosis was 17.95 years old (range=0.06-60), and 38 patients (55.07%) were male. Eighteen (78.26%) were initially treated with chemotherapy combined with RT, whereas 3 (13.04%) were managed with RT alone. One patient (4.35%) received only corticosteroids, while there are not available data for the treatment of another one (4.35%). The remaining 46 patients (66.66%) were initially treated with decompressive surgery. Among them, 40 (57.97%) received postoperative chemotherapy, RT or combined modality therapy, whereas 6 patients (8.69%) were not treated adjuvantly. Sixteen out of 23 patients (69.6%) treated with systemic therapy, and 37 from 46 (80.43%) of those managed with decompressive laminectomy were still alive at a mean follow-up period of 2.11 years (range=0.16-6) and 3.45 years (range=0.16-26.08), respectively. To summarize, spinal resection and reconstruction followed by adjuvant treatment reduce the risk of local recurrence, and improve long-term survival. However, ES of the spine is not a distinct clinical entity and can be either managed with chemotherapy and/or RT, similarly to other localization.
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http://dx.doi.org/10.21873/anticanres.12893DOI Listing
October 2018

Metastatic Spinal Cord Compression: Unraveling the Diagnostic and Therapeutic Challenges.

Anticancer Res 2018 Sep;38(9):4987-4997

Acute Oncology Assessment Unit, Medway NHS Foundation Trust, Kent, U.K.

Malignant spinal cord compression (MSCC) is one of the most devastating complications of cancer. Patients often present with a history of progressive pain, paralysis, sensory loss, progressive spinal deformity, and loss of sphincter control. It is an emergency that requires rapid decision making on the part of several specialists, given the risk of permanent spinal cord injury or death. The goals of treatment in spinal metastases are pain control and improvement of neurological function in order to achieve better quality of life (QoL). The standard of care in most cases is rapid initiation of corticosteroids in combination with either surgical decompression in case of an operable candidate, followed by radiation therapy (RT) or RT alone. Surgery is associated with improved outcomes, but is not appropriate for many patients presenting with advanced symptoms of MSCC, such as paralysis, or those with a poor performance status, or cachexic state, as well as altered mental conditions, co-morbidities, surgical risks, and limited life expectancy. On the other hand, aggressive surgical treatment and post-operative RT is advocated for those with more favorable prognosis, or who are expected to have higher neurological recovery potential. Many candidates may require for combined anterior and posterior approaches to effectively deal with the compressive pathology and stabilize the spine. Most patients are presently treated by primary RT, given with the aim of improving function and symptom management. However, there is still debate regarding the most appropriate RT schedule. Rehabilitation can serve to relieve symptoms, QoL, enhance functional independence, and prevent further complications. Ambulatory status has been found to be an important prognostic factor for patients with MSCC.
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http://dx.doi.org/10.21873/anticanres.12817DOI Listing
September 2018

A review on pregnancy complicated by ovarian epithelial and non-epithelial malignant tumors: Diagnostic and therapeutic perspectives.

J Adv Res 2018 Jul 6;12:1-9. Epub 2018 Mar 6.

Medical School, University of Cyprus, Old road Lefkosias Lemesou, No. 215/6, 2029 Aglantzia, Nicosia, Cyprus.

The management of gestational ovarian cancer can be challenging because of the risk of fetal wastage, and the possibility of treatment-related complications to the fetus; it is based on insufficient data from retrospective studies and case series. Here, a literature review of the diagnostic and surgical approaches to the gestational ovarian cancer has been performed; moreover, data on safety of chemotherapeutic treatments in pregnancy, including both oncologic and fetal outcomes, have also been reviewed. Up to now, 193 cases of ovarian cancers during pregnancy have been reported in the English literature. Treatment of ovarian malignancies during pregnancy depends on histology, stage, and gestational weeks. When possible, surgical excision is indicated, and fertility-sparing surgery can be offered to stage I epithelial ovarian tumours (EOC), germ cell ovarian, or sex-cord stromal ovarian tumours. Neoadjuvant and/or adjuvant chemotherapy for advanced ovarian tumours is indicated as in non-pregnant women. Administration of chemotherapy after the first trimester, can cause fetal growth restriction, while being seemingly safe. The therapeutic approach of ovarian cancer in pregnancy should be individualized and intended in specialized centers.
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http://dx.doi.org/10.1016/j.jare.2018.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032492PMC
July 2018

Extranodal diffuse large B-cell lymphomas: A retrospective case series and review of the literature.

Hematol Rep 2018 Mar 3;10(1):7070. Epub 2018 Apr 3.

Department of Medical Oncology.

Non-Hodgkin lymphomas commonly show extranodal involvement (25-30%) but primary diffuse large B-cell lymphomas (DLBCL) with extranodal localization represent clinically and molecularly distinct entities. The present study involved retrospective analysis of case records of 4 patients who were diagnosed with extranodal DLBCL between 2010 and 2016 at the Medical Oncology and Hematology Departments of the Ioannina University Hospital, Greece. Median age of presentation was 69 years (range 60-77 years). There were 2 males and 2 females. The sites of DLBCL involvement included adrenal gland, mandible, cervix uteri, and ileum. Two patients had B symptoms while none had bone marrow involvement. After staging workup, all the patients fell into I stage. The treatment approach included chemotherapy combined with rituximab (R), whereas one patient received additionally irradiation therapy. Post-treatment positron emission tomography-computed tomography scan was performed in 3 patients. In terms of the outcome, 3 patients are alive in complete response, whereas one was lost in follow-up. Further prospective data analyses are required so as to better elucidate the biology and course of extranodal DLBCL.
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http://dx.doi.org/10.4081/hr.2018.7070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907641PMC
March 2018