Oncology

Forced expression of NR4A3 induced the differentiation of human neuroblastoma-derived NB1 cells Abstract Nuclear receptor subfamily 4, group A, member 3 (NR4A3) is a member of the NR4A subgroup of orphan nuclear receptors, implicated in the regulation of diverse biological functions, including metabolism, angiogenesis, inflammation, cell proliferation, and apoptosis. Although many reports have suggested the involvement of NR4A3 in the development and/or progression of tumors, its role varies among tumor types. Previously, we reported that DNA hypomethylation at NR4A3 exon 3 is associated with lower survival rate of neuroblastoma (NB) patients. As hypomethylation of this region results in reduced expression of NR4A3, our observations suggested that NR4A3 functions as a tumor suppressor in NB. However, the exact mechanisms underlying its functions have not been clarified. In the present study, we analyzed public databases and showed that reduced NR4A3 expression was associated with shorter survival period of NB in two out of three datasets. An in vitro study revealed that forced expression of NR4A3 in human NB-derived cell line NB1 resulted in elongation of neurites along with overexpression of GAP43, one of the differentiation markers of NB. On the other hand, siRNA-mediated knockdown of NR4A3 suppressed the expression level of GAP43. Interestingly, the forced expression of NR4A3 induced only the GAP43 but not the other molecules involved in NB cell differentiation, such as MYCN, TRKA, and PHOX2B. These results indicated that NR4A3 directly activates the expression of GAP43 and induces differentiated phenotypes of NB cells, without affecting the upstream signals regulating GAP43 expression and NB differentiation.

Mortality rates and prognostic factors in patients with malignant salivary tumors Abstract Malignancies of the salivary glands represent a multifarious disease. Evaluating the prognostic factors of these malignancies may help predict patient outcome and aid decision-making in choosing the most suitable therapy. We examined the role of various salivary tumorigenic, clinical and therapeutic features in a cohort of 101 patients diagnosed and treated for primary malignant salivary tumors. These include histo-pathological diagnosis, stage, grade and T, N, M values as well as the existence of perineural invasion and extra-parenchymal spread. We also identified the salivary gland involved, the sub-compartment specific location of the tumor and the therapy administered. All these were related to mortality. Of the 101 patients examined, 79 survived and 22 died due to the disease. Tumor staging, distant metastasis and perineural invasion were highly significant predictors of increased lethality. Histo-pathological grading was also a predictor but to a lesser degree. Neither neck metastasis nor tumor size or type had a significant impact on lethality. Performing neck dissections did not decrease lethality rate. Location of the tumor in the parotid gland and more so in its deep lobe adversely affected lethality; extra-parenchymal spread also had an adverse effect. Our results seem to indicate hematogenous rather than lymphogenous spread of metastasis from malignant salivary tumors. The highest therapeutic priority should be achieving full local control of the disease by safe removal of the primary salivary tumor, accompanied by regional control of perineural invasion and extra-parenchymal spread and appropriate systemic treatment aimed at eradicating distant metastasis.

The role of radiotherapy in epithelial ovarian cancer: a literature overview Abstract Ovarian cancer (OC) accounts for 3% of all cancer in women and for 5% of all cancer-related deaths. Epithelial Ovarian Cancer (EOC) is a radiosensitive malignancy with a poor prognosis. In the pre-chemotherapy era, radiation therapy (RT) delivered to the abdominopelvic region (whole abdominal irradiation, WAI) has historically played a role in the adjuvant and consolidation setting. Specific cluster of patients with early-stage disease and definite histologies may take advantage of RT. Platinum-based chemotherapy (CT) has replaced RT and plays a major role in most of the clinical settings. Radiation Therapy for palliation is recommended in patients with localized symptoms. Nevertheless, modern RT represents a reliable treatment option, with a mild toxicity profile, particularly effective for oligo-recurrent or progressive disease. The present literature review aims to highlight the historical role of RT in EOC, the actual lines of evidence, and the future perspectives.

High total bilirubin level is a significant risk factor for severe neutropenia in patients receiving irinotecan-based chemotherapy Abstract Irinotecan is effective for the treatment of metastatic colorectal cancer (mCRC) and advanced pancreatic cancer (aPC). However, these treatments are often limited due to the incidence of severe neutropenia. We identified risk factors for severe neutropenia in patients with mCRC or aPC, receiving irinotecan-based chemotherapy regimens. The study selected 104 patients (mCRC: 53 and aPC: 51) who received irinotecan-based chemotherapy between January 2014 and May 2018 and who were included in the present study. The initial dose of irinotecan was 150 mg/m2 in all patients, and patients with a lower initial dose of irinotecan were excluded. Severe neutropenia (grade ≥ 3) occurred in 56 patients (53.8%). Multivariable Cox proportional hazards analysis indicated that modified FOLFIRINOX (mFOLFIRINOX) and serum total bilirubin (T-Bil) were significant risk factors for severe neutropenia. Moreover, with receiver-operating characteristic (ROC) curve analysis, the cutoff for T-Bil was found to be 0.7 mg/dL. Among patients treated with mFOLFIRINOX therapy, the incidence of severe neutropenia was significantly higher in patients with high level of T-Bil (> 0.7 mg/dL) than in those without it (93.8% vs 55.0%, P = 0.006). A chemotherapy regimen (modified FOLFIRINOX therapy) and T-Bil > 0.7 mg/dL were significant risk factors for severe neutropenia in patients receiving 150 mg/m2 irinotecan.

