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Radiotherapy with proton therapy (PT) has dosimetric advantages over photon therapy, which helps to enlarge the therapeutic window of radiotherapy for hepatocellular carcinoma (HCC). We evaluated the response of HCC to PT and examined the underlying mechanisms. The human liver cancer cell lines HepG2 and HuH7 and the murine liver cancer cell line Hepa1–6 were selected for cell and animal experiments to examine the response induced by PT irradiation. Biological changes and the immunological response following PT irradiation were examined. In vitro experiments showed no significant difference in cell survival following PT compared with photon radiotherapy. In a murine tumor model, the tumors were obviously smaller in size 12 days after PT irradiation. The underlying changes included increased DNA damage, upregulated IL-6 levels, and a regulated immune tumor microenvironment. Protein analysis in vitro and in vivo showed that PT increased the level of programmed cell death ligand 1 (PD-L1) expressed in tumor cells and recruited myeloid-derived suppressor cells (MDSCs). The increase in PD-L1 was positively correlated with the irradiation dose. In Hepa1–6 syngeneic mouse models, the combination of PT with anti-PD-L1 increased tumor growth delay compared with PT alone, which was associated with increased tumor-infiltrating T cells and attenuated MDSC recruitment in the microenvironment. Furthermore, when PT was applied to the primary HCC tumor, anti-PD-L1 antibody-treated mice showed smaller synchronous unirradiated tumors. In conclusion, the response of HCC to PT was determined by tumor cell killing and the immunological response in the tumor microenvironment. The combination with the anti-PD-L1 antibody to enhance antitumor immunity was responsible for the therapeutic synergism for HCC treated with PT. Based on our results, we suggest that PT combined with anti-PD-L1 may be a promising therapeutic policy for HCC. [ABSTRACT FROM AUTHOR]

Purpose: Increasing evidence indicates that the microbiome may influence tumor growth and modulate the tumor microenvironment of gastrointestinal cancers. However, the role of oral bacteria in the development of esophageal squamous cell carcinoma (EsoSCC) has remained unclear. Herein, we investigated the relationship between the periodontal pathogen Porphyromonas gingivalis and EsoSCC. Methods: To identify bacterial biomarkers associated with EsoSCC, we analyzed microbiomes in oral biofilms. The presence of P. gingivalis in esophageal tissues and relationships of P. gingivalis infection with clinicopathologic characteristics in 156 patients with EsoSCC were assessed using immunohistochemistry. The role of P. gingivalis infection in in vitro and in vivo EsoSCC progression was also assessed. Results: Microbiota profiles in oral biofilms revealed that P. gingivalis abundance was associated with an increased risk of EsoSCC development. In total, 57% of patients with EsoSCC were found to be infected with P. gingivalis. The presence of P. gingivalis was found to be associated with advanced clinical stages and a poor prognosis. It was also found to be associated with an elevated esophageal cancer incidence in a 4-nitroquinoline 1-oxide-induced mouse model and with an increased xenograft tumor growth. P. gingivalis infection increased interleukin (IL)‐6 production and it promoted epithelial-mesenchymal transition and the recruitment of myeloid-derived suppressor cells. Furthermore, inhibited IL‐6 signaling attenuated the tumor-promoting effects of P. gingivalis in 4-nitroquinoline 1-oxide-treated mice and xenograft mouse models. Conclusions: Our data indicate that P. gingivalis may promote esophageal cancer development and progression. Direct targeting of P. gingivalis or concomitant IL-6 signaling may be a promising strategy to prevent and/or treat EsoSCC associated with P. gingivalis infection. [ABSTRACT FROM AUTHOR]

Background: This study aimed to compare the outcomes of proton beam therapy (PBT) and carbon ion radiotherapy (CIRT) by a systematic review and meta‐analysis of the existing clinical evidence. Methods: A systematic literature search was performed to identify studies comparing the clinical outcomes of PBT and CIRT. The included studies were required to report oncological outcomes (local control [LC], progression‐free survival [PFS], or overall survival [OS]) or adverse events. Results: Eighteen articles comprising 1857 patients (947 treated with PBT and 910 treated with CIRT) were included in the analysis. The pooled analysis conducted for the overall population yielded average hazard ratios of 0.690 (95% confidence interval (CI), 0.493–0.967, p = 0.031) for LC, 0.952 (95% CI, 0.604–1.500, p = 0.590) for PFS, and 1.183 (0.872–1.607, p = 0.281) for OS with reference to CIRT. The subgroup analyses included patients treated in the head and neck, areas other than the head and neck, and patients with chordomas and chondrosarcomas. These analyses revealed no significant differences in most outcomes, except for LC in the subgroup of patients treated in areas other than the head and neck. Adverse event rates were comparable in both groups, with an odds ratio (OR) of 1.097 (95% CI, 0.744–1.616, p = 0.641). Meta‐regression analysis for possible heterogeneity did not demonstrate a significant association between treatment outcomes and the ratio of biologically effective doses between modalities. Conclusion: This study highlighted the comparability of PBT and CIRT in terms of oncological outcomes and adverse events. [ABSTRACT FROM AUTHOR]

Background Comorbidity has a great impact on lung cancer survival. Renal function status may affect treatment decisions and drug toxicity. The survival outcome in lung cancer patients with coexisting chronic kidney disease ( CKD) has not been fully evaluated. We hypothesized that CKD is an independent risk factor for mortality in patients with lung cancer. Methods A retrospective, propensity-matched study of 434 patients diagnosed between June 2004 and May 2012 was conducted. CKD was defined as estimated glomerular filtration rate <60 mL/minute. Lung cancer and coexisting CKD patients were matched 1:1 to patients with lung cancer without CKD. Results Age, gender, smoking status, histology, and lung cancer stage were not statistically significantly different between the CKD and non- CKD groups. Kaplan- Meier survival analysis demonstrated a median survival of 7.26 months (95% confidence interval [ CI] 6.06-8.46) in the CKD group compared with 7.82 months (95% CI 6.33-9.30) in the non- CKD group ( P = 0.41). Lung cancer stage-specific survival is not affected by CKD. Although lung cancer patients with CKD presented with an increased risk of death of 6%, this result was not statistically significant ( hazard ratio 1.06, 95% CI 0.93-1.22; P = 0.41). Conclusion According to our limited experience, CKD is not an independent risk factor for survival in lung cancer patients. Clinicians should not be discouraged to treat lung cancer patients with CKD. [ABSTRACT FROM AUTHOR]

Summary: Purpose: This study was designed to estimate the life expectancy (LE) and quality-adjusted life expectancy (QALE) in non-metastatic nasopharyngeal cancer (NPC) patients. Methods and materials: Patients were eligible for the present study if they were diagnosed with NPC and had been treated with intensity-modulated radiotherapy (IMRT) between January 1, 2003 and December 31, 2010. The quality of life (QOL) data were collected using the questionnaires of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-H&N35. The LE of NPC patients was obtained using linear extrapolation of a logit-transformed curve and was adjusted by the corresponding QOL function to calculate the QALE. Results: During the study period, 110 patients met the inclusion criteria, and 53 of these completed questionnaires. The median follow-up was 65.2months (range 4.0–117.3months). The average LE and QALE were estimated to be 20.6years and 11.6 quality-adjusted life years (QALYs) for NPC patients and 24.4years and 24.4 QALYs for the reference population, respectively. Compared to the reference population, the loss of LE and QALE for NPC patients were 3.8years and 12.8 QALYs, respectively. Conclusions: This study offers a quick overview of the LE and the QALE of NPC patients treated with IMRT. Moreover, the results appear more understandable than the 5year survival outcomes when communicating with patients or the general population regarding cancer risk. In the future, evaluating the robustness of comparative assessments for the outcome of NPC patients undergoing different treatment protocols will be possible. [Copyright &y& Elsevier]

The aim of this study was to explore specific molecular markers that could lead to new insights into the identification of innovative treatments. The role of DNMT3b and its predictive power in the prognosis of oral cancer were identified. Human oral cancer cell lines including SCC4 and SCC25 were selected for cellular experiments. Changes in tumor growth, aggressiveness and the responsible signaling pathway were investigated in vitro and in vivo. Furthermore, 125 oral cancer tissue specimens were analyzed using immunohistochemical staining on tissue microarray slides, and correlations calculated between the level of DNMT3b and the clinical outcome of patients. Our data revealed that inhibition of DNMT3b resulted in slower tumor growth, attenuated tumor invasion ability and epithelial mesenchymal transition, as determined by in vitro and in vivo experiments. Activated IL-6 signaling might be responsible to the induction of DNMT3b overexpression on oral cancer. Regarding clinical data, the incidence of DNMT3b immunoreactivity in oral cancer specimens was significantly higher than in non-malignant epithelium, and positively linked to expression of IL-6. Furthermore, expression of DNMT3b was significantly linked with the risk of lymph node involvement, disease recurrence and shorter survival in patients with pathological stage III-IV oral cancer. In conclusion, IL-6 –DNMT3b axis could be used to predict the prognosis of oral cancer in clinics, and targeting DNMT3b could represent a promising treatment strategy. [ABSTRACT FROM AUTHOR]

