Clinical and Translational Oncology

Common misconceptions in the prognostic evaluation of clinically stable patients with febrile neutropenia and solid tumors

A comparative assessment of the effects of integrin inhibitor cilengitide on primary culture of head and neck squamous cell carcinoma (HNSCC) and HNSCC cell lines Abstract Background Integrins are highly attractive targets in oncology due to their involvement in angiogenesis in a wide spectrum of cancer entities. Among several integrin inhibitors, cilengitide is suggested to be one of the most promising inhibitors. However, little is known about the cellular processes induced during cilengitide chemotherapy in head and neck squamous cell carcinoma (HNSCC). Materials and methods For the current study, 3 HNSCC cell lines, SCC4, SCC15 and SCC25; and 3 primary culture cells, TU53, TU57, and TU63 were used. CD90, cytokeratin, and vimentin were stained immunohistochemically to identify the biological characteristics of these cell lines and primary culture cells and the cytostatic effect of cilengitide was evaluated. Quantitative polymerase chain reaction (qPCR) arrays were applied to evaluate target protein genes ITGAV, ITGB3, and ITGB5 of integrin αvβ3 and αvβ5 at respective concentrations of 50 and 100 μM cilengitide for 72 h. Results Cilengitide has significantly inhibited the proliferation of HNSCC cells in a dose-dependent way. At the same concentration, cilengitide suppressed the proliferation of primary culture cells even more strongly than it did that of cell lines, suggesting that primary culture cells retain more of their internal biological characteristics than do cell lines. qPCR assay detected downregulation of ITGAV, ITGB3, and ITGB5 gene expression after exposure to 50 μM of cilengitide. However, after exposure to 100-μM cilengitide, expression of these genes significantly increased both in cell lines and primary culture cells. Conclusions RGD-containing small-molecule synthetic peptides might be considered in tumor chemotherapy in the near future. The different reactions of primary culture cells and cell lines demonstrated that individualized chemotherapy plans may be a feasible option. However, research on the role of cilengitide in HNSCC therapy is still in its early stages, and further investigations are required.

Efficacy of nivolumab as checkpoint inhibitor drug on survival rate of patients with relapsed/refractory classical Hodgkin lymphoma: a meta-analysis of prospective clinical study Abstract Aims The primary standard treatment for classic Hodgkin's lymphoma (cHL) is chemotherapy and radiation therapy. However, some patients get relapsed, or their diseases become resistant. PD1 blocking antibodies have been used to increase the response of treatment in solid tumors, and led to potentially stable responses that are acceptable. Our purpose in this study is to investigate the effect of nivolumab as a PD1 blocking antibody on the survival rate of patients with Hodgkin's cancer. Methods Databases were found in International Medical Sciences, Web of Science, Medline, Scopus, Index Copernicus, PubMed, DOAJ, Google Scholar, EBSCO-CINAHL, and Persian databases containing SID and Magiran using keywords such as: "checkpoint inhibitor", "nivolumab", "Hodgkin lymphoma", and "PD1 Blockade". The risk of bias was determined by two external observers using the Cochrane checklists. After the search, the data provided in 51 documents was independently evaluated. Duplicate papers were excluded. Assessing the full texts of the remaining papers, 7 papers were approved. Results Pooled data of these seven studies revealed that the overall objective response rate was 68% (CI 64.1% to 72.1%; heterogeneity; I2 = 40.19%; p = 0.123) with partial remission (52%; CI 46.5% to 57.6%; heterogeneity; I2 = 28.36%; p = 0.212). In the pooled analysis, complete remission was 16.8 (CI 11.1% to 26.4%). Pooled data of six studies showed that stable disease was averaged to 19% (CI 16% to 23%; heterogeneity; I2 = 30%; p = 0.209; fixed-effect model). Conclusions The results of the study indicate that nivolumab as a PD1 pathway inhibitor can be effective in treating relapsed and refractory cHL patients compared to other therapies, and lead to more effective treatment over the long term. Furthermore, the adverse effects of nivolumab are controllable and have a good safety profile.

