HIV-1 Integrase Inhibitor, Dihydroobionin B, and the Investigation of Its Extraordinary Specific Rotation.

Dihydroobionin B (1), a chiral congener of known obionin B, was isolated from Pseudocoleophoma sp. KT4119, a freshwater fungus collected from a submerged wood block in Kochi Prefecture, Japan, in 2020. The planar structure of 1 was characterized by mass and NMR spectral analysis and confirmed by density functional theory (DFT)-based chemical shift calculations. Its absolute structure was determined by electronic circular dichroism spectral analysis. Notably, 1 exhibited an extraordinarily large specific rotation [[α]20D +1080 (c 0.056, CHCl3)], which was verified by DFT-based specific rotation calculations. However, these calculations indicated that the sign of the specific rotation based on static analysis was insufficient to determine the absolute configuration in this case. Furthermore, Pseudocoleophoma KT4119 produced coleophomapyrones A (2) and B (3) and coleophomaldehyde A (4). While this is the first report of 2 isolated from a natural source, it has also been prepared previously using a synthetic approach. Compound 1 potently inhibited HIV type 1 integrase (IC50 = 0.44 µM) without significant cytotoxicity. Finally, docking experiments were conducted to propose a plausible mechanism for the behavior of 1.

Combination of a synthetic retinoid and a DNA demethylating agent induced differentiation of neuroblastoma through retinoic acid signal reprogramming.

BACKGROUND: The CpG island methylator phenotype of neuroblastoma (NBL) is strongly associated with poor prognosis and can be targeted by 5-aza-2'-deoxycytidine (5-aza-dC). Differentiation therapy is a standard maintenance therapy for high-risk NBLs. However, the in vivo effect of tamibarotene, a synthetic retinoic acid, and the efficacy of its combination with 5-aza-dC have not been studied. Here, we conducted a preclinical study to assess the in vivo tamibarotene effect and the combination. METHODS: Treatment effects were analysed by in vitro cell growth and differentiation state and by in vivo xenograft suppression. Demethylated genes were analysed by DNA methylation microarrays and geneset enrichment. RESULTS: Tamibarotene monotherapy induced neural extension and upregulation of differentiation markers of NBL cells in vitro, and tumour regression without severe side effects in vivo. 5-Aza-dC monotherapy suppressed tumour growth both in vitro and in vivo, and induced demethylation of genes related to nervous system development and function. Pre-treatment with 5-aza-dC in vitro enhanced upregulation of differentiation markers and genes involved in retinoic acid signaling. Pre-treatment with 5-aza-dC in vivo significantly suppressed tumour growth and reduced the variation in tumour sizes. CONCLUSIONS: Epigenetic drug-based differentiation therapy using 5-aza-dC and TBT is a promising strategy for refractory NBLs.

Vonoprazan-based triple therapy is effective for Helicobacter pylori eradication irrespective of clarithromycin susceptibility.

BACKGROUND: Helicobacter pylori causes peptic ulcers and accounts for over 90% of gastric cancers; however, eradication rates have been declining due to antimicrobial resistance. Vonoprazan (VPZ), a potassium-competitive acid blocker, produces rapid and profound gastric acid suppression and has shown promising effects in the improvement of H. pylori eradication rates. The efficacy and safety of VPZ-based triple therapy as a first-line regimen for H. pylori eradication and its relationship with clarithromycin (CAM) susceptibility were evaluated. METHODS: From May 2015 to September 2017, H. pylori-infected patients who underwent esophagogastroduodenoscopy with CAM susceptibility testing were prospectively enrolled. Patients received a 7-day triple therapy regimen (VAC) of VPZ (20 mg), amoxicillin (750 mg), and CAM (200 mg) twice daily. Eradication rates, demographics, CAM susceptibility, and safety profiles were assessed. RESULTS: VAC was administered to 146 patients (median age: 63, range: 22-85 years) (60% of whom were females) who underwent CAM susceptibility testing, and 131 patients underwent 13C-urea breath testing to evaluate eradication success. The prevalence of CAM resistance was 34.2%. The overall eradication rates of VAC in per protocol (PP) and "intention to treat" (ITT) analyses were 90.8% (n = 131) and 81.5% (n = 146), respectively. In PP analysis for CAM susceptibility, the eradication rates of VAC were comparable between CAM-sensitive (91.6%, n = 83) and CAM-resistant (89.4%, n = 47) strains. The corresponding rates from the ITT analysis were 80.0% (n = 95) and 84.0% (n = 50), respectively. No adverse events requiring discontinuation of VAC were observed. CONCLUSIONS: CAM-resistant H. pylori was prevalent in one-third of patients in the Tokyo metropolitan area. VPZ-based triple therapy was highly effective and well-tolerated irrespective of CAM susceptibility. Therefore, it could be a valuable first-line treatment regimen for H. pylori infection.