Identification of potential tumor markers will help stratify and identify a tumor's malignant potential and its response to specific therapies. IL-6 has been reported to be a predictor in various cancers. Therefore, the present study was performed to highlight the role of IL-6 in improving treatment and determining prognosis of bladder cancer. The human bladder cancer cell lines HT1376 and HT1197 were selected for cell and animal experiments, in which biological changes after experimental manipulation of IL-6 were explored, including tumor behavior and related signaling in bladder cancer. In addition, clinical specimens from 85 patients with muscle-invasive, and 50 with non-muscle invasive bladder cancers were selected for immunohistochemical staining to evaluate the predictive capacity of IL-6 in relation to clinical outcome. The data revealed that IL-6 was overexpressed in the bladder cancer specimens compared with non-malignant tissues at both mRNA and protein levels. Positive staining of IL-6 was significantly correlated with higher clinical stage, higher recurrence rate after curative treatment, and reduced survival rate. Tumor growth and invasive capability were attenuated when IL-6 was blocked. The underlying changes included decreased cell proliferation, less epithelial-mesenchymal transition (EMT), decreased DNA methyltransferase 1 expression and attenuated angiogenesis. In conclusion, our findings showed that IL-6 could be a significant predictor for clinical stage and prognosis of bladder cancer. Moreover, targeting IL-6 may be a promising strategy for treating bladder cancer. [ABSTRACT FROM AUTHOR]

Background: The aim of this study is to compare the results between surgery alone, preoperative radiotherapy (RT), or preoperative concurrent chemoradiotherapy (CCRT) followed by surgery in the treatment of locally advanced rectal cancer in Asian patients. Methods: This study included 151 consecutive patients with clinical T3, T4 or node-positive rectal cancer from Jan. 2005 to Dec. 2007. Eighty-six patients underwent total mesorectal excision (TME) alone, 28 patients received preoperative RT (25 Gy in 5 fractions) followed by TME in 1 week, and 37 patients received preoperative CCRT (50.4 Gy in 28 fractions) followed by TME in 4-6 weeks. Results: The 3-year loco-regional recurrence (LRR), distant metastasis, overall and disease-free survival rates are comparable among Surgery, RT and CCRT groups. By multivariate analysis, pT4, distal margin <2 cm, the ratio of positive lymph nodes to totally dissected lymph nodes ≥0.2, and non-R0 resection were significant factors for LRR. In subgroup analysis, TME alone produced comparable LRR to RT or CCRT (3.3 vs.. 4.8%) for favorable patients (0-1 risk factors). For unfavorable patients (2 or more risk factors), the LRR rose to 37% in patients receiving surgery alone as compared with 15% in the RT or CCRT patients. Conclusions: Preoperative RT or CCRT followed by TME produced good local control in favorable and unfavorable patients with locally advanced rectal cancer. If preoperative RT or CCRT is not given, TME alone has a high incidence of local recurrence in unfavorable patients with 2 or more risk factors. [ABSTRACT FROM AUTHOR]

BACKGROUND: The identification of potential tumor markers can improve therapeutic planning and patient management. The objective of this study was to highlight the role of DNA methyltransferase 3b (DNMT3b) in esophageal squamous cell carcinoma (SCC). METHODS: One hundred seventy-three esophageal SCC samples were analyzed using immunohistochemical staining to correlate the expression of DNMT3b with clinical outcome. Furthermore, a human esophageal SCC cell line, CE81T, was selected for cellular and animal experiments to investigate changes in tumor behavior and treatment response after the manipulation of DNMT3b expression. RESULTS: The incidence of nuclear DNMT3b immunoreactivity in esophageal cancer specimens was significantly higher than in nonmalignant epithelium, and this incidence was linked positively to developing distant metastasis (56% in localized disease vs 80% in distant metastasis; P = .002). Furthermore, increased expression of DNMT3b was linked significantly to lower treatment response rates ( P = .002) and reduced survival rates ( P = .000). Inhibition of DNMT3b expression resulted in slower cellular proliferation, increased cell death, a less invasive capacity, and less epithelial-mesenchymal-transition changes. Moreover, DNMT3b silencing vectors sensitized esophageal cancer cells to irradiation and cisplatin treatment. The current results also indicated that constitutional activation of signal transducer and activator of transcription 3 (STAT3) signaling associated with inhibited expression of suppressor of cytokine signaling 3 (SOCS3) may be the mechanism underlying more aggressive tumor growth in DNMT3b-positive esophageal cancer. CONCLUSIONS: DNMT3b was linked significantly to a poor prognosis for patients with esophageal cancer. Moreover, the current results indicated that targeting this enzyme may be a promising strategy for treating esophageal cancer, as evidenced by inhibited aggressive tumor behavior and treatment resistance. Cancer 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-1 beta has been reported to be a marker of shorter survival in gastric and colorectal adenocarcinoma. In the present study, we examined the potential role and prognostic value of IL-1 beta in esophageal squamous cell carcinoma (SCC). Human esophageal SCC cell line, CE81T, was selected for cellular and animal experiments, in which biological changes after experimental manipulation of IL-1 beta signaling were explored, including tumor growth, invasion capacity, and the sensitivity to treatment. Moreover, 147 esophageal SCC samples were analyzed using immunohistochemical staining to correlate the expression of IL-1 beta with clinical outcome. Our data revealed that IL-1 beta was significantly overexpressed both at mRNA and protein levels in cancer specimens compared to nonmalignant tissues. When IL-1 beta signaling was blocked, tumor growth, invasion ability, and treatment resistance were attenuated. Activation of NF-kappa B, increase of E2-EPF ubiquitin carrier protein and subsequent epithelial-mesenchymal transition might be the underlying mechanisms of the more aggressive tumor growth in IL-1 beta-positive esophageal cancer. The immunochemistry findings indicate that positivity staining of IL-1 beta correlated significantly with higher clinical stage, lower response rate to concurrent chemoradiotherapy (CCRT), and higher recurrence rate after curative treatment. Moreover, IL-1 beta was a significant predictor of survival in patients undergoing surgical intervention or definite CCRT. In conclusion, IL-1 beta is significantly linked to poor prognosis for patients with esophageal cancer and may be a promising molecular target for therapeutic intervention for esophageal SCC. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant chemoradiotherapy is widely accepted for the treatment of localized rectal cancer. Although peroxiredoxin I (PrxI) and p53 have been implicated in carcinogenesis and cancer treatment, the role of PrxI and its interaction with p53 in the prognosis and treatment response of rectal cancer remain relatively unstudied. Methods and Materials: In the present study, we examined the levels of PrxI and p53 in rectal cancer patients using membrane arrays and compared them with normal population samples. To demonstrate the biologic changes after manipulation of PrxI expression, we established stable transfectants of HCT-116 (wild-type p53) and HT-29 (mutant p53) cells with a PrxI silencing vector. The predictive capacities of PrxI and p53 were also assessed by relating the immunohistochemical staining of a retrospective series of rectal cancer cases to the clinical outcome. Results: The membrane array and immunochemical staining data showed that PrxI, but not p53, was significantly associated with the tumor burden. Our immunochemistry findings further indicated that PrxI positivity was linked to a poor response to neoadjuvant therapy and worse survival. In cellular and animal experiments, the inhibition of PrxI significantly decreased tumor growth and sensitized the tumor to irradiation, as indicated by a lower capacity to scavenge reactive oxygen species and more extensive DNA damage. The p53 status might have contributed to the difference between HCT-116 and HT-29 after knockdown of PrxI. Conclusion: According to our data, the level of PrxI combined with the p53 status is relevant to the prognosis and the treatment response. We suggested that PrxI might be a new biomarker for rectal cancer. [ABSTRACT FROM AUTHOR]

