Masanori Someya

High-dose-rate versus low-dose-rate intracavitary therapy for carcinoma of the uterine cervix: a randomized trial.

This was a prospective randomized clinical trial undertaken at our institution to compare low‐dose‐rate (LDR) intracavitary radiation therapy versus high‐dose‐rate (HDR) intracavitary radiation therapy for the treatment of cervical carcinoma.

Expression of matrix metalloproteinase 9 is a prognostic factor in patients with non‐Hodgkin lymphoma

Non‐Hodgkin lymphoma (NHL) represents a heterogeneous group of tumors that vary with regard to their biologic aggressiveness and clinical course. In in vitro studies, matrix metalloproteinase 9 (MMP9) was reportedly expressed by human NHL cells and elevated levels of MMP9 have been observed in a subset of patients with high‐grade NHL.

Ability to repair DNA double-strand breaks related to cancer susceptibility and radiosensitivity

Traditional radiobiology has aimed at elucidating the mechanism of radiosensitivity of cancer cells and normal cells. Because the mechanism of DNA double-strand break (DSB) repair, which is inherently important to radiosensitivity, was unknown, it has been difficult to obtain results applicable to clinical radiotherapy from traditional radiobiology research. Today, however, the molecular mechanism of DNA DSB repair has been elucidated because of the rapid advances in molecular biology. In DNA DSB repair, at least two major repair mechanisms, homologous recombination and nonhomologous end joining (NHEJ) have been reported. In the NHEJ pathway, DSBs are directly, or after processing of the DNA ends, rejoined at an appropriate chromosomal end. DNA-dependent protein kinase (DNA-PK) plays an important role in DNA DSB repair by NHEJ. We have investigated how the ability of repair of DNA DSB influences cancer susceptibility and the radiosensitivity of tumors and normal tissues by focusing on the activity of DNA-PK. In the near future, research on DNA DSB repair mechanism will be able to be applied to research on carcinogenesis, prediction of radiosensitivity of tumors and normal cells, and sensitization of tumor cells.

HIGH-DOSE-RATE INTRACAVITARY BRACHYTHERAPY: RESULTS OF ANALYSES OF LATE RECTAL COMPLICATIONS

PURPOSE To examine the incidence of radiation-induced late rectal complications by analyzing the data of measured rectal doses in patients with cancer of the uterine cervix treated with high-dose-rate intracavitary brachytherapy. METHODS AND MATERIALS We measured doses to the rectum in 105 patients with cancer of the cervix during high-dose-rate intracavitary brachytherapy with a semiconductor dosimeter that can measure five points in the rectum simultaneously. On the basis of these measurements, equivalent doses, to which the biologically equivalent doses were converted as if given as fractionated irradiation at 2 Gy/fraction, were calculated as components of the cumulative dose at five rectal points in intracavitary brachytherapy combined with the external whole pelvic dose. RESULTS The calculated values of equivalent doses for late effects at the rectum ranged from 15 to 100 Gy (median 60 Gy for patients who did not develop complications and 76 Gy for patients who subsequently developed Grade II or III complications). When converted to a graph of absolute rectal complication probability, the data could be fitted to a sigmoid curve. The data showed a very definite dose-response relationship, with a threshold for complications at approximately 50 Gy and the curve starting to rise more steeply at approximately 60 Gy. The steepest part of the curve had a slope equivalent to approximately 4% incidence/1 Gy increase in equivalent doses. CONCLUSION The radiation tolerance dose, 5% and 50% complication probability, was about 64 and 79 Gy, respectively. Our data almost agree with the prescribed dose for the rectum for the radiation tolerance doses on the basis of the recorded human and animal data. The probability of rectal complications increased drastically after the maximal rectal dose was >60 Gy.

Gimeracil sensitizes cells to radiation via inhibition of homologous recombination

BACKGROUND AND PURPOSE 5-Chloro-2,4-dihydroxypyridine (Gimeracil) is a component of an oral fluoropyrimidine derivative S-1. Gimeracil is originally added to S-1 to yield prolonged 5-FU concentrations in tumor tissues by inhibiting dihydropyrimidine dehydrogenase, which degrades 5-FU. We found that Gimeracil by itself had the radiosensitizing effect. METHODS AND MATERIALS We used various cell lines deficient in non-homologous end-joining (NHEJ) or homologous recombination (HR) as well as DLD-1 and HeLa in clonogenic assay. gamma-H2AX focus formation and SCneo assay was performed to examine the effects of Gimeracil on DNA double strand break (DSB) repair mechanisms. RESULTS Results of gamma-H2AX focus assay indicated that Gimeracil inhibited DNA DSB repair. It did not sensitize cells deficient in HR but sensitized those deficient in NHEJ. In SCneo assay, Gimeracil reduced the frequency of neo-positive clones. Additionally, it sensitized the cells in S-phase more than in G0/G1. CONCLUSIONS Gimeracil inhibits HR. Because HR plays key roles in the repair of DSBH caused by radiotherapy, Gimeracil may enhance the efficacy of radiotherapy through the suppression of HR-mediated DNA repair pathways.