Epigenetic priming sensitizes gastric cancer cells to irinotecan and cisplatin by restoring multiple pathways.

BACKGROUND: Gastric cancer is heavily influenced by aberrant DNA methylation that alters multiple cancer-related pathways, and may respond to DNA demethylating agents, such as 5-aza-2'-deoxycytidine (5-aza-dC). Here, we aimed to analyze whether 5-aza-dC can sensitize gastric cancer cells to clinically used cytotoxic drugs. METHODS: Ten gastric cancer cell lines were treated with 5-aza-dC for 72 h and their growth was analyzed by conducting WST assay. In vivo effect of the drugs was analyzed using xenografts of OCUM-2 M/SN38 cells. Genome-wide expression and DNA methylation analyses were conducted using microarrays, and biological functions were identified through ingenuity pathway analysis. RESULTS: The cell lines most resistant to SN38 (an active metabolite of irinotecan), CDDP, PTX, and 5-FU, were identified. 5-Aza-dC pre-treatment of the resistant cell lines decreased the IC50 values for SN38 (TMK1, 226.4 nM to 32.91 nM; 44As3, 128.2 nM to 19.32 nM; OCUM2 M/SN38, 74.43 nM to 16.47 nM) and CDDP (TMK1, 5.05 µM to 2.26 µM; OCUM2 M, 10.79 µM to 2.77 µM), but not PTX and 5-FU. The reactivation of apoptosis-related genes, such as RUNX3, PYCARD, TNF, FAS, and FASLG, was induced by pre-treatment with 5-aza-dC, and the DNA demethylation of promoter CpG islands of RUNX3 and PYCARD was confirmed. In a xenograft model with OCUM2 M/SN38, treatment with 5-aza-dC before irinotecan showed markedly enhanced tumor suppression. CONCLUSION: Epigenetic priming with 5-aza-dC can improve the sensitivity of gastric cancer cells to SN38 and CDDP.

Correction to: Epigenetic priming sensitizes gastric cancer cells to irinotecan and cisplatin by restoring multiple pathways.

Recently published the priming.

Novel prodrugs of decitabine with greater metabolic stability and less toxicity.