The ubiquitin proteasome pathway has been implicated in carcinogenesis. However, the role of E2-EPF ubiquitin carrier protein (UCP) in esophageal cancer remains relatively unstudied. In the study, we examined the mRNA level of circulating tumor cells from 60 esophageal cancer patients by membrane arrays consisting of a panel of potential markers including UCP, compared to 40 normal populations. The predictive capacity of UCP was also assessed by immunohistochemical staining of a retrospective series of 84 biopsied esophageal squamous cell carcinomas in relation to clinical outcome. In addition, we studied in vitro biological changes including tumor growth, metastatic capacity, and the sensitivity to irradiation and cisplatin, after experimental manipulation of UCP expression in esophageal cancer cells. By the data of 25-gene membrane array analysis, UCP was the only factor significantly associated with the extent of tumor burden in esophageal cancer patients. Our immunochemistry findings further indicate that UCP positivity was linked to poor response to neoadjuvant therapy and worse survival. In cell culture, inhibited UCP significantly decrease tumor growth and the capacity for metastasis. The epithelial–mesenchymal transition (EMT) induced by VHL/HIF-1α-TGF-β1 pathway might be the underlying mechanism responsible to the more aggressive tumor growth in UCP-positive esophageal cancer. Our results suggest that UCP was significantly associated with poor prognosis of esophageal cancer and may be a new molecular target for therapeutic intervention for esophageal squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the value of Foxo3a in predicting the response to neoadjuvant treatment of, and prognosis for, esophageal squamous cell carcinoma. Methods and Materials: Immunohistochemical staining was performed in a retrospective series of 60 biopsied esophageal squamous cell carcinomas, and the correlation between nuclear accumulation of Foxo3a and clinicopathologic features was analyzed, including patient survival. In addition, in vitro biologic changes, radiosensitivity, and in vivo tumorigenicity of esophageal carcinoma cells after experimental manipulation of Foxo3a expression levels were determined. Results: Clinical findings point to a significant correlation between the nuclear accumulation of Foxo3a and the survival rate of esophageal cancer patients. In addition, Foxo3a is a significant predictor for the response to neoadjuvant therapy. In cell culture, irradiation and oxidative stress seemed to result in nuclear accumulation of Foxo3a. Down-regulation of Foxo3a significantly decreased radiosensitivity but had no obvious effect on tumor growth, as measured by a clonogenic assay in vitro and growth delay in vivo. Conclusions: Nuclear accumulation of Foxo3a in tumor cells was correlated with increased radiosensitivity and with improved patient survival. Thus, it is suggested that Foxo3a may be a potential marker for esophageal cancer. [Copyright &y& Elsevier]

Purpose: To assess local control and acute and chronic toxicity with intensity-modulated radiation therapy (IMRT) as adjuvant treatment of cervical cancer. Methods and Materials: Between April 2002 and February 2006, 68 patients at high risk of cervical cancer after hysterectomy were treated with adjuvant pelvic radiotherapy and concurrent chemotherapy. Adjuvant chemotherapy consisted of cisplatin (50 mg/m2) for six cycles every week. Thirty-three patients received adjuvant radiotherapy by IMRT. Before the IMRT series was initiated, 35 other patients underwent conventional four-field radiotherapy (Box-RT). The two groups did not differ significantly in respect of clinicopathologic and treatment factors. Results: IMRT provided compatible local tumor control compared with Box-RT. The actuarial 1-year locoregional control for patients in the IMRT and Box-RT groups was 93% and 94%, respectively. IMRT was well tolerated, with significant reduction in acute gastrointestinal (GI) and genitourinary (GU) toxicities compared with the Box-RT group (GI 36 vs. 80%, p = 0.00012; GU 30 vs. 60%, p = 0.022). Furthermore, the IMRT group had lower rates of chronic GI and GU toxicities than the Box-RT patients (GI 6 vs. 34%, p = 0.002; GU 9 vs. 23%, p = 0.231). Conclusion: Our results suggest that IMRT significantly improved the tolerance to adjuvant chemoradiotherapy with compatible locoregional control compared with conventional Box-RT. However, longer follow-up and more patients are needed to confirm the benefits of IMRT. [Copyright &y& Elsevier]

Purpose: The potential roles of peroxiredoxin (Prx) I in carcinogenesis and treatment have been explored. Our previous study revealed differences between A549 (functional p53) and H1299 (null p53) Prx I antisense transfectants. The discrepancy might have resulted from the p53 status. In this study, we further investigated the role of Prx I and p53 on lung cancer growth and the response to treatment in vitro and in vivo. Methods: We established stable A549 and H1299 transfectants with Prx I antisense and p53, respectively. We then examined their characteristics in vitro and used nude mice xenografts of these cell lines to compare their capacity for tumor invasion and spontaneous metastasis and their sensitivity to radiotherapy. Results: Increased reactive oxygen species caused by lower Prx I activity induced p53 expression. In lethal stress, the augmentation of reactive oxygen species was partially reversed by blocking p53 in A549 with Prx I antisense. We demonstrated the potential contribution of p53-dependent mechanisms to inhibit lung tumor growth and increase radiosensitization using H1299 transfected with p53 in vitro and in vivo. An increased p53 level attenuated the capacity of the cells for metastasis by decreasing vascular endothelial growth factor and induced radiosensitization by increased apoptosis and cell senescence and by regulating intracellular reactive oxygen species. Conclusion: These results suggest that p53 status has an important role in the tumor-inhibiting and radiosensitizing effects of decreasing Prx I. Both Prx I and p53 may be powerful prognosticators for lung cancer. [Copyright &y& Elsevier]

Purpose: Recent studies have shown that mesenchymal stem cells (MSCs) obtained from bone marrow transplantation patients originate from the host. This clinical observation suggests that MSCs in their niches could be resistant to irradiation. However, the biologic responses of bone marrow MSCs to irradiation have rarely been described in the literature. Methods and Materials: In this study, human bone marrow–derived, clonally expanded MSCs were used to investigate their sensitivity to irradiation in vitro, and the cellular mechanisms that may facilitate resistance to irradiation. The human lung cancer cell line A549 and the breast cancer cell line HCC1937 were used as controls for radiosensitivity; the former line has been shown to be radioresistant and the latter radiosensitive. We then examined their in vitro biologic changes and sensitivities to radiation therapy. Results: Our results suggest that MSCs are characterized as resistant to irradiation. Several cellular mechanisms were demonstrated that may facilitate resistance to irradiation: ATM protein phosphorylation, activation of cell-cycle checkpoints, double-strand break repair by homologous recombination and nonhomologous end joining (NHEJ), and the antioxidant capacity for scavenging reactive oxygen species. Conclusions: As demonstrated, MSCs possess a better antioxidant reactive oxygen species–scavenging capacity and active double-strand break repair to facilitate their radioresistance. These findings provide a better understanding of radiation-induced biologic responses in MSCs and may lead to the development of better strategies for stem cell treatment and cancer therapy. [Copyright &y& Elsevier]

Purpose: In this study, we examined the role of peroxiredoxin I (Prx I) in lung cancer cell growth in vitro and in vivo and its influence on these tumor cells’ sensitivity to radiotherapy. Methods and materials: We established stable transfectants of A549 (p53+) and H1299 (p53−) lung carcinoma cell lines with Prx I antisense to downregulate their Prx I protein. We then examined their in vitro biologic changes and used nude mice xenografts of these cell lines to compare tumor invasion, spontaneous metastatic capacity, and sensitivity to radiotherapy. Results: The Prx I antisense transfectants of both cell lines showed a significant reduction in Prx I protein production. Prx I antisense transfectants grew more slowly than did the wild type. As xenografts in mice, A549 Prx I antisense transfectants showed a threefold delay in the generation of palpable tumors. The incidence of spontaneous metastasis of Prx I antisense transfectants was significantly less than that of the wild-type cells. Furthermore, irradiation of Prx I antisense transfectants caused more than twice the growth delay compared with the wild type. Conclusion: The results of these studies suggest that inactivation of Prx I may be a promising approach to improve the treatment outcome of patients with lung cancer. [Copyright &y& Elsevier]

Background: Spheroids generated by tumor cells collected from malignant pleural effusion (MPE) were shown to retain the characteristics of the original tumors. This ex vivo model might be used to predict the response of non-small cell lung cancer (NSCLC) to anticancer treatments. Methods: The characteristics, epidermal growth factor receptor (EGFR) mutation status, and clinical response to EGFR-TKIs treatment of enrolled patients were recorded. The viability of the spheroids generated from MPE of enrolled patients were evaluated by visualization of the formazan product of the MTT assay. Results: Spheroids were generated from 14 patients with NSCLC-related MPE. Patients with EGFR L861Q, L858R, or Exon 19 deletion all received EGFR-TKIs, and five of these seven patients responded to treatment. The viability of the spheroids generated from MPE of these five patients who responded to EGFR-TKIs treatment was significantly reduced after gefitinib treatment. On the other hand, gefitinib treatment did not reduce the viability of the spheroids generated from MPE of patients with EGFR wild type, Exon 20 insertion, or patients with sensitive EGFR mutation but did not respond to EGFR-TKIs treatment. Conclusion: Multicellular spheroids generated from NSCLC-related MPE might be used to predict the response of NSCLC to treatment. [ABSTRACT FROM AUTHOR]

To assess if surgery provided survival benefit to patients with esophageal squamous cell carcinoma (SCC), we performed a retrospective review of 1230 patients who were newly diagnosed with stage T2-T4 esophageal SCC from 2007 to 2014 in our hospital. There were greater than 70% of patients with age under 65 years, and more than 85% were stage T3-T4 at the time of diagnosis. The median survival time was 1.06 year (95% CI 0.99-1.1 yrs). Survival analyses showed that survival time was significantly associated with age, T stage, clinical lymph node involvement and treatment modality (surgery versus definite chemoradiotherapy). Surgery still possessed a powerful impact on overall survival by multivariable analysis. Death risk of patients treated with curative surgery was significantly lower than those with definite chemoradiotherapy. Furthermore, for patients of stage T3N(+) and T4, surgery combined with (neo-)adjuvant treatment were significantly associated with higher survival rate than surgery alone or definite chemoradiotherapy. In conclusion, the patients who undergo surgery were significantly associated longer survival, therefore, curative resection should be considered for esophageal cancer patients who are medically fit for surgery. Moreover, combined with (neo-)adjuvant treatment is recommended for surgically resectable stage T3-T4 esophageal SCC. [ABSTRACT FROM AUTHOR]

