Oncology

Identification of important invasion and proliferation related genes in adrenocortical carcinoma Abstract Adrenocortical carcinoma (ACC) is an end‐stage hormonal syndrome. Although profound attempts have been made to illuminate the pathogenesis, the molecular mechanisms of ACC remain to be clarified. To identify the important genes in the progression of ACC, microarray datasets GSE19775 was downloaded from the gene expression omnibus database. The differentially-expressed genes (DEGs) were identified, and pathway and GO enrichment analyses were performed. The protein–protein interaction (PPI) network was constructed and the module analysis was performed using the protein interaction network analysis and Cytoscape. Also constructed target genes–miRNA regulatory network and target genes–TF regulatory network. Correlation of the hub genes were analyzed in The Cancer Genome Atlas. The prognostic values of hub genes were further validated by online tool UALCAN. Mutation analysis was done by online tool CBio Cancer Genomics Portal. A total of 884 DEGs were identified, with 441 in up regulation and 443 in down regulation. Pathways in catecholamine biosynthesis, aldosterone synthesis and secretion, pyrimidine deoxyribonucleosides salvage and systemic lupus erythematosus were the most significantly enriched for DEGs (up and down regulated). Blood vessel morphogenesis and cell cycle phase transition were the most significantly enriched term in biological processes, while extracellular matrix and chromosome, centromeric region were in cellular component and heparin binding and protein dimerization activity were in molecular function. Among the PPI networks and its module, target genes–miRNA regulatory network and target genes–TF regulatory network, hub genes were YWHAZ, FN1, GRK5, VCAM1, GATA6, TXNIP, HSPA1A, and F11R. Hub genes such as YWHAZ, STAT1, ICAM1, SH3BP5, CD83, FN1, TK1, HIST1H1C, CABLES1, and MCM3 were associated with poor overall survival, while hub genes such as STAT1, ICAM1, CD83, FN1, TK1, HIST1H1C, and MCM3 were highly expressed in stage 4. In conclusion, DEGs and hub genes diagnosed in this study may deepen our understanding of molecular mechanisms underlying the progression of ACC, and provide important targets for diagnosis and treatment of ACC.

Anti-cancer drugs-induced arterial injury: risk stratification, prevention, and treatment Abstract Vascular side effects of standard chemotherapeutic drugs and novel anti-tumor agents complicate treatment cycles, increase non-cancer-related mortality rates, and decrease the quality of life in cancer survivors. Arterial thromboembolic events (ATEE) are associated with most anti-cancer medications. Previous articles have reported a variety of vascular events including ST-segment elevation myocardial infarction as one of the most severe acute arterial attacks. Cardiologists should play an early role in identifying those at high risk for vascular complications and tailor anti-thrombotic therapies in keeping with thromboembolic and bleeding risks. Early preventive steps and individualized chemotherapy may decrease anti-tumor treatment-related vascular events. Here, we aim to provide an extensive review of anti-tumor drug-induced vascular injury (DIVI), pathomechanisms, and risk stratification underlining arterial events. We give a summary of clinical manifestations, treatment options, and possible preventive measures of DIVI. Additionally, the treatment of modifiable risk factors and tailored choice of chemotherapy must be considered in all oncology patients to prevent DIVI. We propose a complex tool for ATEE risk stratification which is warranted for early prediction leading to less frequent complications in cancer patients.

Functional coding and non-coding variants in human BRCA1 gene and their use in genetic screening Abstract BRCA1 is involved in double-strand DNA damage repair pathways, and mutations in the gene are associated with hereditary breast and ovarian cancers. With great help of the development of high-throughput DNA sequencing techniques numerous single-nucleotide polymorphisms (SNPs) and insertion deletion (Indel) mutations are detected on both coding and non-coding/regulatory regions of the BRCA1. Mutations may cause pathogenic or benign changes on the protein function or affect its expression. In the last decade, use of genetic screening tests to detect mutations on such genes has become greatly popular. However, it is very important to know the effect of the detected mutations, which is mostly possible by the use of predictive softwares, and also the related family history to be able to correctly analyse the screening results and to inform the patient. Therefore, use of in silico and in vitro techniques to score the pathogenicity of detected variants on genes like BRCA1 is now of great importance. Otherwise, results obtained from screening tests and family history cannot be analysed precisely.