BACKGROUND: DNA demethylation therapy is now used in practice for hematological tumors and is being developed for solid tumors. Nevertheless, it is difficult to achieve stable pharmacokinetics with the current DNA-demethylating agents, azacitidine (AZA) and decitabine (DAC), because of their rapid deamination by cytidine deaminase in vivo and spontaneous hydrolytic cleavage. Here, we aimed to develop metabolically stable prodrugs of AZA and DAC as novel DNA-demethylating agents. RESULTS: Thirty-five 5'-O-trialkylsilylated AZAs/DACs were synthesized with potential resistance to deamination. Out of these, 11 compounds exhibited demethylating activity similar to that of DAC and guadecitabine, and a suitable aqueous solubility. Pharmacokinetic analysis in mice showed that OR-2003 displayed the highest serum concentration and the area under the curve in an intraperitoneal experiment, whereas OR-2100 exhibited high stability to cytidine deaminase. Treatment of cells with OR-2003 and OR-2100 depleted DNA methyltransferase 1 completely and induced both gene-specific and genome-wide demethylation. The treatment suppressed the growth of multiple types of cancer cells and induced re-expression of tumor suppressor genes. The anti-tumor effect and DNA demethylation effect of OR-2003 and OR-2100 were comparable to that of DAC with fewer adverse effects in vivo. CONCLUSIONS: We developed two novel prodrugs of DAC that exhibited greater stability, comparable DNA demethylation activity, and less toxicity. These compounds are expected to overcome the difficulty in achieving stable pharmacokinetics in patients, leading to maximum DNA demethylation activity with minimum adverse effects.

Decrease in Secondary Neck Vessels in Multiple Sclerosis: A 5-year Longitudinal Magnetic Resonance Angiography Study.

BACKGROUND: Studies have previously shown greater arterial and venous extracranial vascular changes in persons with multiple sclerosis (PwMS) when compared to healthy controls (HCs). OBJECTIVES: To determine the change in the number and size of secondary neck vessels in PwMS and HCs over a 5-year follow-up period. METHODS: Both at baseline and follow-up, 83 PwMS and 25 HCs underwent magnetic resonance angiography (MRA) imaging and analysis. The number and cross-sectional area (CSA) of all secondary neck vessels (excluding the common/internal carotid, vertebral artery, and internal jugular vein) measured at levels from C2-T1 were determined by semi-automated edge detection/ contouring software. The longitudinal change in the number and CSA of the secondary neck vessels from the PwMS and HCs were analyzed by non-parametric Wilcoxon repeated measure. Benjamini-Hochberg procedure adjusted for false discovery rate (FDR). RESULTS: For over 5 years, PwMS demonstrated a consistent longitudinal decrease in both the number of secondary neck vessels (Z-change between -3.3 and -5.4, q=0.001) and their CSA (Zchange between -2.9 and -5.2, q=0.004). On the contrary, the HCs did not demonstrate a significant longitudinal change in secondary neck vessels over the follow-up period. Due to the longitudinal decrease, the PwMS showed a lower number of secondary neck vessels when compared to HCs measured at follow-up (p<0.029, except for C4 with trending p=0.071). The PwMS changes were also corroborated within each MS phenotype. CONCLUSION: PwMS demonstrate a significant mid-term decrease in the number and the size of the secondary neck vessels. The clinical relevance of these findings and the effect on intracranial blood flow are currently unknown.

LINC00162 confers sensitivity to 5-Aza-2'-deoxycytidine via modulation of an RNA splicing protein, HNRNPH1.

DNA demethylation therapy is now expanding from hematological tumors to solid tumors. To exploit its maximum efficacy, long-term treatment is needed, and stratification of sensitive patients is critically important. Here, we identified a long non-coding RNA, LINC00162, as highly and frequently expressed in gastric cancer cell lines sensitive to 5-aza-2'-deoxycytidine (5-aza-dC). Knockdown of LINC00162 decreased the sensitivity while its overexpression increased the sensitivity. In vivo experiments also showed that LINC00162 overexpression increased the sensitivity. LINC00162 enhanced cell cycle arrest and apoptosis induced by 5-aza-dC, but did not affect its DNA demethylation effect. Mechanistically, LINC00162 interacted with an RNA splicing protein, HNRNPH1, and decreased splicing of an anti-apoptotic splicing variant, BCL-XL. LINC00162 may have translational value to predict patients who will respond to 5-aza-dC.

Abnormal venous postural control: multiple sclerosis-specific change related to gray matter pathology or age-related neurodegenerative phenomena?