Effectiveness of a genetic test panel designed for gynecological cancer: an exploratory study Abstract To increase diagnostic efficiency and cost-effectiveness, we performed an exploratory genetic test using a newly designed panel containing 28 actionable and druggable genes, alterations in which are frequently reported in gynecological cancers (TANRE-G, Targeted variants ANalysis RElated to Gynecological cancers). Samples consisted of the formalin-fixed, paraffin-embedded tissue of endometrial (4 cases), cervical (3 cases), and ovarian (4 cases) carcinomas. The sequencing procedure was performed using Ion PGM in our institute with related sequencing kits, and data were analyzed using ClinVar. The present system achieved more than 2500 reads in all tumor samples, and enabled a copy number variation analysis. Results showed that actionable and druggable mutations were detected in 82% (9/11) and 64% (7/11) of cases, respectively, which was similar to other commercially available genetic tests. The amplification of MYC and KRAS was also detected. The analysis cost for each sample was JPY 94,000 (USD 850). These results demonstrate the potential of the TANRE-G panel as an effective tool for examining genetic alterations in gynecological cancers.

Expression of cellular apoptosis susceptibility (CAS) in the human testis and testicular germ cell tumors Abstract Testicular germ cell tumors are the most frequent malignancies found in men between 15 and 44 years old. Although cellular apoptosis susceptibility (CAS) was demonstrated to be upregulated in breast cancer and colon cancer, the expression of CAS in the human testis and testicular germ cell tumors remained elusive. In the present study, CAS-positive signals were detected in the normal testicular tissues, cancer adjacent normal testicular tissues, seminoma, yolk sac tumor, and teratoma. Interestingly, the expression level of CAS in testicular germ cell tumors (TGCTs) (but not seminoma) was significantly lower than that of human testicular tissues and cancer adjacent normal testicular tissues, suggesting that decreased CAS contributed to the progression of TGCTs. Notably, the expression of CAS in seminoma was significantly higher than that of in the non-seminomas, consistent with the results from TCGA database. Furthermore, the localization of CAS is mainly restricted in the nucleus in the lesions of normal human testicular tissue and cancer adjacent normal testicular tissue. Although the expression of CAS was not significantly different between normal testicular tissue and seminoma, CAS was more enriched in cytoplasm in seminoma compared to the normal, cancer adjacent tissue and other types of TGCTs. The current results demonstrated reduced expression of CAS in the human testicular germ cell tumors and the CAS translocation from the nuclear to cytoplasm in seminoma, thereby supporting a possible role in normal testis function and in the development of seminoma.

Clinical significance of soluble forms of immune checkpoint molecules in advanced esophageal cancer Abstract Immune checkpoint molecules are expressed on cancer cells and regulate tumor immunity by binding to ligands on immune cells. Although soluble forms of immune checkpoint molecules have been detected in the blood of patients with some types of tumors, their roles have not been fully elucidated. Soluble PD-L1, PD-1, CD155, LAG3, and CD226 (sPD-L1, sPD-1, sCD155, sLAG3, and sCD226, respectively) were measured in the sera of 47 patients with advanced esophageal cancer and compared with those of 24 control subjects. Pretreatment levels of sPD-1 and sCD155 were significantly higher in the patients with cancer than in the control subjects (P = 0.023, P = 0.001). The sPD-1 levels tended to be higher in the patients with lymph node metastasis, a large tumor diameter, and higher levels of serum SCC antigen (P = 0.150, P = 0.189, and P = 0.078, respectively). However, higher levels of sCD155 were associated with a better response to chemotherapy and favorable overall survival (P = 0.111 and P = 0.068, respectively). After 2 courses of chemotherapy, the levels of sCD155 and sCD226 were significantly increased (P < 0.001 and P = 0.002, respectively). Moreover, the increase in sCD226 during chemotherapy was associated with poor treatment response (P = 0.019). sPD-1 levels are possibly dependent on the tumor aggressiveness of the esophageal cancer. Furthermore, the pretreatment levels of sCD155 and kinetic change of sCD226 after chemotherapy may be used as biomarkers of the treatment response and prognosis in patients with esophageal cancer.