A study of mechanistic mapping of novel SNPs to male breast cancer Abstract Alterations in BRCA2, PALB2, CHEK2, and p53 genes have been identified for their association with male breast cancer in various studies. The incidence of male breast cancer in India is consistent with its global rate. The present study was carried out with an aim to evaluate the genetic alterations in male breast cancer patients from Malwa region of Punjab, India. Four male breast cancer patients belonging to different families were recruited from Guru Gobind Singh Medical College and Hospital, Faridkot, India. A total of 51 genes reported with implications in the pathogenesis of breast cancer were screened using next generation sequencing. Germline variations were found in BRCA1, BRCA2, PMS2, p53, and PALB2 genes, previously reported to be associated with MBC as well as FBC. In addition to these, 13 novel missense alterations were detected in eight genes including STK11, FZR1, PALB2, BRCA2, NF2, BAP1, BARD1, and CHEK2. Impact of these missense alterations on structure and function of protein was also analyzed through molecular dynamics simulation. Structural analysis of these single nucleotide polymorphisms (SNPs) revealed significant impact on the encoded protein functioning.

Vitamin D supplementation and colorectal cancer prognosis

Recurrent prostate cancer after radical prostatectomy: restaging performance of 18F-choline hybrid PET/MRI Abstract To evaluate the diagnostic performance of a whole-body 18F-choline (FCH) hybrid PET/MRI for prostate cancer patients at biochemical relapse after radical prostatectomy (RP) compared to pelvic multiparametric MRI (mpMRI), one of the standard imaging modality for this patient population. From 2010 to 2016, 58 whole-body FCH PET/MRI studies with mpMRI acquisitions were performed in 53 prostate cancer patients relapsing after curative RP. Median PSA and PSA doubling time (PSA DT) at PET study were 1.5 ng/ml and 6.5 months, respectively. The overall positivity rate of FCH PET/MRI was 58.6% (n = 34), dropping to 44% in patients with a PSA ≤ 2 ng/ml (n = 36). Median PSA values in positive and negative PET/MRI studies were 2.2 ng/ml and 0.8 ng/ml, respectively, with no differences in PSA DT (6.5 vs. 6.6 months). A PSA value ≥ 1.5 ng/ml was a significant predictor of positivity on PET/MRI studies. Compared to PET, mpMRI identified more local relapses (17 vs. 14, p = 0.453) while PET outperformed whole-body Dixon MRI for regional (16 vs. 9, p = 0.016) and distant (12 vs. 6, p = 0.031) metastases. Compared to pelvic mpMRI, the treatment approach turned out to be influenced more frequently using whole-body FCH hybrid PET/MRI studies (58.6% vs. 38%). In prostate cancer patients with biochemical recurrence after RP, whole-body FCH PET/MRI achieved a higher detection rate of nodal/distant metastases compared to pelvic mpMRI alone, increasing the change of treatment strategy by more than 20%.

Hypofractionated radiotherapy combined with cetuximab in vulnerable elderly patients with locally advanced head and neck squamous cell carcinoma Abstract This study was designed to evaluate the objective response after hypofractionated radiotherapy (HFRT) combined with cetuximab (HFBRT) in vulnerable elderly patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Vulnerable elderly patients with histologically proven HNSCC received HFRT (total dose 60 Gy, 3 Gy/fraction) with concurrent cetuximab (250 mg/m2 with a loading dose of 400 mg/m2 1 week before HFRT). Elderly patients were categorized as vulnerable based on mini-cog test and adult comorbidity evaluation-27 score. All patients completed the programmed HFRT and two patients received the planned cetuximab infusion. Severe acute toxicity, observed in four patients, was gastrointestinal (oral mucositis in four cases; nausea/vomiting in one case) and dermatological (acneiform eruption in three cases; radiation dermatitis in one case). Three serious adverse events were recorded in three out of six patients Overall, three patients had a partial response and three patients had progression disease 3 months after the end of the treatment. No complete response was observed. HFBRT seems to be not a safer alternative approach for vulnerable elderly patients with locally advanced HNSCC. Further prospective trials are needed to define better tumor control with less incidence of toxic effects in vulnerable elderly HNSCC patients.

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.