BACKGROUND: Autonomic nervous system dysfunction has been previously observed in multiple sclerosis (MS) patients. OBJECTIVE: To assess associations between magnetic resonance imaging-detected neuroinflammatory and neurodegenerative pathology and postural venous flow changes indicative of autonomic nervous system function. METHODS: We used a standardized 3T magnetic resonance imaging protocol to scan 138 patients with MS and 49 healthy controls. Lesion volume and brain volumes were assessed. The cerebral venous flow (CVF) was examined by color-Doppler sonography in supine and upright positions and the difference was calculated as ΔCVF. Based on ΔCVF, subjects were split into absolute or quartile groups. Student's t test, χ2-test, and analysis of covariance adjusted for age and sex were used accordingly. Benjamini-Hochberg procedure corrected the p-values for multiple comparisons. RESULTS: No differences were found between healthy controls and patients with MS in both supine and upright Doppler-derived CVF, nor in prevalence of abnormal postural venous control. Patients with absolute negative ΔCVF had higher disability scores (p = 0.013), lower gray matter (p = 0.039) and cortical (p = 0.044) volumes. The negative ΔCVF MS group also showed numerically worse bladder/bowel function when compared to the positive ΔCVF (2.3 vs. 1.5, p = 0.052). Similarly, the lowest quartile ΔCVF MS group had higher T1-lesion volumes (p = 0.033), T2-lesion volumes (p = 0.032), and lower deep gray matter (p = 0.043) and thalamus (p = 0.033) volumes when compared to those with higher ΔCVF quartiles. CONCLUSION: No difference in postural venous outflow between patients with MS and healthy controls was found. However, when the abnormal ΔCVF is present within the MS population, it may be associated with more inflammatory and neurodegenerative pathology. Further studies should explore whether the orthostatic venous changes are an aging or an MS-related phenomenon and if the etiology is due to impaired autonomic nervous system functioning.

Antibiotics suppress colon tumorigenesis through inhibition of aberrant DNA methylation in an azoxymethane and dextran sulfate sodium colitis model.

Chronic inflammation is involved in the development of colon cancer by inducing mutations and aberrant DNA methylation in colon epithelial cells. Furthermore, there is growing evidence that colonic microbiota modulates the inflammation response in the host and influences colon tumorigenesis. However, the influence of colonic microbiota on aberrant DNA methylation remains unknown. Here, we show the effect of colonic microbes on DNA methylation and tumorigenicity using a mouse model of human ulcerative colitis. Mice treated with azoxymethane (AOM) and dextran sulfate sodium (DSS) showed an increase in degree of colitis, as estimated by body weight, occult blood, and stool consistency/diarrhea at 2 weeks after treatment, but treatment with antibiotics markedly reduced the severity of the colitis. Although mucosal hyperplasia and increased inflammation-related genes were observed in the colonic epithelial cells of the AOM/DSS-treated mice, treatment with antibiotics abrogated these changes. In addition, treatment with antibiotics significantly decreased the number of mucosal nodules from 5.9 ± 5.3 to 0.2 ± 0.6 (P < .01) and area of occupancy from 50.1 ± 57.4 to 0.5 ± 1.4 mm2 (P < .01). Aberrant DNA methylation of three marker CpG islands (Cbln4, Fosb, and Msx1) was induced by AOM/DSS treatment in colonic mucosae, but this increase was suppressed by 50%-92% (P < .05) with antibiotic treatment. Microbiome analysis showed that this change was associated with a decrease of the Clostridium leptum subgroup. These data indicate that antibiotics suppressed tumorigenesis through inhibition of aberrant DNA methylation induced by chronic inflammation.

Gross tumor volume in sinonasal tract cancer as a predictor of local recurrence after chemoradiotherapy.