Background: Hormone-resistant (HR) prostate cancers are highly aggressive and respond poorly to treatment. IL-6/STAT3 signaling has been identified to link with the transition of HR and aggressive tumor behavior. The role of IL-6 in the radiation response of prostate cancer was investigated in the present study.Material and Methods: The murine prostate cancer cell line (TRAMP-C1) and the hormone-resistant cell sub-line, TRAMP-HR, were used to assess the radiation response using in vitro clonogenic assays and tumor growth delay in vivo. Biological changes following irradiation were investigated by means of experimental manipulation of IL-6 signaling. Correlations among IL-6 levels, tumor regrowth, angiogenesis and myeloid-derived suppressor cell (MDSC) recruitment were examined in an animal model.Results: HR prostate cancer cells had a higher expression of IL-6 and more activated STAT3, compared to TRAMP-C1 cells. HR prostate cancer cells had a greater capacity to scavenge reactive oxygen species, suffered less apoptosis, and subsequently were more likely to survive after irradiation. Moreover, IL-6 expression was positively linked to irradiation and radiation resistance. IL-6 inhibition enhanced the radiation sensitivity of prostate cancer, which was associated with increased p53, RT-induced ROS and oxidative DNA damage. Furthermore, when mice were irradiated with a sub-lethal dose, inhibition of IL-6 protein expression attenuated angiogenesis, MDSC recruitment, and decreased tumor regrowth.Conclusion: These data demonstrate that IL-6 is important in the biological sequelae following irradiation. Therefore, treatment with concurrent IL-6 inhibition is a potential therapeutic strategy for increasing the radiation response of prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the role of interleukin (IL)-6 in biological sequelae and tumor regrowth after irradiation for hepatic malignancy, which are critical for the clinical radiation response of liver tumors. Methods and Materials: The Hepa 1-6 murine hepatocellular cancer cell line was used to examine the radiation response by clonogenic assays and tumor growth delay in vivo. After irradiation in a single dose of 6 Gy in vitro or 15 Gy in vivo, biological changes including cell death and tumor regrowth were examined by experimental manipulation of IL-6 signaling. The effects of blocking IL-6 were assessed by cells preincubated in the presence of IL-6–neutralizing antibody for 24 hours or stably transfected with IL-6–silencing vectors. The correlations among tumor responses, IL-6 levels, and myeloid-derived suppressor cells (MDSC) recruitment were examined using animal experiments. Results: Interleukin-6 expression was positively linked to irradiation and radiation resistance, as demonstrated by in vitro and in vivo experiments. Interleukin-6–silencing vectors induced more tumor inhibition and DNA damage after irradiation. When subjects were irradiated with a sublethal dose, the regrowth of irradiated tumors significantly correlated with IL-6 levels and MDSC recruitment in vivo. Furthermore, blocking of IL-6 could overcome irradiation-induced MDSC recruitment and tumor regrowth after treatment. Conclusion: These data demonstrate that IL-6 is important in determining the radiation response of liver tumor cells. Irradiation-induced IL-6 and the subsequent recruitment of MDSC could be responsible for tumor regrowth. Therefore, treatment with concurrent IL-6 inhibition could be a potential therapeutic strategy for increasing the radiation response of tumors. [Copyright &y& Elsevier]

Simple Summary: Although upper tract urothelial carcinoma (UTUC) is a relatively rare malignancy in Western countries, recurrence and distant metastasis are common even after definitive surgery. Many prognostic factors have been identified from previous studies, allowing clinicians to better stratify risk to select patients for perioperative systemic therapy; however, the applicability of adjuvant chemotherapy for patients with stage II UTUC after radical surgery remains unclear. In this study, we found that patients with primary tumor location at ureter or renal pelvis plus synchronous ureter had more frequent disease relapse and worse long-term oncological outcomes than other patients. Male sex, older age, history of previous bladder cancer, and positive surgical margins remain important unfavorable prognostic factors for recurrence and survival. Additional treatment and closer surveillance in patients with these negative prognostic factors are warranted despite complete pathological removal of the tumor. Background: Oncologic outcomes for pT2N0M0 upper tract urothelial carcinoma (UTUC) after nephroureterectomy are not well defined, with most previous studies focused on a heterogeneous population. Therefore, we aimed to investigate the clinical determinants of extraurinary tract recurrence and survival after radical surgery in patients with localized UTUC. Methods: We retrospectively identified 476 patients with pT2N0M0 UTUC who underwent radical nephroureterectomy or ureterectomy between October 2002 and March 2022. To evaluate the prognostic impact, patients were divided into renal pelvic, ureteral, and both-region (renal pelvis plus synchronous ureter) groups based on tumor location. The outcomes included recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Associations were evaluated using multivariable Cox regression analyses for prognostic factors and Kaplan–Meier analyses for survival curves. Results: The renal pelvic, ureteral, and both-region groups consisted of 151 (31.7%), 314 (66.0%), and 11 (2.3%) patients, respectively. Kaplan–Meier analyses comparing the three tumor types showed significant differences in 5-year RFS (83.6% vs. 73.6% vs. 52.5%, p = 0.013), CSS (88.6% vs. 80.7% vs. 51.0%, p = 0.011), and OS (83.4% vs. 70.1% vs. 45.6%, p = 0.002). Multivariable analyses showed that age >60 years, previous bladder cancer history, ureteral involvement (ureteral and both-regional groups), and positive surgical margins were significant negative prognostic factors for the studied outcomes. Conclusions: Patients with pT2 UTUC and presence of ureteral involvement had more frequent disease relapse. Subsequent adjuvant therapy regimens and close follow-up in patients with negative prognostic factors are warranted despite complete pathological removal of the tumor. [ABSTRACT FROM AUTHOR]

Simple Summary: Urothelial carcinoma (UC) of the bladder is the most common malignancy in dialysis patients in Taiwan compared with renal cell carcinoma in Western countries. Radical cystectomy is the standard of care for localized muscle-invasive bladder cancer (MIBC), as well as for selected patients with high-risk non-MIBC. Despite improvements in anesthetic competency, surgical techniques, and postoperative care, dialysis patients undergoing radical cystectomy are at a higher risk of perioperative morbidity and mortality than non-dialysis patients. Due to the relative rarity of the condition, published data on predictors of outcome in ESRD patients undergoing radical cystectomy are scant. Our study revealed that accurate reporting of complications is necessary for preoperative counseling, identifying modifiable risk factors, and planning risk mitigation strategies. High comorbidity and low-volume surgeons were interrelated as notable risk factors for major complications. In addition to tumor-related factors, male sex, older age, and major complications significantly influence survival. Background: We investigated the use of a standardized reporting system to study perioperative complications and oncologic outcomes after radical cystectomy in end-stage renal disease (ESRD) patients with bladder cancer. Methods: We reviewed retrospective outcomes in 141 ESRD patients with bladder cancer who underwent radical cystectomy between 2004 and 2015. Complications were graded using the Clavien–Dindo classification system with 0–2 classified as "No Major Complications" and Clavien 3–5 as "Major Complications". Low-volume surgeons were classified as those performing fewer than nine cases during the study. Fisher's exact test along with the chi-squared test, two-tailed t tests, logistic regression, and the Cox proportional hazard model were used to evaluate all clinically meaningful covariates. Results: Ninety-nine (99, 70.2%) patients had no major complications, and forty-two (29.8%) patients had major complications. Patients in the major complications group were older, had a higher Charlson comorbidity index (CCI), and had a longer hospitalization duration than those in the no major complications group (all, p < 0.05). Major complications were also more common when the procedure was performed by low-volume surgeons (p = 0.003). In multivariate logistic regression models, CCI ≥ 5 (p = 0.006) and low-volume surgeon (p = 0.004) were independent predictors of major complications. According to multivariate analysis with the Cox hazards regression, male sex, age > 70 years, CCI ≥ 5, bladder cancer stage ≥ 3, lymphovascular invasion, and experiencing major complications were significant poor prognostic factors for overall survival (all, p < 0.05). Conclusions: Accurate reporting of complications is necessary for preoperative counseling, identifying modifiable risk factors, and planning risk mitigation strategies. High comorbidity and low-volume surgeons were interrelated as notable risk factors for major complications. In addition to tumor-related factors, male sex, older age, and major complications significantly influence overall survival. [ABSTRACT FROM AUTHOR]