Rhabdomyosarcoma in adults: analysis of treatment modalities in a prospective single-center series Abstract Rhabdomyosarcoma (RMS) is rare in adults and it is generally characterized by poor outcome. In a previous retrospective study, we demonstrated a better prognosis in adults treated with multimodality approach resembling pediatric protocols. Thereafter, we developed specific recommendations based on the principles adopted in pediatric oncology. The present analysis reports the results in a subsequent prospective series. The study included 95 consecutive patients (age 18–77 years) treated from 2002 to 2015 for embryonal and alveolar RMS. As in the previous series, patients were stratified by the appropriateness of their treatment according to therapeutic guidelines for childhood RMS. The 5-year event-free survival (EFS) and overall survival (OS) rates were 33.6% and 40.3%, respectively. The 5-year EFS was 40.8% for patients with the highest treatment score, and 15% for those with lower score, while OS was 44.4% and 24.5%, respectively. The developing of specific recommendations enabled an increase in the number of patients treated with intensive multimodal treatment resembling pediatric strategy (69.7% vs. 39.1% in the retrospective series). This study reinforced the idea that adherence to the principles of pediatric protocols, improves adult RMS outcomes. However, treating adults with pediatric-type strategy is not enough to achieve the results obtained in children. Issues in compliance and a more aggressive biology of adult RMS might have a role in the different outcome according to age. Improving the collaboration between pediatric and adult oncologists in promoting specific clinical and biological research is crucial to improve the outcome for this patient population.

Bone marrow examination in patients with Ewing sarcoma/peripheral primitive neuroectodermal tumor without metastasis based on 18 F-fluorodeoxyglucose positron emission tomography/computed tomography Abstract Ewing sarcoma/peripheral primitive neuroectodermal tumor (ES/PNET) is an aggressive bone tumor. Bone marrow aspiration and biopsy (BMAB) has been recognized as the gold standard for assessing bone marrow status. While the latest guideline suggests the need to omit bone marrow aspiration in patients with no findings on 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) based on one retrospective report, there is no study using 18F-FDG PET/computed tomography (CT). We retrospectively reviewed 26 consecutive, previously untreated, ES/PNET patients. We compare the results of bone marrow aspiration and biopsy (BMAB) and those of 18F-FDG PET/CT in ES/PNET patients. All of the 21 patients without metastases on 18F-FDG PET/CT had negative BMAB. The sensitivity of bone marrow involvement in bone metastases positive patients on 18F-FDG PET/CT was 75% (3/4), and the specificity was 100% (22/22). In addition to the metastatic findings on 18F-FDG PET/CT, tumor diameter, lactate dehydrogenase level at diagnosis, and the presence or absence of bone metastasis were factors related to bone marrow involvement. It may be a reasonable option to omit BMAB in ES/PNET patients with no distant metastasis based on 18F-FDG PET/CT findings.

Influence of ABCB1 polymorphisms on the pharmacokinetics and toxicity of lenalidomide in patients with multiple myeloma Abstract Individual diversity in plasma concentrations of lenalidomide occurs despite dosage modifications based on creatinine clearance (CCr), which can lead to unexpected toxicity. We have previously identified a cutoff value of area under the concentration–time curve (AUC0–24) for lenalidomide to avoid severe toxicity. Here, we investigated the association between ABCB1 polymorphisms and pharmacokinetics of lenalidomide in patients with multiple myeloma (MM) treated with lenalidomide and dexamethasone. Plasma concentrations of lenalidomide were analyzed using liquid chromatography–tandem mass spectrometry. Genotyping for ABCB1 1236C>T, 2677G>A/T, and 3435C>T polymorphisms was performed, and the effects of ABCB1 polymorphisms on AUC0–24 for lenalidomide were compared in 36 patients with MM who were administered lenalidomide according to the drug label based on CCr. Genotyping analysis showed that although there were no differences in AUC0–24 in 1236C>T and 2677G>A/T polymorphisms. AUC0–24 was significantly higher in patients with the T allele of 3435C>T (n = 15) than in those without (n = 21) (median 6324.6 ng h/mL vs. 2857.4 ng h/mL, p = 0.028). The AUC0–24 value exceeded the aforementioned cutoff value in 95% of the patients with the T allele of 3435C>T but in 60% with C/C genotype (p = 0.013). Multivariate logistic analysis confirmed the significance of T allele of ABCB1 3435C>T as a factor due to which the AUC0–24 cutoff value was exceeded (hazard ratio of 15.0, p = 0.019). We show that lenalidomide pharmacokinetics is influenced by the ABCB1 3435C>T polymorphism, which could be useful to individualize dosage design and reduce unexpected toxicity.

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

6948891480

alsfakia@gmail.com