Cancer Research and Clinical Oncology

Correction to: Neoadjuvant chemoradiotherapy delivered with helical tomotherapy under daily image guidance for rectal cancer patients: efficacy and safety in a large, multi-institutional series The article "Neoadjuvant chemoradiotherapy delivered with helical tomotherapy under daily image guidance for rectal cancer patients: efficacy and safety in a large, multi-institutional series"

Low number of intrafollicular T cells may predict favourable response to rituximab-based immuno-chemotherapy in advanced follicular lymphoma: a secondary analysis of a randomized clinical trial Abstract Background First-line rituximab therapy together with chemotherapy is the standard care for patients with advanced follicular B-cell lymphoma, as rituximab together with chemotherapy prolongs progression-free and overall survival (Herold et al. 2007; Marcus et al. 2005). However, as not all patient subgroups benefit from combined immuno-chemotherapy, we asked whether the microenvironment may predict benefit from rituximab-based therapy. Design To address this question, we performed a retrospective immunohistochemical analysis on pathological specimens of 18 patients recruited into a randomized clinical trial, where patients with advanced follicular lymphoma were randomized into either chemotherapy or immuno-chemotherapy with rituximab (Herold et al. 2007). Results We show here that rituximab exerts beneficial effects, especially in the subgroup of follicular lymphoma patients with low intrafollicular CD3, CD5, CD8, and ZAP70 and high CD56 and CD68 expression. Conclusion Rituximab may overcome immune-dormancy in follicular lymphoma in cases with lower intrafollicular T-cell numbers and higher CD56 and CD68 cell counts. As this was a retrospective analysis on a small subgroup of patients, these data need to be corroborated in larger clinical trials.

A prognostic score system with lymph node ratio in stage IIIA-N2 NSCLC patients after surgery and adjuvant chemotherapy Abstract Purpose The survival of patients with IIIA-N2 non-small cell lung cancer after surgery followed by adjuvant chemotherapy is heterogeneous. The aim of this study is to form a prognostic system and a heat map method to visualize the overall survival rates in those patients. Methods Univariate and multivariate Cox hazards regression models and the associated Wald Chi square coefficient were used to form the prognostic score system. Recursive partitioning analysis was used to determine the cutoff values of lymph node ratio and prognostic score in SEER cohort and validated in FDUSCC cohort. Meanwhile, a heat map method was used to visualize the overall survival probabilities of 3, 5 and 10 years for individual patient of both cohorts. Results Lymph node ratio (with cutoff of 0.36) significantly correlates with overall survival of these patients. In addition, in patients with the same level of N2 disease, lymph node ratio still significantly affects survival. Also, after the multivariate analysis in SEER cohort, six factors were independent prognostic factors including age, sex, type of surgery, size, lymph node ratio and differentiation. A prognostic sore system with these factors (with cutoff of 12) was validated as a predictor for overall survival in FDUSCC cohort. Conclusions This prognostic score system including lymph node ratio can predict the survival rates of IIIA-N2 patient after surgery and post-operative chemotherapy. Lymph node ratio could be a useful supplementation in TNM stage classification for IIIA-N2 patients. The heat map method can visualize the predicted overall survival of an individual patient.

Genetic profiling as a clinical tool in advanced parathyroid carcinoma Abstract Context Parathyroid carcinoma (PC) is a rare endocrine malignancy with no approved systemic therapies for unresectable locally invasive or distant metastatic disease. Understanding the molecular changes in advanced PC can provide better understanding of this disease and potentially help directing targeted therapy. Objective To evaluate tumor-specific genetic changes using next-generation sequencing (NGS) panels. Design All patients with advanced PC were tested for hot-spot panels using NGS panels including a 50-gene panel, a 409-gene panel if the standard 50-gene panel (Ion Torrent, Life Technology) was negative or a FoundationOne panel. Setting The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Patients or other participants 11 patients with advanced PC were selected to undergo molecular testing. Main outcome measure(s) Genetic profiles of advanced PC. Results Among the 11 patients, 4 patients had the 50-gene panel only, 6 had 409-gene panel after a negative 50-gene panel and 1 had FoundationOne. One patient who had 50-gene panel only also had his metastatic site (esophagus) of his tumor tested with FoundationOne. The most common mutations identified were in the PI3 K (PIK3CA, TSC1 and ATM) (4/11 patients) and TP53 (3/11) pathways. Genes not previously reported to be mutated in PC included: SDHA, TERT promoter and DICER1. Actionable mutations were found in 54% (6/11) of the patients. Conclusions Mutational profiling using NGS panels in advanced PC has yielded important potentially targetable genetic alterations. Larger studies are needed to identify commonly mutated genes in advanced PC patients. Development of novel therapies targeting these cellular pathways should be considered.