To investigate postoperative complications and oncologic outcomes of prophylactic nephroureterectomy and/or cystectomy in dialysis patients with urothelial carcinoma (UC), we retrospectively reviewed the records of dialysis patients with UC and a final status of complete urinary tract extirpation (CUTE, i.e., the removal of both kidneys, ureters, and bladder) between January 2004 and December 2015. Patients undergoing dialysis after initial radical nephroureterectomy and/or cystectomy were excluded. Eighty-four and 27 dialysis patients, undergoing one-stage and multi-stage CUTE, were enrolled in this study, respectively. Demographic, medical, perioperative, and pathologic features were collected to determine variables associated with oncologic outcomes. Although there was no significant difference in mortality between the 2 groups (p = 0.333), all 5 (4.5%) patients with Clavien–Dindo grade 5 complications were from the one-stage CUTE group. On multivariate logistic regression analysis, advanced age (p = 0.042) and high Charlson comorbidity index (CCI) (p = 0.000) were related to postoperative major complications. Compared with multi-stage CUTE, one-stage CUTE had no overall, cancer-specific, and recurrence-free survival benefits (all p > 0.05). According to multivariate analysis with Cox regression, age > 70 years (HR 2.70, 95% CI 1.2–6.12; p = 0.017), CCI ≥ 5 (HR 2.16, 95% CI 1.01–4.63; p = 0.048), and bladder cancer stage ≥ 3 (HR 12.4, 95% CI 1.82–84.7; p = 0.010) were independent, unfavorable prognostic factors for the overall survival. One-stage CUTE is not associated with superior oncologic outcomes, and all perioperative mortalities in our series occurred in the one-stage CUTE group. Our data do not support prophylactic nephroureterectomy and/or cystectomy for uremic patients with UC. [ABSTRACT FROM AUTHOR]

This study investigated changes in the immune system and the biological consequences of androgen deprivation therapy (ADT) and radiotherapy (RT) for augmenting the treatment response in prostate cancer, particularly for castration-resistant prostate cancer (CRPC). Human and murine prostate cancer cell lines were used to examine the response to ADT and RT in vitro and in vivo. Biological changes following treatment and related immune modulation in the tumor microenvironment were examined. Our results showed that CRPC cells were demonstrated to be more resistant to the RT and ADT treatments. ADT increased tumor inhibition following irradiation. The underlying changes included increased cell death, attenuated myeloid-derived suppressor cell recruitment, and an increase in the number of tumor-infiltrating T cells (TILs). Furthermore, when high-dose fractionated RT was given to the primary CRPC tumor, a smaller size of secondary non-irradiated tumor associated with increased TILs was noted in ADT-treated mice. In conclusion, treatment resistance in CRPC was associated with a more immunosuppressive microenvironment. Enhanced antitumor immunity was responsible for the augmented RT-induced tumoricidal effect induced by ADT. Immune modulation could be a promising strategy for prostate cancer, especially for metastatic CRPC. [ABSTRACT FROM AUTHOR]

We explored the effects of various parameters on taste impairments (TIs) in head-and-neck (H&N) cancer patients receiving intensity-modulated radiotherapy (IMRT). From January 2014 to September 2017, 88 H&N cancer patients subjected to curative or postoperative IMRT were enrolled in this prospective study. All patients underwent at least 1 year of follow-up after IMRT. Quality-of-life assessments in terms of patient-reported gustatory function were measured using the taste-related questions of the European Organization for Research and Treatment of Cancer H&N35 questionnaires. At a median follow-up time of 27 months, 27 of 88 patients (30.7%) reported long-term TIs. In multivariate analyses, glossectomy most significantly predicted TIs (P = 0.04). The percentage of TIs (61.5%) was significantly (P = 0.03) higher in patients who underwent partial or total glossectomy than in patients who did not undergo surgery (28.0%) and those who underwent radical surgery without glossectomy (20.0%). When we excluded surgical patients from analyses, the mean radiation dose to the oral cavity was of borderline significance in terms of TI prediction (P = 0.05). Only 14.3% of patients suffered from TIs when the mean radiation dose was <5000 centi-Gray (cGy) compared with 28.3% when the mean dose was ≥5000 cGy. In conclusion, glossectomy is the major cause of long-term TIs in H&N cancer patients receiving IMRT. In patients who do not undergo glossectomy, reduction of the mean radiation dose to the oral cavity may reduce TIs after IMRT. [ABSTRACT FROM AUTHOR]

Evasion of immune surveillance is a significant factor in head and neck squamous cell carcinoma (HNSCC) carcinogenesis. IL-6 signaling is a critical mechanism for the induction of dysfunctional immune responses. In the present study, we examined the role of IL-6 in the prognosis of HNSCC regarding the immunosuppressive tumor microenvironment. We retrospectively analyzed the clinical outcomes of HNSCC patients and examined its correlation with the levels of IL-6 in tumors and circulating myeloid-derived suppressor cells (MDSCs) in peripheral blood. Furthermore, the relationships between IL and 6, programmed death ligand (PD-L1) expression, and immune response were examined in vitro and in vivo. Our data revealed that IL-6 overexpression was associated with the increased risk of developing disease failure and poor prognosis for HNSCC. The immunoreactivity of IL-6 in HNSCC specimens was positively linked to the staining of PD-L1 and the level of circulating MDSCs. By cellular and animal experiments, there were augmented radiation-induced increases in the expression of PD-L1 and the activation of MDSCs noted in IL-6-positive tumors. When IL-6 signaling was inhibited, the levels of PD-L1 and MDSC recruitment were significantly down-regulated. Furthermore, the neutrophil-to-lymphocyte ratio (NLR) was positively correlated with the levels of IL-6 and PD-L1 in tumor, and circulating MDSCs. In conclusion, IL-6 is a significant predictor of treatment outcome in HNSCC patients, and plays an important role in the induction of immunosuppressive tumor microenvironment mediated by increased MDSCs and PD-L1 expression. Furthermore, IL-6 combined with NLR can assist the clinician to make an informed decision regarding treatment options. [ABSTRACT FROM AUTHOR]

Background: The survival outcomes of lung cancer patients with coexisting chronic kidney disease (CKD) reported in the literature have been conflicting. We evaluate whether the survival of lung cancer patients with and without CKD differ significantly using two different formulas. Methods: A retrospective, multicenter, propensity‐matched study of lung cancer patients with and without CKD was conducted. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/minute. Kaplan–Meier survival analysis was used to determine survival differences between CKD and non‐CKD patients using the Cockcroft–Gault formula (CKD–CG) compared to the Chronic Kidney Disease Epidemiology Collaboration Formula (CKD‐EPI). Results: Baseline clinical characteristics did not differ statistically significantly between the groups. The CKD‐CG formula demonstrated median survival of 10.61 months (95% confidence interval [CI] 9.33–11.89) for the non‐CKD group compared to 10.58 months (95% CI 9.03–12.13) for the CKD group (P = 0.76). The CKD‐EPI formula demonstrated median survival of 9.10 months (95% CI 8.01–10.20) for the non‐CKD group compared to 7.59 months (95% CI 6.50–8.68) for the CKD group (P = 0.19). Cox regression analysis using both models revealed that CKD is not an independent risk factor for mortality in lung cancer patients. Although the CKD‐EPI formula revealed an increased risk of mortality and the CKD‐CG formula revealed decreased survival, these results were not statistically significant. Conclusion: Lung cancer survival did not differ significantly between CKD and non‐CKD patients using either formula. [ABSTRACT FROM AUTHOR]

• Due to the disease rarity and diverse histologic subtypes, the role of postoperative chemoradiotherapy for salivary gland carcinoma (SGC) remains poorly defined. • This multi-center cohort included 411 patients with surgically resected SGC who underwent postoperative chemoradiotherapy (N = 148) or radiotherapy alone (N = 263). • The use of postoperative chemoradiotherapy was associated with superior overall survival and progression-free survival in patients with nodal metastasis and improved locoregional control in patients with postoperative macroscopic residual tumors (R2 resection) or adenoid cystic carcinoma. The aim of this study was to interrogate if the use of postoperative chemoradiotherapy (POCRT) correlated with superior oncological outcomes for certain subgroups of patients with high-risk salivary gland carcinoma (SGC), compared with postoperative radiotherapy (PORT) alone. This multicenter retrospective study included 411 patients with surgically resected SGC who underwent PORT (n = 263) or POCRT (n = 148) between 2000 and 2015. Possible correlations of clinical parameters with outcomes were examined using the Kaplan-Meier analysis and Cox proportional-hazards regression model. The median follow-up of survivors is 10.9 years. For the entire cohort, adding concurrent chemotherapy to PORT was not associated with OS, PFS, or LRC improvement. However, patients with nodal metastasis who underwent POCRT had significantly higher 10-year OS (46.2% vs. 18.2%, P = 0.009) and PFS (38.7% vs. 10.0%, P = 0.009) rates than those treated with PORT alone. The presence of postoperative macroscopic residual tumor (R2 resection) was identified as an independent prognosticator for inferior OS (P = 0.032), PFS (P = 0.001), and LRC (P = 0.007). Importantly, POCRT significantly correlated with higher 10-year LRC rates in patients with R2 resection (74.2% vs. 40.7%, P = 0.034) or adenoid cystic carcinoma (AdCC, 97.6% vs. 83.6%, P = 0.039). On multivariate analyses, the use of POCRT significantly predicted superior OS (P = 0.037) and PFS (P = 0.013) for node-positive patients and LRC for patients with R2 resection (P = 0.041) or AdCC (P = 0.005). For surgically resected SGC, POCRT was associated with improved long-term OS and PFS for patients with nodal metastasis and superior LRC for patients with R2 resection or AdCC. [ABSTRACT FROM AUTHOR]