A clinical study of hypoxia using endogenous hypoxic markers and polarographic oxygen electrodes.

Purpose:To examine various kinds of endogenous hypoxia markers’ expression in the tissues of uterine cervix cancer and to elucidate the characteristics and pitfalls when they are used as a hypoxia marker, by comparing these expressions with tumor oxygen partial pressure (pO2) values.Patients and Methods:Assessment of pO2 using polarographic oxygen electrodes was performed in 69 patients with cervix carcinomas. Biopsies were taken from the region of electrode measurements. Expression of endogenous hypoxic markers in biopsy specimens such as vascular endothelial growth factor, glucose transporter-1 (GLUT-1), involucrin, and osteopontin was detected by immunohistochemistry. A double immunolabeling technique with GLUT-1 and MIB-1 as a marker of proliferation was also performed.Results:There was no significant correlation between expression of endogenous hypoxic markers and pO2. The only significant association seen was between the fraction of necrosis and pO2. A significant but weak correlation was found among expression of endogenous hypoxic markers. The levels of necrosis were related negatively with levels of expression of endogenous hypoxic markers. The double immunolabeling technique with GLUT-1 and MIB-1 indicated that there were about 20% MIB-1-positive tumor cells without GLUT-1 expression in tissues adjacent to areas of necrosis.Conclusion:The existence of necrosis affected the expression of endogenous hypoxic markers. Some hypoxic tumor cells without expressions of hypoxia markers can maintain clonogenicity and influence the treatment results. The combined use of hypoxic markers is recommended because their expression is influenced by factors other than hypoxia.Ziel:Prüfung der Expression verschiedener endogener Hypoxiemarker in Zervixkarzinom-Geweben und Ermitteln ihrer Eignung als Marker zur Hypoxiemessung durch Vergleich mit den Werten des Sauerstoffpartialdrucks (pO2) im Tumor.Patienten und Methodik:Polarographische pO2-Bestimmungen wurden bei 69 Zervixkarzinom-Patientinnen durchgeführt. Es wurden aus dem Bereich der Messelektrode Biopsien genommen. In den Gewebeproben wurde immunhistologisch die Expression endogener Hypoxiemarker—wie Vascular Endothelial Growth Factor (VEGF), Glukose-Transporter-1 (GLUT-1), Involucrin und Osteopontin—nachgewiesen. Eine immunhistologische Doppelmarkierung mit GLUT-1 and MIB-1 als Proliferationsmarker wurde ebenfalls durchgeführt.Ergebnisse:Es bestand keine signifikante Korrelation zwischen der Expression endogener Hypoxiemarker und pO2. Die einzige signifikante Assoziation fand sich zwischen Nekrose-Anteil und pO2. Es zeigte sich eine signifikante, aber schwache Korrelation unter den exprimierten endogenen Hypoxiemarkern. Das Ausmaß der Nekrose korrelierte negativ mit den Spiegeln der exprimierten endogenen Hypoxiemarker. Die immunhistologische Doppelmarkierung mit GLUT-1 und MIB-1 ergab, dass etwa 20% der MIB- 1-positiven Tumorzellen in der Umgebung nekrotischer Bereiche kein GLUT-1 bildeten.Schlussfolgerung:Nekrose beeinflusst die Expression endogener Hypoxiemarker. Einige hypoxische Tumorzellen, die keine Hypoxiemarker exprimieren, können klonogen bleiben und die Behandlungsergebnisse beeinflussen. Empfohlen wird die Anwendung einer Kombination von Hypoxiemarkern, da deren Expression auch durch Hypoxie-unabhängige Faktoren beeinflusst wird.