OBJECTIVE: This study investigated whether gross tumor volume of the primary tumor before treatment was a predictor for local recurrence in patients with resectable sinonasal tract squamous cell carcinoma who were treated by chemoradiotherapy. METHODS: A total of 24 patients were enrolled. Pretreatment gross tumor volume of primary tumor was assessed by palpitation, perception and imaging. The cut-off value of the gross tumor volume for local recurrence was determined by receiver-operating curve analysis. A log-rank test and Cox's proportional hazards model were used for univariate and multivariate analyses with adjustment for the clinical T category (cT1-T4a/cT4b), respectively. RESULTS: In the univariate analysis, patients with the gross tumor volume ≥83.7 ml were significantly associated with shorter local recurrence-free rate (P = 0.0023) and disease-free survival (P = 0.0064) than those with gross tumor volume <83.7 ml. In the multivariate analysis, gross tumor volume ≥83.7 ml were significantly associated with shorter local recurrence-free rate (P = 0.041). CONCLUSIONS: Pretreatment gross tumor volume of primary tumor ≥83.7 ml was significantly associated with local recurrence-free rate in resectable sinonasal tract squamous cell carcinoma.

Study Protocol: Prospective Study of Concurrent Chemoradiotherapy with S-1 and Hypofractionated Radiotherapy for Outpatients with Early Glottic Squamous Cell Carcinomas

Background: The recommended treatment strategies for early glottic carcinoma with intent of larynx preservation are primarily radiotherapy. However, the outcomes of radiotherapy for bulky T1 or T2 glottic carcinoma are unsatisfactory. We designed a protocol consisting of concurrent chemoradiotherapy using S-1 as the radiosensitizer. We have performed this protocol in patients with favorable T2 lesions and demonstrated its efficacy and safety. In contrast, we have treated non-bulky T1 glottic carcinomas with 2.25 Gy per fraction, for a total of 25-28 fractions, starting in 2011 to improve efficacy and shorten the treatment period. Since this treatment strategy was implemented for T1 disease, no local failure has occurred to date, and it appears to be almost as safe as radiotherapy using 2.0 Gy per fraction. With the aim of improving the local control rate and shortening the treatment period primarily for favorable T2 disease, we changed the dose of radiation in our protocol from 2.0 Gy to 2.25 Gy per fraction, for a total of 25 fractions (from 30 fractions). The present study aims to evaluate the efficacy and safety of this new protocol. Methods: This study will be conducted as a clinical, prospective, single-armed, non-randomized trial. Patients are to receive S-1 (55.3 mg /m2 /day, once daily) and radiotherapy (2.25 Gy per fraction, for a total of 25 fractions). S-1 and radiotherapy are started on the same day that radiotherapy is performed, 3-6 hours after oral administration of S-1. The primary study aim is the 3-year local control rate. The secondary study aims are overall survival, voice-preservation survival, disease-free survival, complete response rate, completion rate, and toxicity. Result and conclusion: This is the first single-center, non-randomized, prospective study of concurrent chemoradiotherapy with S-1 and hypofractionated radiotherapy to be conducted. The trial will evaluate the efficacy and safety of our protocol.

Establishment of a high-throughput detection system for DNA demethylating agents.

Epigenetic alterations underlie various human disorders, including cancer, and this has resulted in the development of drugs targeting epigenetic alterations. Although DNA demethylating agents are one of the major epigenetic drugs, only two compounds-5-azacytidine (5-aza-CR, azacitidine) and 5-aza-2'-deoxycytidine (5-aza-dC, decitabine)-have obtained clinical approval. Here, we aimed to establish a detection system for DNA demethylating agents suitable for a high-throughput screening (HTS) in mammalian cells. We inserted luciferase and EGFP reporter genes under the UCHL1 promoter, which is methylation-silenced in human colon cancers and can be readily demethylated to drive strong expression. Methylated UCHL1 promoter was introduced into HCT116 colon cancer cells, and transfectants with methylated exogenous UCHL1 promoter were obtained. By screening subclones from each of the epigenetically heterogeneous transfectant clones, we finally obtained three optimal subclones that expressed luciferase and EGFP after 5-aza-dC treatment with high signal-to-noise ratios. Nucleosomes with H3K9me2 were present around the exogenous UCHL1 promoter in all three subclones. Using one of the subclones (HML58-3), HTS was conducted using 19,840 small molecules. Two hit compounds were obtained, and these turned out to be 5-aza-dC and 5-aza-CR. The assay system constructed here demonstrates a robust response to DNA demethylating agents, along with high specificity, and will be useful for screening and biological assays in epigenetics.

