Human herpesvirus multiplex ddPCR detection in brain tissue from low- and high-grade astrocytoma cases and controls

BACKGROUND: Glioblastoma (GBM) is a fatal CNS malignancy, representing 50 % of all gliomas with approximately 12–18 months survival time after initial diagnosis. Recently, the human herpesvirus cytomegalovirus (CMV) has been suggested to have an oncogenic role, yet this association remains controversial. In addition, human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) have also been associated with low-grade gliomas, but few studies have examined HHV-6 and EBV in glioblastomas. Droplet digital PCR (ddPCR) is a highly precise diagnostic tool that enables the absolute quantification of target DNA. This study examines the association between multiple human herpesviruses and astrocytomas. METHODS: This study analyzed 112 brain tissue specimens, including 45 glioblastoma, 12 astrocytoma grade III, 2 astrocytoma grade II, 4 astrocytoma grade I, and 49 controls. All brain tissue samples were de-identified and pathologically confirmed. Each tissue block was sectioned for DNA extraction and CMV, EBV, HHV-6A and HHV-6B, and a cellular housekeeping gene were amplified by ddPCR. RESULTS: Neither CMV nor HHV-6A were detected in any of the astrocytoma samples. However, HHV-6B (p = 0.147) and EBV (p = 0.049) had a higher positivity frequency in the GBM compared to the controls. CONCLUSION: The undetectable CMV DNA in the astrocytoma cohort does not support the observation of an increased prevalence of CMV DNA in GBM, as reported in other studies. EBV has a significantly higher positivity in the GBM cohort compared to the controls, while HHV-6B has a higher but not statistically significant positivity in the case cohort. Whether these viruses play an oncogenic role in GBM remains to be further investigated

Glioblastoma multiforme: Pathogenesis and treatment

Each year, about 5-6 cases out of 100,000 people are diagnosed with primary malignant brain tumors, of which about 80% are malignant gliomas (MGs). Glioblastoma multiforme (GBM) accounts for more than half of MG cases. They are associated with high morbidity and mortality. Despite current multimodality treatment efforts including maximal surgical resection if feasible, followed by a combination of radiotherapy and/or chemotherapy, the median survival is short: only about 15 months. A deeper understanding of the pathogenesis of these tumors has presented opportunities for newer therapies to evolve and an expectation of better control of this disease. Lately, efforts have been made to investigate tumor resistance, which results from complex alternate signaling pathways, the existence of glioma stem-cells, the influence of the blood-brain barrier as well as the expression of 06-methylguanine-DNA methyltransferase. In this paper, we review up-to-date information on MGs treatment including current approaches, novel drug-delivering strategies, molecular targeted agents and immunomodulative treatments, and discuss future treatment perspectives. © 2015 Elsevier Ltd. All rights reserved

Targeting Programmed Cell Death -1 (PD-1) and Ligand (PD-L1): A new era in cancer active immunotherapy

Improved understanding of the immune system and its role in cancer development and progression has led to impressive advances in the field of cancer immunotherapy over the last decade. Whilst the field is rapidly evolving and the list of drugs receiving regulatory approval for the treatment of various cancers is fast growing, the group of PD1- PDL-1 inhibitors is establishing a leading role amongst immunomodulatory agents. PD1- PDL-1 inhibitors act against pathways involved in adaptive immune suppression resulting in immune checkpoint blockade. Within the last four years two PD-1 and three PD-L1 inhibitors have been utilized in clinical practice against a variety of malignancies. Focus was initially placed on targeting cancers considered immunogenic such as melanoma, renal and lung cancers but subsequently the application expanded to include amongst others Hodgkin Lymphoma, urothelial as well as head and neck cancer. This article provides a comprehensive review of the early and late phase trials that led to the regulatory approval of all five PD1- PDL-1 inhibitors in the corresponding cancer types. It presents available data on the combinations of PD1- PDL-1 inhibitors with other therapies (immunotherapy, targeted therapy and chemotherapy), the toxicity profile of the PD1- PDL-1 inhibitors and ongoing trials testing the efficacy of these agents in cancer types beyond those that have been addressed already. Finally, current and future challenges in the application of PD-1 and PD-L1 inhibitors are discussed with emphasis on the role of predictive biomarkers. © 201

Indications for an alternative effective treatment of head and neck squamous cell carcinoma with temsirolimus plus bevacizumab: From bench to bedside?