Objectives: Aldehyde dehydrogenase 1 (ALDH1) is associated with tumorigenesis, and shown to identify cancer stem cells (CSC)-like cells. We aimed to investigate the significance of ALDH1 in oral squamous cell carcinoma (OSCC) and its correlation with DNMT3b and immune evasion in the present study.Methods: We retrospectively analyzed the clinical outcomes of OSCC patients and examined its correlation with the levels of ALDH1 in tumors and circulating myeloid-derived suppressor cells (MDSCs) in the peripheral blood. Furthermore, the relationships between the DNMT3b, ALDH1 expression, and immune response were examined via clinical specimens and cellular and animal experiments. We also investigated the therapeutic potential of DNA hypomethylating agents in OSCC.Results: Our data revealed that the levels of ALDH1 expression were linked to treatment resistance, CSC-like properties, higher circulating MDSC and poor prognosis for OSCC. The radiation resistance noted in ALDH1-positive tumors was associated with augmented radiation-induced increases in the expression of programmed death ligand (PD-L1) and the activation of MDSCs. Furthermore, there was a positive link between ALDH1 and DNMT3b expression shown by clinical specimens and cellular experiments. DNA hypomethylating agents attenuated the radioresistance of ALDH1-positive cancer cells associated with the decreased ALDH1 and the increased DNA damages. In addition, the activation of MDSCs and the expression of PD-L1 were significantly attenuated by epigenetic therapy.Conclusions: Our findings suggested that ALDH1 played an important role in treatment response and the tumor-promoting microenvironment in OSCC. Moreover, epigenetic therapy could be a promising strategy for the treatment of OSCC. [ABSTRACT FROM AUTHOR]

This study aimed to construct a scoring system developed exclusively from the preoperative data that predicts 1-year postoperative mortality in patients with solid cancers. A total of 20,632 patients who had a curative resection for solid-organ cancers between 2007 and 2012 at Chang Gung Memorial Hospital Linkou Medical Center were included in the derivation cohort. Multivariate logistic regression analysis was performed to develop a risk model that predicts 1-year postoperative mortality. Patients were then stratified into four risk groups (low-, intermediate-, high-, and very high-risk) according to the total score (0-43) form mortality risk analysis. An independent cohort of 16,656 patients who underwent curative cancer surgeries at three other hospitals during the same study period (validation cohort) was enrolled to verify the risk model. Age, gender, cancer site, history of previous cancer, tumor stage, Charlson comorbidity index, American Society of Anesthesiologist score, admission type, and Eastern Cooperative Oncology Group performance status were independently predictive of 1-year postoperative mortality. The 1-year postoperative mortality rates were 0.5%, 3.8%, 14.6%, and 33.8%, respectively, among the four risk groups in the derivation cohort (c-statistic, 0.80), compared with 0.9%, 4.2%, 14.6%, and 32.6%, respectively, in the validation cohort (c-statistic, 0.78). The risk stratification model also demonstrated good discrimination of long-term survival outcome of the four-tier risk groups (P < 0.01 for both cohorts). The risk stratification model not only predicts 1-year postoperative mortality but also differentiates long-term survival outcome between the risk groups. [ABSTRACT FROM AUTHOR]

Radiotherapy is the main treatment modality for prostate cancer. This study investigated the role of TGF-β1 in biological sequelae and tumor regrowth following irradiation, which are critical for the clinical radiation response of prostate cancer. Human and murine prostate cancer cell lines, and corresponding hormone-refractory (HR) cells, were used to examine the radiation response by clonogenic assays in vitro and tumor growth delay in vivo. Biological changes after irradiation, including cell death and tumor regrowth, were examined by experimental manipulation of TGF-β1 signaling. The correlations among tumor radiation responses, TGF-β1 levels, and regulatory T cells (Tregs) recruitment were also evaluated using animal experiments. HR prostate cancer cells appeared more radioresistant and had higher expression of TGF-β1 compared to hormone-sensitive (HS) cells. TGF-β1 expression was positively linked to irradiation and radioresistance, as demonstrated by in vitro and in vivo experiments. Inhibition of TGF-β1 increased tumor inhibition and DNA damage after irradiation. When mice were irradiated with a sub-lethal dose, the regrowth of irradiated tumors was significantly correlated with TGF-β1 levels and Tregs accumulation in vivo. Furthermore, blocking TGF-β1 clearly attenuated Tregs accumulation and tumor regrowth following treatment. These data demonstrate that TGF-β1 is important in determining the radiation response of prostate cancer, including tumor cell killing and the tumor microenvironment. Therefore, concurrent treatment with a TGF-β1 inhibitor is a potential therapeutic strategy for increasing the radiation response of prostate cancer, particularly for more aggressive or HR cancer cells. Key message: • HR prostate cancer cells appeared more radioresistant and had higher expression of TGF-β1. • TGF-β1 was positively linked to the radiation resistance of prostate cancer. • Tumor regrowth following irradiation was significantly correlated with TGF-β1 and Tregs levels. • Blocking TGF-β1 significantly attenuated RT-induced DNA repair and Tregs. • TGF-β1 inhibitor increases the radiation response of HR cancer cells. [ABSTRACT FROM AUTHOR]

Abstract: Oxaliplatin treatment is a mainstay of treatment for advanced gastrointestinal tract cancer, but the underlying mechanisms of acquired oxaliplatin resistance remain largely obscured. We previously demonstrated that increased DNA repair capacity and copper-transporting ATPase 1 (ATP7A) level contributed to oxaliplatin resistance in the human gastric carcinoma cell line TSGH-S3 (S3). In the present study, we applied gene array technology to identify additional resistance factors in S3 cells. We found that interleukin-6 (IL-6), aldo-keto reductase 1C1 (AKR1C1), and AKR1C3 are the top 3 upregulated genes in S3 cells when compared with parent TSGH cells. Despite a higher level of endogenous IL-6 in S3, IL-6 receptor (IR-6R, gp-80, and gp-130) levels were similar between TSGH and S3 cells. The addition of exogenous IL-6, IL-6 targeted siRNA, or neutralizing antibodies neither affected Stat3 activation, a downstream target of IL-6, nor changed oxaliplatin sensitivity in S3 cells. However, manipulation of AKR1C activity with siRNA or AKR1C inhibitors significantly reversed oxaliplatin resistance. AKR1Cs are classical antioxidant response element (ARE) genes that can be transcriptionally upregulated by nuclear factor erythroid 2-related factor 2 (Nrf2). Knockdown of Nrf2 not only decreased the levels of AKR1C1, AKR1C2, and AKR1C3 mRNA and protein but also reversed oxaliplatin resistance in S3 cells. Taken together, these results suggest that activation of the Nrf2/AKR1C axis may contribute to oxaliplatin resistance in S3 cells but that the IL-6 signaling pathway did not contribute to resistance. Manipulation of Nrf2/AKR1Cs activity may be useful for management of oxaliplatin-refractory gastric cancers. [Copyright &y& Elsevier]

Summary: Objective: We investigated salivary function using quantitative scintigraphy and sought to identify functional correlations between parotid dose and quality of life (QoL) for head and neck cancer (HNC) patients receiving intensity-modulated radiotherapy (IMRT). Materials and methods: Between August, 2007 and June, 2008, 31 patients treated IMRT for HNC were enrolled in this prospective study. Salivary excretion function (SEF) was previously measured by salivary scintigraphy at annual intervals for 2 years after IMRT. A dose-volume histogram of each parotid gland was calculated, and the normal tissue complication probability (NTCP) was used to determine the tolerance dose. QoL was longitudinally assessed by the EORTC QLQ-C30 and H&N35 questionnaires prior to RT, and at one, three, 12 and 24months after RT. Results: A significant correlation was found between the reduction of SEF and the mean parotid dose measured at 1year (correlation coefficient, R 2 =0.651) and 2 years (R 2 =0.310) after IMRT (p <0.001). The TD50 of the parotid gland at 1 year after IMRT is 43.6Gy, comparable to results from western countries. We further found that contralateral parotid and submandibular gland function preservation was correlated with reduced sticky saliva and a better QoL compared to the functional preservation of both parotid glands, as determined by the EORTC QLQ-H&N35 questionnaire. Conclusion: A significant correlation was found between the reduction of SEF and the mean parotid dose. Preservation of contralateral parotid and submandibular gland function predicts a better QoL compared to preservation of the function of both parotid glands. [ABSTRACT FROM AUTHOR]