Optimized treatment strategy of radiotherapy for early glottic squamous cell carcinomas: An initial analysis.

The purpose of this study was to evaluate the clinical outcomes of radiotherapy for patients with T1/T2 glottic carcinoma. Patients with T1/T2 glottic carcinoma histopathologically diagnosed with squamous cell carcinoma and treated at our hospital between 2007 and 2015 were analyzed retrospectively. Our strategy for T1/T2 glottic carcinoma was as follows: radiotherapy alone with 2.25 Gy per fraction to a total of 25-28 fractions for patients with non-bulky T1 glottic carcinoma; concurrent chemoradiotherapy with oral S-1 and radiotherapy with 2 Gy per fraction to a total of 30 fractions for patients with T1 bulky/T2 favorable glottic carcinoma; or chemoradiotherapy with high-dose cisplatin and radiotherapy with 2 Gy per fraction to a total of 35 fractions for T2 unfavorable glottic carcinoma. Forty-eight patients were eligible. The median follow-up period among surviving patients was 38 months (range, 11-107). The disease was T1a in 23%, T1b in 13%, and T2 in 65% of patients. The 3-year local control rate in all patients, T1a, T1b, and T2 was 96.7%, 100%, 100%, and 96.0%, respectively. Of the 46 patients, one with T2 glottic carcinoma developed recurrent disease at the primary site, and one with T2 glottic carcinoma had lymph node recurrences in the neck. Acute Grade 3 dermatitis occurred in 8 (17%) patients and late Grade 2 hypothyroidism occurred in 2 (4%) patients. This retrospective study shows that our optimized treatment strategy of radiotherapy depending on the stage of early glottic carcinoma is not only effective but also well-tolerated.

Targeting of super-enhancers and mutant BRAF can suppress growth of BRAF-mutant colon cancer cells via repression of MAPK signaling pathway.

Bromodomain and extra-terminal (BET) inhibitors suppress super-enhancers and show cytotoxicity against multiple types of tumors. However, early clinical trials with BET inhibitors showed severe hematopoietic toxicities, highlighting the need for sensitive tumors and rational combination strategies to enhance their therapeutic potential. Here, we identified colon cancer-specific super-enhancers that were associated with multiple oncogenic pathways, including the mitogen-activated protein kinase (MAPK) signaling pathway. Among the 14 colon cancer cell lines tested, their sensitivity to JQ1, a BET inhibitor, was not correlated with c-MYC expression. Three of four BRAFV600E-mutant cell lines were sensitive. Addition of JQ1 to vemurafenib, a specific mutant BRAF inhibitor, suppressed cell growth by arresting cell cycle progression and inducing apoptosis in the BRAFV600E-mutant cells. Mechanistically, the feedback activation of MAPK signaling pathway by vemurafenib was repressed by JQ1. Further, the addition of JQ1 to a BRAF inhibitor enhanced the in vivo anti-tumor effect. Thus, this study indicates the therapeutic potential of targeting of super-enhancers and mutant BRAF in patients with BRAFV600E-mutant colorectal cancer.

High-dose radiotherapy with helical tomotherapy and long-term androgen deprivation therapy for prostate cancer: 5-year outcomes.