Effect of age on the effectiveness of the first-line standard of care treatment in patients with metastatic colorectal cancer: systematic review of observational studies Abstract Purpose Most metastatic colorectal cancer (mCRC) patients are elderly. This systematic review identifies and describes observational studies evaluating the influence of age on first-line treatment effectiveness in real-world practice. Methods Medline and EMBASE were searched up to May 2016. The included studies were those that investigated first-line treatment of mCRC and reported age groups and overall survival (OS), progression-free survival (PFS) or overall response rate (ORR) were included. Studies published before 2008 were excluded. Study quality was assessed using the Newcastle–Ottawa Scale. Data were evaluated by age group (< 70 vs. ≥ 70 years; 65–75 vs. ≥ 75 years) and outcome. A pooled survival median was calculated for patients (cutoff = 70 years). Results In total, 11 articles with 11,063 patients were included. Four studies using a cutoff of 70 years of age reported OS and PFS, and two studies reported ORRs. In terms of OS, all studies showed a higher OS for those < 70 years of age than for those ≥ 70 years of age. PFS did not find differences by age. For ORRs, one study favoured the younger group, while the second study did not differ by age. Based on three studies, the pooled medians for  < 70 years of age and ≥ 70 years of age were the same for PFS (10.2) and were 27.0 and 22.9 for OS, respectively. All included studies were of high or acceptable quality. Conclusions The results suggest that age has no effect on PFS. For ORR, the results were inconsistent between studies. Younger patients in general had better OS, which might be partly explained by more aggressive treatment. This treatment seemed not to be guided by performance status or number of metastatic sites.

Targeting cathepsin K diminishes prostate cancer establishment and growth in murine bone Abstract Background The processes of prostate cancer (PCa) invasion and metastasis are facilitated by proteolytic cascade involving multiple proteases, such as matrix metalloproteinases, serine proteases and cysteine proteases including cathepsin K (CatK). CatK is predominantly secreted by osteoclasts and specifically degrades collagen I leading to bone destruction. PCa and breast cancer preferentially metastasize to the bone. Importantly, CatK expression level is greater in PCa bone metastatic sites compared to primary tumor and normal prostate tissues. However, the underlying mechanism of CatK during PCa metastases into the bone remains to be elucidated. We investigated the functional role of CatK during the PCa establishment and growth process in the murine bone. Methods CatK mRNA expression was validated by RT-PCR, protein expression by immunoblotting in PCa LNCaP, C4-2B, and PC3 cells as well as in PCa tissues. Its protein production was measured using ELISA assay. The effect of both knockdowns via siRNA and CatK inhibitor was compared in regard to PCa cell invasion. We further studied the dose-dependent CatK inhibitor effect on conditioned media-induced bone resorption. In setting up an animal model, C4-2B cells were injected into the tibiae of SCID mice. The animals treated with either vehicle or CatK inhibitor for 8 weeks at the time of tumor cell injection (tumor establishment model; protocol I) or 4 weeks after tumor cell injection (tumor progression model; protocol II) were applied to histological and histomorphometric analyses. Results We confirmed CatK expression in PCa LNCaP, C4-2B, and PC3 cells as well as in PCa tissues. Furthermore, we observed the inhibitory effects of a selective CatK inhibitor on PCa cell invasion. The CatK inhibitor dose-dependently inhibited PCa-conditioned media-induced bone resorption. Upon injection of C4-2B cells into the tibiae of SCID mice, the selective CatK inhibitor significantly prevented the tumor establishment in protocol I, and reduced the tumor growth in bone in protocol II. It also decreased serum PSA levels in both animal models. The inhibitory effects of the CatK inhibitor were enhanced in combination with zoledronic acid (ZA). Conclusion The selective CatK inhibitor may prevent the establishment and progression of PCa in bone, thus making it a novel therapeutic approach for advanced PCa.

Aberrant expression of Sec61α in esophageal cancers Abstract Introduction The heterotrimeric Sec61α translocon complex is topological located in the membrane of the endoplasmic reticulum (ER) and allows protein transport and calcium across the membrane. Recently, aberrant expression of Sec proteins was linked to carcinogenesis and prognosis of patients. Materials and methods Here, we analysed the role of Sec61α in esophageal cancer, and we analysed Sec61α staining on a tissue microarray containing more than 600 esophageal cancer specimens by immunohistochemistry. Results Sec61α staining was always strong in benign esophagus, but was only found in 5% of interpretable esophageal adenocarcinomas (EACs) and 14.5% of squamous cell carcinomas (ESCCs). Reduced Sec61α staining was not strongly linked to tumor phenotype in both subgroups of esophageal cancers and was unrelated to clinical outcome of patients (EACs: p = 0.8051 and ESCCs: p = 0.2751). Conclusions Thus, Sec61α measurement has not an additional prognostic benefit for the patients.