Hormone-resistant (HR) prostate cancers are highly aggressive and respond poorly to treatment. A better understanding of the molecular mechanisms involved in HR should lead to more rational approaches to therapy. The role of IL-6/STAT3 signaling in the transition of HR with aggressive tumor behavior and its possible link with myeloid-derived suppressor cells (MDSCs) were identified. In the present study, murine prostate cancer cell line (TRAMP-C1) and a hormone-resistant cell sub-line (TRAMP-HR) were used. Changes in tumor growth, invasion ability, and the responsible pathway were investigated in vitro and in vivo. We also examined the role of IL-6 in HR tumor progression and the recruitment of MDSCs. As seen in both in vitro and in vivo experiments, HR had aggressive tumor growth compared to TRAMP-C1. From mRNA and protein analysis, a higher expression of IL-6 associated with a more activated STAT3 was noted in HR tumor. When IL-6 signaling in prostate cancer was blocked, aggressive tumor behavior could be overcome. The underlying changes included decreased cell proliferation, less epithelial-mesenchymal transition, and decreased STAT3 activation. In addition to tumor progression, circulating IL-6 levels were significantly correlated with MDSC recruitment in vivo. Inhibition of IL-6 abrogated the recruitment of MDSCs in tumor- bearing mice, associated with slower tumor growth and attenuated angiogenesis. In conclusion, altered IL-6/STAT3 signaling is crucial in HR transition, aggressive behavior, and MDSC recruitment. These findings provide evidence for therapeutically targeting IL-6 signaling in prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluated the feasibility of screening mucosal recurrent nasopharyngeal carcinoma with narrow-band imaging (NBI) endoscopy. Methods and Materials: One hundred and six patients were enrolled. All patients underwent conventional white-light (WL) endoscopic examination of the nasopharynx followed by NBI endoscopy. Biopsies were performed if recurrence was suspected. Results: We identified 32 suspected lesions by endoscopy in WL and/or NBI mode. Scattered brown spots (BS) were identified in 22 patients, and 4 of the 22 who had negative MRI findings were histopathologically confirmed to be neoplasias that were successfully removed via endoscopy. A comparison of the visualization in NBI closer view corresponded to histopathological findings in 22 BS, and the prevalence rates of neoplasias in tail signs, round signs, and irregularities signs were 0% (0/6), 0% (0/7), and 44.4% (4/9), respectively (p = 0.048). The sensitivity, specificity, and diagnostic capability were 37.5%, 92.9% and 0.652 for WL, 87.5%, 74.5% and 0.810 for NBI, and 87.5%, 87.8%, and 0.876 for NBI closer view, respectively. NBI closer view was effective in increasing specificity compared with NBI alone (87.8% vs. 74.5%, p < 0.05), and in increasing sensitivity and diagnostic capability compared to WL alone (87.5% vs. 37.5%, p < 0.05; 0.876 vs. 0.652, p = 0.0001). Conclusions: Although NBI in endoscopy can improve sensitivity of mucosal recurrent nasopharyngeal neoplasias, false-positive (nonneoplasia BS) results may be obtained in areas with nonspecific inflammatory changes due to postradiation effects. NBI closer view not only can offer a timely, convenient, and highly reliable assessment of mucosal recurrent nasopharyngeal carcinoma, it can also make endoscopic removal possible. [Copyright &y& Elsevier]

BACKGROUND: The identification of potential tumor markers will help improve therapeutic planning and patient management. Therefore, the aim of this study was to highlight the role of DNA methyltransferase 1 (DNMT1) in bladder cancer. METHODS: A total of 50 samples of nonmalignant urothelium, 65 of muscle-invasive bladder cancers, 15 of distant metastasis, and 50 of nonmuscle-invasive bladder cancers were selected for immunohistochemical staining analysis. Furthermore, human bladder cancer cell lines HT1376 and HT1197 were selected for cell and animal experiments investigating changes in tumor behavior, treatment response, and related signaling in bladder cancer. RESULTS: The incidence of nuclear DNMT1 immunoreactivity in the bladder cancer specimens (45%) was significantly higher than in nonmalignant urothelium (15%, P = .0005), and the incidence in cancer was positively linked to clinical stage (24% in ≤T1 vs 55% in T2-T4, P = .0007). The staining of DNMT1 was also significantly linked to lower complete response rates ( P = .0014) and reduced survival rates ( P = .000). By in vitro and in vivo experiments, DNMT1 silencing vector reduced tumor growth and attenuated treatment resistance in bladder cancer cells. Less epithelial-mesenchymal transition, less invasion, and slower tumor growth were noted in cancer cells with inhibited DNMT1. Furthermore, the epidermal growth factor receptor-mediated phosphatidylinositol 3′-kinase-protein kinase B pathway might be the mechanism underlying the effects of DNMT1 on bladder cancer. CONCLUSIONS: DNMT1 could be a significant clinical predictor for stage and treatment response of bladder cancer. Moreover, targeting this enzyme could be a promising strategy for treating bladder cancer, as evidenced by inhibited tumor growth and enhanced radiosensitivity. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Purpose: Tumor eradication by chemoradiotherapy for pharyngeal cancer has not been particularly successful. Targeting epithelial growth factor receptor (EGFR) could be a potential treatment strategy providing additional benefits, but only a subset of these tumors gives a clinically significant response to EGFR inhibitors. The aim has been to identify the role of interleukin-6 (IL-6) signaling and its predictive power in the treatment response of pharyngeal cancer. Methods and Materials: Human pharyngeal cancer cell lines, including the hypopharyngeal cancer cell line FaDu and its derived cell line FaDu-C225-R, were selected. Changes in tumor growth, response to treatment, and responsible signaling pathway were investigated in vitro. Furthermore, 95 pharyngeal cancer tissue specimens were analyzed by immunohistochemical staining, and correlations were made between levels of IL-6, IL-6 receptor (IL-6R), p-AKT, and p-STAT3 expression and the clinical outcome of patients. Results: In vitro, either extrinsic IL-6 stimulation of cancer cells or intrinsically activated IL-6 signaling detected in FADu-C225-R cells results in resistance to irradiation and EGFR inhibitor. Blocking IL-6 signaling attenuated aggressive tumor behavior and sensitized the cells to treatments. The responsible mechanisms included decreased p-STAT3, less nuclear translocation of EGFR, and subsequently attenuated epithelial-mesenchymal transition. Regarding clinical data, staining of p-STAT3 and IL-6 was significantly linked with lower response rates to treatments and shorter survival in pharyngeal cancer patients. Conclusions: IL-6 and p-STAT3 may be significant predictors of pharyngeal carcinoma, and regulating IL-6 signaling can be considered a promising therapeutic approach. [Copyright &y& Elsevier]

Abstract: The use of Synthetic Amphiphile INTeraction-18 (SAINT-18) carrying plasmid pigment epithelium-derived factor (p-PEDF) as an anti-angiogenesis strategy to treat corneal neovascularization in a rat model was evaluated. Four partially dried forms (Group A: 0 μg, B: 0.1 μg, C: 1 μg, D: 10 μg) of a p-PEDF–SAINT-18 were prepared and implanted into the rat subconjunctival substantia propria 1.5 mm from the limbus at the temporal side. The 1 μg of plasmid-basic fibroblast growth factor–-SAINT-18 (p-bFGF–SAINT-18) (1 μg) was prepared and implanted into the rat corneal stroma 1.5 mm from the limbus on the same side. Inhibition of neovascularization was observed and quantified from day 1 to day 60. PEDF (50-kDa) and bFGF (18-kDa) protein expression were analyzed by biomicroscopic examination, Western blot analysis, and immunohistochemistry. Gene expression in corneal and conjunctival tissue was observed as early as 3 days after gene transfer and stably lasted for over 3 months with minimal immune reaction. Subconjunctival injection of a highly efficient p-PEDF–SAINT-18 successfully inhibited corneal neovascularization. Successful gene expression of bFGF, PEDF and a mild immune response of HLA-DR were shown by immunohistochemistry staining. We concluded that SAINT-18 was capable of directly delivering genes to the ocular surface by way of subconjunctival injection, and delivered sustained, high levels of gene expression in vivo to inhibit angiogenesis. [Copyright &y& Elsevier]

Summary: The aim of this study was to assess the treatment results and toxicity profiles of post-operative conventional radiotherapy (Conv-RT) and intensity-modulated radiotherapy (IMRT) for stage III and IV oral cavity cancer. During the period from April 2002 to December 2005, a total of 49 patients with stage III and IV squamous cell carcinoma of the oral cavity were treated with radical surgery followed by post-operative RT. Twenty-seven patients received Conv-RT while 22 received IMRT. Only three patients received adjuvant chemotherapy. With a median follow-up time of 3.3years, the 3-year overall survival and disease-free survival rates for patients who received Conv-RT vs IMRT were comparable. There was no significant difference in acute toxicity between the two different RT techniques. However, in terms of late toxicity, patients receiving IMRT had significantly less moderate to severe xerostomia and dysphagia than those receiving Conv-RT (36% vs 82%, p =0.01 for xerostomia and 21% vs 59%, p =0.02 for dysphagia). Post-operative Conv-RT and IMRT are equally effective in terms of tumor control for locally advanced oral cavity cancer. Patients receiving IMRT had comparable acute and significant less late toxicity than those receiving Conv-RT. [Copyright &y& Elsevier]