Head and neck squamous cell carcinoma (HNSCC) is a group of tumors known to be sensitive to chemotherapy and radiotherapy in patients who are treatment naive. However, when recurrences do occur, these tumors generally become resistant and objective responses to therapy at that point tend to be less effective. There has been an increasing interest in developing novel molecular-targeted agents that specifically modulate growth factor and signaling pathways that are unregulated in HNSCC tumor cells. Combinations of vascular endothelial growth factor and mammalian target of rapamycin inhibitors have been used in some types of neoplasms, but no such efforts have been made in HNSCC. In this study, we investigated the in vitro, in vivo, and clinical effects of the temsirolimus (mammalian target of rapamycin inhibitor, Tem) and bevacizumab (antivascular endothelial growth factor antibody, Bev) combination. In-vitro studies were carried out on the A431 human squamous epidermoid carcinoma cell line and in-vivo studies were carried out on A431 tumor cells implanted on female Nu/Nu*nuBR (athymic nude) mice. Also, the effectiveness of the Tem and Bev combination was tested clinically in two separate clinical cases of chemoresistant HNSCC. The in-vitro, in-vivo, and clinical results showed that this combination can be significantly effective. In conclusion, we discuss the theoretical basis of the molecular pharmacological interactions between Bev and Tem that could explain these good results. If the therapeutic index is ultimately well determined, the antitumor effect of Bev and Tem is very likely to yield fruitful results. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Evidence for Efficacy of Treatment with the Anti-PD-1 Mab Nivolumab in Radiation and Multichemorefractory Advanced Penile Squamous Cell Carcinoma

Penile squamous cell carcinoma (PeSCC) is a rare tumor and advanced PeSCC is associated with poor survival due to the aggressiveness of the disease and lack of effective systemic therapies. We describe for the first time a case with advanced chemoradiation refractory PeSCC who had documented response to active immunotherapy with the immune checkpoint inhibitor, anti-programmed death-1 monoclonal antibody Nivolumab. The patient suffered from a poor prognosis human papillomavirus-negative PeSCC, with a somatic inactivation mutation of cyclin-dependent kinase inhibitor 2A (CDKN2A) gene in tumor cells, and treatment with Nivolumab resulted in a partial response to therapy and significant tumor shrinkage. Histology transitions and alterations in tumorinfiltrating cytotoxic CD8+ T-cell lymphocytes, programmed death ligand-1 expression on tumor cells and immune cells in tumor lesion biopsies pretreatment and posttreatment with Nivolumab were observed and described. In conclusion, in patients with metastatic PeSCC active immunotherapy combinations with an anti-programmed death-1/programmed death ligand-1 agent may be beneficial and further relative clinical studies are required. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved

Topotecan and pegylated liposomal doxorubicin combination as palliative treatment in patients with pretreated advanced malignant pleural mesothelioma

Background: Malignant pleural mesothelioma (MPM) is an aggressive disease with poor or modest responses to chemotherapy and dismal prognosis. In most of the cases the scope of the treatment is only palliative. In the current study, the combination of i.v. topotecan and pegylated liposomal doxorubicin (PLD) in advanced multi-treated MPM was tested. Primary objective was palliation of the symptoms, with the secondary ones being the establishment of the regimen's safety and efficacy. Patients and methods: Nine patients were enrolled (7 males/2 females, median age 57.5 years, ECOG performance status ≤ 2), having progressed after 2 or 3 lines of chemotherapy including pemetrexed and cisplatin. Main symptoms were dyspnea, cough, chest pain, fatigue, and anorexia. The treatment included topotecan 1.2 mg/m2 i.v. on Days 1-3 and PLD 40 mg/m2 on Day 4, every 28 days. The patients received 4-8 chemotherapy cycles (median 5.8). Results: In all cases, symptoms were significantly improved after the 2nd treatment cycle. Respiratory function tests showed considerable enhancement, while cough and pain were drastically reduced. All patients had objective clinical benefit, 1 patient achieving partial response and 8 stable disease. Median time to progression and overall survival was 7 and 9 months, respectively. The chosen dose of the topotecan/ PLD combination was well-tolerated with no Grade 3/4 toxicities. Quality of life, as it was evaluated by the QLQ-C30 and QLQ-LC13 questionnaires, had improved scores especially the ones referring symptomatology. Conclusion: The current study shows a significant palliative effect of the topotecan/ PLD combination in pretreated patients with advanced MPM. ©2012 Dustri-Verlag Dr. K. Feistle