Association of glutathione- S -transferase p1 gene promoter methylation and the incidence of prostate cancer: a systematic review and meta-analysis Abstract Objective Some studies have shown that the methylation status of the GSTP1 gene promoter is related to the incidence of prostate cancer, but this finding is still controversial. The aim of this study was to evaluate the association between glutathione-S-transferase p1 (GSTP1) promoter methylation and the incidence of prostate cancer. Methods The Medline, Embase, Web of Science, and Cochrane CENTRAL databases were searched from their inception to February 22, 2019. According to the inclusion criteria, studies of the association between the methylation status of the GSTP1 gene promoter and prostate cancer were included. The difference in the incidence of GSTP1 promoter methylation in tissues, blood, or urine between patients with prostate cancer and those without prostate cancer were compared, and the results were expressed as the odds ratio (OR) and 95% confidence interval (CI). The pooled OR of each study was estimated using a fixed-effects model or a random-effects model to generate forest plots. Results Ultimately, 15 studies (1540 samples) were included. The estimated effect from our meta-analysis showed that the incidence of GSTP1 promoter methylation was higher in patients with prostate cancer than in those without prostate cancer (OR 18.58, 95% CI 9.60–35.95, P = 0.000). GSTP1 promoter methylation was highly correlated with the incidence of prostate cancer. Conclusions Methylation of the GSTP1 promoter may increase the risk of prostate cancer. This study may provide a strategic direction for prostate cancer research. Pending validation of these findings, the methylation of the GSTP1 promoter may be a potential biomarker to diagnose prostate cancer.

RRx-001 protects normal tissues but not tumors via Nrf2 induction and Bcl-2 inhibition Abstract Background RRx-001, a minimally toxic next-generation checkpoint inhibitor that targets myeloid suppressor cells in the tumor microenvironment, has also been shown to protect normal tissues from the cytotoxic effects of chemotherapy and radiation. The following experiments were carried out to determine whether the cytoprotective functions of RRx-001 in normal cells were operative in tumor cells. Design The effects of RRx-001 on normal cells, and ovarian cancer A2780 and UWB1 cells were evaluated with a colony-forming assay. Western blot densitometry was used to measure Nrf2 nuclear translocation in Caco2 cells after exposure to RRx-001. Following incubation with RRx-001, levels of the antioxidant, NQO1, were determined in Caco2 cells by measuring absorbance over 300 min at 440 nm. RRx-001-mediated cytotoxicity in HCT-116 colorectal cancer cells was evaluated with an MTT assay. In addition, the effect of RRx-001 incubation on the protein expression of Nrf2, PARP, cleaved PARP, procaspases 3, 8, and 9, Bcl-2, and Bax in HCT-116 colorectal cells was determined by western blot analysis. Results RRx-001 is demonstrated to induce Nrf2 in normal tissues, mediating protection, and to downregulate the Nrf2-controlled antiapoptotic target gene, B-cell lymphoma 2 (Bcl-2) in tumors, mediating cytotoxicity. Conclusion Through Nrf2 induction in normal cells and inhibition of Bcl-2 in tumor cells, RRx-001 selectively protects normal cells against lethality in normal cells, but induces apoptosis in tumor cells.

Human papillomavirus and lung cancer: an overview and a meta-analysis Abstract Purpose This review is devoted to assessing the prevalence of human papillomavirus (HPV) in lung cancer (LC) in the world. HPV is recognized as the etiological factor of cervical cancer, however, there is widespread evidence that this virus is detected not only in gynecological carcinomas, but also in tumors of other organs, in particular the upper respiratory tract and digestive tract. Materials and methods  A search was conducted to a depth of 29 years in the PubMed, Web of Science, Scopus, databases. The review includes 95 articles. Results Of all the analyzed studies (9195 patients), 12 works showed a complete absence of HPV in the biological material in patients with LC. The absence of a virus among lung cancer patients has been established for Canada, the Netherlands and Singapore. The highest average percent of occurrence of this virus is shown for such countries as: Brazil, Korea, Greece and Taiwan (more than 40%). But the highest percentage of HPV occurrence by region is observed in Latin America (33.5%), followed by the Asian countries (31%), in European countries the frequency is 18%. Interestingly, the highest occurrence of high oncogenic types (16 and 18) is observed in Asia (40.3%), then in Latin America (33.6%), Europe (25.6%) and North America (15.4%). Low-oncogenic types (6 and 11) are also predominantly observed in Asia (39.9%), while in Europe and North America 30% and 12.8%, respectively. A meta-analysis of the prevalence of HPV was conducted using Comprehensive Meta-Analysis 3.0. Program, which included 26 studies, the results of which revealed: the prevalence of HPV infection in tumor lung tissue was compared with normal lung tissue OR (95% CI) = 5.38 (3.21–9.00) p < 0.0001, significance was also found for Chinese studies OR = 6.3, 95% CI 3.42–11.53, p < 0.0001, I2 = 71.8% and for nine studies in Europe OR = 6.3, 95% CI 1.8–22.18, p = 0.004, I2 = 51.0%. However, given the fact that the frequency of occurrence of HPV in lung tumor tissue varies greatly, a question may arise about the real role of HPV in LC carcinogenesis, which makes further research relevant and promising.

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

6948891480

alsfakia@gmail.com