Purpose: We describe a novel vector system of nonviral gene transfer into the cornea using a partially dried form of a plasmid expressing 18-kDa basic fibroblast growth factor (p-bFGF)-synthetic amphiphile INTeraction-18 (SAINT-18) complex. Methods: Corneal neovascularization (NV) was evaluated in 48 eyes of Sprague-Dawley rats after implantation of SAINT-18 containing 2 μ g of plasmid-expressing green fluorescent protein (p-GFP; control group), 0.2 μ g, 2 μ g, or 20 μ g of p-bFGF from day 0 to day 60. bFGF protein expression was analyzed by Western blotting and immunohistochemistry. Results: The p-bFGF-SAINT-18 complex induced dose-dependent corneal neovascularization, which reached a maximum on days 15-21 in the 20-μ g p-bFGF group, days 12-18 in the 2-μ g p-bFGF group, and on days 9-15 in the 0.2-μ g p-bFGF group, and then regressed progressively. No NV was observed in the p-GFP group. Conclusions: This noninflammatory corneal transfection model using partially dried p-bFGF-SAINT-18 complex allows precise localization of tranfection reagents for producing corneal neovascularization. [ABSTRACT FROM AUTHOR]

: PurposeTo investigate the tolerance and efficacy of a modified concurrent chemoradiation (CCRT) protocol for patients with invasive bladder cancer “unfit” for radical cystectomy.: Methods and materialsTwenty-three muscle-invasive bladder cancer patients who were unfit for or unwilling to receive radical cystectomy were enrolled in this study. All patients had transitional cell carcinoma of bladder, and distribution of stage was 14 (61%), 1 (4%), and 8 (35%) for T3a, T3b, and T4, respectively. This study included a relatively old-age population, with the median age being 75 and 70% of patients over 70 years old. Patients were treated with maximal transurethral resection of the bladder tumor followed by curative CCRT. The chemotherapy (C/T) regimen was comprised of cisplatin, 50 mg/m2 intravenously (i.v.) on Day 1; 5-fluorouracil (5-FU), 500 mg/m2/day by continuous i.v. infusion on Days 1–3; and leucovorin, 50 mg/day by continuous i.v. infusion on Days 1–3. Chemotherapy course was repeated at 21-day intervals. The radiation dose was 44–45 Gy to whole pelvis and 60–61.2 Gy to bladder, with a daily fraction of 1.8–2 Gy. The completeness of the CCRT protocol was defined as patients receiving at least 55 Gy of radiotherapy to the whole bladder and at least three courses C/T.: ResultsSeventy-four percent of patients (17/23) completed the CCRT protocol. Radiation Therapy Oncology Group (RTOG) Grade 3 acute toxicities were observed in 4 patients, which included leucopenia, vomiting, genitourinary (GU) tract infection, and diarrhea. No treatment-related deaths occurred during the CCRT period. RTOG Grade 3 or more late complications were observed in 3 patients; one of them died of radiation cystitis superimposed with GU infection. Of the 18 patients whose response to CCRT was evaluated, a complete tumor response was documented in 16 patients (89%). With a median follow-up of 3 years, the 3-year overall survival (OS) and disease-free survival (DFS) for all patients was 69% and 65% respectively. Meanwhile, the 3-year overall and DFS rates for patients who completed CCRT vs. those who did not complete CCRT were 82% vs. 33% and 75% vs. 33%, respectively (p = 0.18 for OS and p = 0.04 for DFS).: ConclusionsConcurrent cisplatin, 5-FU, leucovorin, and radiotherapy for treatment of invasive bladder cancer is a feasible and promising treatment even for relatively old patients. Our results are comparable to those in recent studies by using combined modality treatment or neoadjuvant chemotherapy plus radical cystectomy. Consequently, this novel protocol warrants a prospective clinical trial and may be a safe, effective alternative to radical cystectomy. [Copyright &y& Elsevier]

Simple Summary: A part of localized prostate cancer (PC) was an incidental finding in patients who received transurethral resection of the prostate (TURP) for urinary symptoms. The present study examined whether changes in prostate-specific antigen (PSA) levels after TURP possess a predictive value for localized PC. Our data revealed that patients at intermediate risk who are associated with tumor involvement ≤5% in TURP specimens, PSA_TURP ≤ 4 ng/mL, and ≥68% PSA reduction following TURP might be suitable for conservation management instead of immediate local therapy. Moreover, for patients with no pre-TURP PSA, Gleason score (GS) < 7, and low PSA_TURP could potentially be utilized to select which patients could be considered for conservative management after TURP. The findings suggest the pathologic finding of TURP and changes in PSA could be used as adjuvant markers to guide a risk-adaptive strategy for patients with localized PC. Regarding localized prostate cancer (PC), questions remain regarding which patients are appropriate candidates for conservative management. Some localized PC was an incidental finding in patients who received transurethral resection of the prostate (TURP) for urinary symptoms. It is known that TURP usually affects the level of prostate-specific antigen (PSA). In the present study, we examined whether changes in PSA levels after TURP possess a predictive value for localized PC. We retrospectively reviewed the clinical data of 846 early-stage PC patients who underwent TURP for urinary symptoms upon diagnosis at our hospital. Of 846 patients, 687 had tumor involvement in TURP specimens, and 362 had post-TURP PSA assessment. Our data revealed that, in addition to low GS and PSA levels at diagnosis, ≤5% tumor involvement in TURP specimens, greater PSA reduction (≥68%) following TURP, and post-TURP PSA ≤ 4 were significantly associated with better progression-free survival (PFS). Survival analysis revealed that the addition of prostate-directed local therapy significantly improved PFS in intermediate- and high-risk groups, but not in the low-risk group. Moreover, in the intermediate-risk group, local therapy improved PFS only for patients who were associated with post-TURP PSA > 4 ng/mL or <68% PSA reduction following TURP. We also found that local therapy had no obvious improvement in PFS for those with post-TURP ≤ 4 ng/mL regardless of pre-TURP PSA. In conclusion, conservative management is considered for patients at low or intermediate risk who have greater PSA reduction following TURP and low post-TURP PSA. Therefore, the levels of PSA following TURP might be helpful for risk stratification and the selection of patients for conservative management. [ABSTRACT FROM AUTHOR]

Local treatment is known to improve survival in men with locally advanced prostate cancer (LAPC), but the underlying mechanisms remain unclear. In the present study, we examined the role of tumor burden in tumor aggressiveness, as well as the pathway responsible for these changes. We used human and murine prostate cancer cell lines to examine the role of tumor burden in tumor aggressiveness, as well as its correlation with cancer stem cell (CSC) marker levels and IL-6 signaling. Furthermore, 167 prostate cancer biopsy specimens were analyzed in terms of correlations of IL-6 and CD44 levels with clinical patient characteristics. Data from preclinical models showed that larger tumor burden was associated with more aggressive tumor growth associated and increased CD44 expression. Using cellular experiments and orthotopic tumor models, we showed that CD44+ prostate cancer cells have CSC-like properties, enhanced epithelial–mesenchymal transition (EMT), and a more immunosuppressive microenvironment. There was a significant correlation between IL-6 and CD44 levels based on in vitro testing of clinical samples. Blockade of IL-6/STAT3 signaling attenuated the expression of CD44, CSC-like properties, and aggressive tumor behavior in vitro and in vivo. In conclusion, CD44 expression is significantly associated with tumor aggressiveness in prostate cancer and activation of IL-6 signaling leads to a suitable microenvironment for the induction of CD44 expression. Based on our study, reduced tumor burden was associated with attenuated IL-6 signaling and augmented tumor rejection in the microenvironment, which might mediate the benefit of clinical adoption with aggressive local therapy. [ABSTRACT FROM AUTHOR]

A correction to the article "long-term taste impairment after intensity-modulated radiotherapy to treat head-and-neck cancer: correlations with glossectomy and the mean radiation dose to the oral cavity" which appeared in the previous is presented.

The article presents a case study of 51-year-old lady who was diagnosed with cytogenetically normal acute myeloid leukemia (CN-AML) (M2) with molecular profile of mutant Nucleophosmin 1 (NPM1) and wild type MLL- partial tandem duplication (PTD). She received induction chemotherapy with cytarabine along with the amplification of exons of DNA (cytosine-5-)-methyltransferase 3 alpha(DNMT3A). It concludes the multiple clonalities of AML and emergence of Chemo-resistant subclones after treatment.

A correction to the article "Significance of IL-6 in the transition of hormone-resistant prostate cancer and the induction of myeloid-derived suppressor cells" in the 2012 issue is presented.