Efficacy of rechallenge with BRAF inhibition therapy in patients with advanced BRAFV600 mutant melanoma Abstract Background The treatment of patients with BRAFv600 mutant melanomas progressing to BRAF inhibitors (BRAFi) and immunotherapy remains challenging. Preclinical studies and a small phase 2 trials have recently suggested that rechallenging with BRAFi may have a roll in these patients. The aim of this systematic review was to summarise the current evidence on the efficacy of BRAF inhibition therapy rechallenge after progression to BRAFi in metastatic BRAFv600 melanoma patients. Materials and methods We performed a systematic literature search in MEDLINE, Embase and the Cochrane Library CENTRAL up to November 2018. The target was restricted to patients with unresectable and/or metastatic BRAF V600 mutant melanoma that had previously progressed on BRAFi, were off-treatment for a period of time and then retreated with a BRAF inhibition strategy. We included prospective trials, observational studies and case reports. The primary outcomes were overall response rate (ORR), disease control rate (DCR), median progression-free survival (PFS) and median overall survival since the start of the treatment. Results Up to November 2018, nine reports met our inclusion criteria: five case reports, three observational studies and a phase 2 trial. No comparative studies have been reported. In total, 188 patients met the inclusion criteria for this review. Efficacy results of the observational reports and the clinical trial are presented. ORR varied between 28 and 43% and DCR between 57 and 72%. Duration of response was reported in 1 retrospective study and was of 14 months. PFS varied between 4.9 and 5 months and OS was not reported in all studies. Conclusion Although no comparative studies have been conducted, rechallenging with BRAF inhibition therapy seems a plausible treatment option. Randomized trials are needed to confirm these results.

The RANK–RANKL axis: an opportunity for drug repurposing in cancer? Abstract Drug repurposing offers advantages over traditional drug development in terms of cost, speed and improved patient outcomes. The receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) inhibitor denosumab is approved for the prevention of skeletal-related events in patients with advanced malignancies involving bone, including solid tumours and multiple myeloma. Following improved understanding of the role of RANK/RANKL in cancer biology, denosumab has already been repurposed as a treatment for giant cell tumour of bone. Here, we review the role of RANK/RANKL in tumourigenesis, including effects on tumour initiation, progression and metastasis and consider the impact of RANK/RANKL on tumour immunology and immune evasion. Finally, we look briefly at ongoing trials and future opportunities for therapeutic synergy when combining denosumab with anti-cancer agents such as immune checkpoint inhibitors.

The role of immunotherapy in small cell lung cancer Abstract Despite decades of research, prognosis for SCLC patients remains poor, and treatment options limited. SCLC is an immunogenic tumor with high somatic mutation rates due to tobacco exposure resulting in potential neo-antigens, the presence of suppressed immune responses, and occurrence of paraneoplastic disorders. The use of T cell immune-checkpoint inhibitors (anti-PD1: nivolumab, pembrolizumab; anti-PD-L1: atezolizumab, durvalumab; anti-CTLA-4: ipilimumab, tremelimumab) have shown promising antitumor activity with the potential to prolong survival in SCLC patients. In fact, atezolizumab when combined with chemotherapy has achieved the milestone of being the first drug to improve survival in patients with newly diagnosed extensive-stage SCLC. Other immunotherapeutic approaches evaluated in clinical trials for SCLC include the use of cytokines, cancer vaccines, antiganglioside therapies, TLR9 inhibition, anti-Notch signaling, and anti-CD47. This review discusses the rationale and clinical evidence of immunotherapy in SCLC, the conflictive clinical results of novel immunotherapeutic agents and combinatorial therapies under evaluation in SCLC patients.

Letrozole improves the sensitivity of breast cancer cells overexpressing aromatase to cisplatin via down-regulation of FEN1 Abstract Purpose Flap endonuclease 1 (FEN1) is up-regulated by estrogen (17β-estradiol, E2) and related to cisplatin resistance of human breast cancer cells. Letrozole, an aromatase inhibitor, suppresses the change of testosterone into estrogen and is frequently used to treat breast cancer. However, the effects of letrozole on FEN1 expression and cisplatin sensitivity in breast cancer cells overexpressing aromatase have not been revealed. Methods The expression of FEN1 and the proteins in ERK/Elk-1 signaling were evaluated by RT-PCR and Western blot. Cisplatin sensitivity was explored through CCK-8 and flow cytometry analysis, respectively. FEN1 siRNAs and FEN1 expression plasmid were transfected into cells to down-regulate or up-regulate FEN1 expression. The promotor activity of FEN1 was detected using luciferase reporter assay. Results FEN1 down-regulation improved cisplatin sensitivity of breast cancer cells overexpressing aromatase. Letrozole down-regulated FEN1 expression and increased cisplatin sensitivity. The sensitizing effect of letrozole to cisplatin was dependent on FEN1 down-regulation. FEN1 overexpression could block the sensitizing effect of letrozole to cisplatin. Testosterone up-regulated the promotor activity, protein expression of FEN1, and phosphorylation of ERK/Elk-1, which could be eliminated by both letrozole and MEK1/2 inhibitor U0126. Letrozole down-regulated FEN1 expression in an ERK/Elk-1-dependent manner. Conclusions Our findings clearly demonstrate that letrozole improves cisplatin sensitivity of breast cancer cells overexpressing aromatase via down-regulation of FEN1 and suggest that a combined use of letrozole and cisplatin may be a potential treatment protocol for relieving cisplatin resistance in human breast cancer.