PURPOSE: We aimed to examine outcomes of high-dose radiotherapy with helical tomotherapy (HT) and long-term androgen deprivation therapy (ADT) for T1-4N0M0 prostate cancer. METHODS: A total of 391 patients treated with HT between June 2006 and December 2013 were included in this retrospective study. All patients received neoadjuvant ADT for a median duration of 10 months followed by HT at a median dose of 78 Gy [interquartile range (IQR) 78-78]. The times of median adjuvant and total ADT were 19 and 27 months (IQR 20-31), respectively. The risk stratification followed the 2015 National Comprehensive Cancer Network criteria. Biochemical disease-free survival (bDFS) followed the Phoenix definition. Toxicity was scored according to the Radiation Therapy Oncology Group morbidity grading scale. RESULTS: Median follow-up from HT start was 60 months (IQR 42-81). Five-year bDFS rates for low-, intermediate-, high-, and very-high-risk groups were 100, 98.2, 97.7, and 87.9 %, respectively. We observed clinical relapse in nine very-high-risk patients and one high-risk patient, resulting in a 5-year clinical relapse-free survival of 100, 100, 99.4, and 91.7 %, respectively, for each risk group. Three patients died of prostate cancer, resulting in a 5-year prostate cancer-specific survival of 99.6 %. The late grade 2 or higher gastrointestinal and genitourinary toxicities were 9.7 and 10.7 %. No cardiovascular fatal events were observed. CONCLUSIONS: This report confirmed the excellent outcomes with acceptable late toxicities with the combination of HT and long-term ADT. Longer follow-up is crucial to further determine the treatment effect and toxicity.

Retrospective analysis of the clinical efficacy of definitive chemoradiotherapy for patients with hypopharyngeal cancer.

OBJECTIVE: A retrospective analysis was performed to evaluate the clinical efficacy of definitive chemoradiotherapy including intensity-modulated radiotherapy for patients with hypopharyngeal cancer. METHODS: Previously untreated 204 patients with hypopharyngeal cancer were treated with definitive chemoradiotherapy. Of note, 66-70 Gy was delivered to the primary and involved nodes and 36-54 Gy was delivered to the prophylactic lymph node using standard fractionated radiotherapy. One hundred and forty-six patients received induction chemotherapy as a larynx preservation strategy, followed by definitive radiotherapy with or without concurrent chemotherapy. Intensity-modulated radiotherapy was also performed after 2006. RESULTS: The median follow-up time of this cohort was 43.4 months (range; 6.9-151.0). The 3-year overall survival, progression-free survival and larynx preservation survival rates were 78.8% (95% confidence interval; 73.0-85.0), 58.4% (95% confidence interval; 51.8-65.9) and 67.5% (95% confidence interval; 61.0-74.7), respectively. Multivariate analyses identified the following significant prognostic factors: an advanced age, the T category and N category for overall survival, the T category and N category for progression-free survival and the T category for larynx preservation survival. Acute toxicities of Grade 3 or higher were observed in 47 patients (23.0%). Two patients (1.0%) had Grade 4 pharyngeal edema. Suspicious treatment-related death due to lethal pharyngeal hemorrhage occurred in 1 (0.4%) patient. The rates of Grade 2 xerostomia in patients treated with intensity-modulated radiotherapy were 28.1, 17.4 and 9.5% at 6 months, 1 and 2 years after the completion of radiotherapy, respectively. CONCLUSIONS: The efficacy and safety of definitive chemoradiotherapy are considered feasible with sufficient laryngeal preservation.

Clinical results of definitive intensity-modulated radiation therapy for oropharyngeal cancer: retrospective analysis of treatment efficacy and safety.

OBJECTIVE: To evaluate the clinical outcomes of intensity-modulated radiotherapy for patients with oropharyngeal carcinoma. METHODS: Ninety-three oropharyngeal carcinoma patients histopathologically diagnosed with squamous cell carcinoma and treated with definitive intensity-modulated radiotherapy using helical tomotherapy between January 2006 and December 2013 were analyzed. Planning target volume primary and involved nodes was delivered 66-70 Gy at 2 Gy per fraction, while planning target volume prophylactic was delivered 54 Gy using the simultaneous integrated boost technique. RESULTS: The median follow-up period among the surviving patients was 40 months (range, 13-96). There were 76 males and 17 females with a median age of 60 years (range, 34-80). The disease was Stage II in 13%, Stage III in 10% and Stage IV in 77% of patients. Ninety-two patients received chemotherapy (99%); 68 patients received induction chemotherapy (73%), while 21 received concurrent chemotherapy (23%). The 3-year overall survival, progression-free survival and locoregional control rates were 80, 68 and 79%, respectively. Multivariate analysis identified an advanced T-category (T3-4), having double cancer, and smoking habit as significantly unfavorable factors for overall survival, progression-free survival and both progression-free survival and locoregional control, respectively. Only two patients who achieved disease control required percutaneous endoscopic gastrostomy tubes in the last follow-up. The rate of Grade 2 xerostomia at 2 years was 23%. CONCLUSIONS: Intensity-modulated radiotherapy using helical tomotherapy for patients with oropharyngeal carcinoma provided not only sufficient efficacy, but also preserved parotid function.

International prostate symptom score (IPSS) change and changing factor in intensity-modulated radiotherapy combined with androgen deprivation therapy for prostate cancer.

The purposes of this study on prostate cancer are to demonstrate the time course of International Prostate Symptom Score (IPSS) after intensity-modulated radiation therapy (IMRT) combined with androgen deprivation therapy (ADT) and to examine the factor associated with the IPSS change. This study included 216 patients treated with IMRT between 2006 and 2010. Patients were evaluated in three groups according to baseline IPSS as defined by the American Urological Association classification, where IPSSs of 0 to 7, 8 to 19, and 20 to 35 represent mild (n = 124), moderate (n = 70), and severe (n = 22) symptom groups, respectively. The average IPSSs ± standard deviation at baseline vs. those at 24 months after IMRT were 3.5 ± 2.1 vs. 5.1 ± 3.6 in the mild group (P < 0.001), 12.6 ± 3.4 vs. 10.0 ± 6.0 in the moderate group (P = 0.0015), and 23.8 ± 2.9 vs. 14.4 ± 9.1 in the severe group (P < 0.001). Among factors of patient and treatment characteristics, age, IPSS classification, pretreatment GU medications, and positive biopsy rates were associated with the IPSS difference between baseline and 24 months (P = 0.023, < 0.001, 0.044, and 0.028, respectively). In conclusion, patients with moderate to severe urinary symptoms can exhibit improvement in urinary function after IMRT, whereas patients with mild symptoms may have slightly worsened functions. Age, baseline IPSS, GU medications, and tumor burden in the prostate can have an effect on the IPSS changes.

Critical evaluation of a prospective study of concurrent chemoradiotherapy with S-1 for early glottic carcinoma.

AIM: To improve the outcomes of radiotherapy alone for T2 glottic carcinoma (GC), we initiated a prospective study of concurrent chemoradiotherapy with S-1 for patients with early GC, primarily T2 cases. We report the efficacy and safety of this protocol. PATIENTS AND METHODS: Eligible patients had T1b or T2 glottic squamous cell carcinomas. Patients received S-1 (55.3 mg/m(2)/day, once daily) and radiotherapy (2 Gy/day, five days/week, to a total of 30 fractions). RESULTS: Thirteen patients were eligible. Complete responses were observed in all 13 patients (100%). At a median follow-up duration of 53 months (range=23-68 months), the 3-year local control and overall survival rates were both 100%. Grade 3 dermatitis occurred in only one patient. CONCLUSION: This chemoradiotherapy protocol is well -tolerated and effective in patients with early glottic carcinoma. Furthermore, due to its once-daily administration, this protocol is considered to be easier than usual chemoradiotherapy, and makes outpatient-treatment possible.