Neurotrophic tropomyosin receptor kinase (NTRK) and nerve growth factor (NGF) are not expressed in Caucasian patients with biliary tract cancers: pooled data from three independent cohorts Abstract Background Neuronal signaling has been implicated in the pathophysiology of multiple malignancies. In biliary tract cancers (BTCs), tumor cell expression of nerve growth factor (NGF) and its receptor neurotrophic tropomyosin receptor kinase (NTRK) has been reported in Asian patients and linked to inferior clinical outcome. Furthermore, NTRK fusions have emerged as a promising target in various cancers. Expression patterns of these markers in Caucasian patients remain unknown. Methods In this study, 106 patients with BTCs were included. Immunohistochemistry for pan-NTRK and NGF-beta was performed on > 90 samples of this cohort. Additionally, samples from two independent cohorts, incorporating 254 cases, were used to confirm the findings of the original cohort. Results While expression of pan-NTRK and NGF-beta was readily detectable in peri-tumoral nerves, these markers were not detectable in malignant epithelial cells in our cohort. Conclusions In a large cohort of Caucasian patients with BTC, NTRK and NGF-beta were not detectable, underscoring potential differences between Caucasian and Asian patient populations.

Cost–utility analysis of germline BRCA1/2 testing in women with high-grade epithelial ovarian cancer in Spain Abstract Purpose Germline mutations in BRCA1 and/or BRCA2 genes (gBRCA1/2m) are associated with an increased risk of breast cancer (BC) and ovarian cancer (OC). The aim of this study was to estimate the efficiency of providing germline BRCA1/2 testing to high-grade epithelial ovarian cancer (HGEOC) patients without family history of OC or BC and the subsequent testing and management of their relatives with gBRCA1/2m in Spain. Methods/patients Incident HGEOC patients without family history of OC or BC who were gBRCA1/2m carriers and their relatives were simulated in a 50-year time horizon. The study compared two scenarios: BRCA1/2 testing vs no testing, using the perspective of the Spanish National Health Service. Cancer risk among gBRCA1/2m carriers was estimated based on their age and whether they had undergone risk-reducing surgeries. Direct healthcare costs and utilities of patients who developed EOC and BC were also included. A probabilistic sensitivity analysis (PSA) with 5 thousand simulations was developed considering ± 25% of the base-case value. Results The BRCA1/2-testing scenario amounted to €13,437,897.43 while the no-testing scenario amounted to €12,053,291.17. It was estimated that the screening test improved the quality of life among the patients' relatives by 43.8 quality-adjusted life years (QALYs). The incremental cost–utility ratio (ICUR) was €31,621.33/QALY in the base case. The PSA showed that 89.12% of the simulations were below the €50,000/QALY threshold. Conclusion Providing this screening test to HGEOC patients and their relatives is cost-effective and it allows one to identify a target population with high risk of cancer to provide effective prevention strategies.

Clinical significance of serum EGFR gene mutation and serum tumor markers in predicting tyrosine kinase inhibitor efficacy in lung adenocarcinoma Abstract Objective To study the clinical significance of serum epidermal growth factor receptor (EGFR) gene mutation and serum tumor markers in the prediction of tyrosine kinase inhibitor (TKI) efficacy in patients with lung adenocarcinoma. Methods Ninety patients with pathologically diagnosed lung adenocarcinoma were enrolled. Further, 51 out of 90 patients received the EGFR-TKI therapy, oral gefitinib. The correlations among serum EGFR gene mutations in exons 18–21, serum tumor markers such as carcinoembryonic antigen (CEA), carbohydrate antigen 24-2 (CA24-2), carbohydrate antigen 125, carbohydrate antigen 15-3 as well as carbohydrate antigen 19-9 (CA19-9) levels, and EGFR-TKI efficacy were determined. Results There was a high consistency of EGFR gene mutation rate between serum and tissue samples. The serum EGFR gene mutation rate in female patients or non-smokers was significantly higher than that in male patients or smokers, respectively. Serum CA19-9, CA24-2, and CEA levels were significantly correlated with serum EGFR mutation. After receiving gefitinib, the progression-free survivals (PFSs) of patients with high serum CEA level, high serum CA19-9 level, or serum EGFR gene mutation were significantly higher than those of normal patients, respectively. The PFSs were significantly prolonged in patients with EGFR gene mutation and high serum CEA level or patients with EGFR gene mutation and high serum CA19-9 level compared with those in patients with one abnormal biomarker and normal patients. Conclusion Combined detection of EGFR gene mutations as well as CA19-9 and CEA levels in peripheral blood can predict the efficacy of EGFR-TKI in the treatment of patients with lung adenocarcinoma.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com