Pancreas: imaging diagnosis with color/power Doppler ultrasonography, endoscopic ultrasonography, and intraductal ultrasonography

Recent advances of ultrasound imaging have made possible to depict various diseases and conditions of the pancreas. Color/power Doppler ultrasonography, endoscopic ultrasonography, and intraductal ultrasonography are feasible to show vascular abnormalities, differentiate the solid and cystic tumors, decide tumor extent, and help to perform interventional treatments of the pancreatic diseases. Those techniques will contribute to the more precise and easier diagnosis and to prompt decision of the treatments of the pancreatic disorders. Radiologists should recognize the diagnostic feasibility and limitations of those techniques in order to avoid unnecessary examinations on the patients, and obtain precise diagnostic images.

Results and DVH analysis of late rectal bleeding in patients treated with 3D-CRT or IMRT for localized prostate cancer

In patients undergoing radiotherapy for localized prostate cancer, dose–volume histograms and clinical variables were examined to search for correlations between radiation treatment planning parameters and late rectal bleeding. We analyzed 129 patients with localized prostate cancer who were managed from 2002 to 2010 at our institution. They were treated with 3D conformal radiation therapy (3D-CRT, 70 Gy/35 fractions, 55 patients) or intensity-modulated radiation therapy (IMRT, 76 Gy/38 fractions, 74 patients). All radiation treatment plans were retrospectively reconstructed, dose–volume histograms of the rectum were generated, and the doses delivered to the rectum were calculated. Time to rectal bleeding ranged from 9–53 months, with a median of 18.7 months. Of the 129 patients, 33 patients had Grade 1 bleeding and were treated with steroid suppositories, while 25 patients with Grade 2 bleeding received argon plasma laser coagulation therapy (APC). Three patients with Grade 3 bleeding required both APC and blood transfusion. The 5-year incidence rate of Grade 2 or 3 rectal bleeding was 21.8% for the 3D-CRT group and 21.6% for the IMRT group. Univariate analysis showed significant differences in the average values from V65 to V10 between Grades 0–1 and Grades 2–3. Multivariate analysis demonstrated that patients with V65 ≥ 17% had a significantly increased risk (P = 0.032) of Grade 2 or 3 rectal bleeding. Of the 28 patients of Grade 2 or 3 rectal bleeding, 17 patients (60.7%) were cured by a single session of APC, while the other 11 patients required two sessions. Thus, none of the patients had any further rectal bleeding after the second APC session.

The combination of olaparib and camptothecin for effective radiosensitization

BackgroundPoly (ADP-ribose) polymerase-1 (PARP-1) is a key enzyme involved in the repair of radiation-induced single-strand DNA breaks. PARP inhibitors such as olaparib (KU-0059436, AZD-2281) enhance tumor sensitivity to radiation and to topoisomerase I inhibitors like camptothecin (CPT). Olaparib is an orally bioavailable inhibitor of PARP-1 and PARP-2 that has been tested in multiple clinical trials. The purpose of this study was to investigate the characteristics of the sensitizing effect of olaparib for radiation and CPT in order to support clinical application of this agent.MethodsDLD-1 cells (a human colorectal cancer cell line) and H1299 cells (a non-small cell lung cancer cell line) with differences of p53 gene status were used. The survival of these cells was determined by clonogenic assay after treatment with drugs and X-ray irradiation. The γH2AX focus formation assay was performed to examine the influence of olaparib on induction and repair of double-stranded DNA breaks after exposure to radiation or CPT.ResultsA radiosensitizing effect of olaparib was seen even at 0.01 μM. Its radiosensitizing effect after exposure for 2 h was similar to that after 24 h. H1299 cells with depletion or mutation of p53 were more radioresistant than H1299 cells with wild-type p53. However, similar enhancement of radiosensitization by olaparib was observed with all of the tested cell lines regardless of the p53 status. Olaparib also sensitized cells to CPT. This sensitizing effect was seen at low concentrations of olaparib such as 0.01 μM, and its sensitizing effect was the same at both 0.01 μM and 1 μM. The combination of olaparib and CPT had a stronger radiosensitizing effect. The results of the γH2AX focus assay corresponded with the clonogenic assay findings.ConclusionOlaparib enhanced sensitivity to radiation and CPT at low concentrations and after relatively short exposure times such as 2 h. The radiosensitizing effect of olaprib was not dependent on the p53 status of tumor cells. These characteristics could be advantageous for clinical radiotherapy since tumor cells may be exposed to low concentrations of olaparib and/or may have different levels of p53 mutation. The combination of olaparib and CPT had a stronger radiosensitizing effect, indicating that combining a PARP inihibitor with a topoiomerase I inhibitor could be promising for clinical radiosensitization.

The enhanced expression of the matrix metalloproteinase 9 in nasal NK/T-cell lymphoma

BackgroundNasal NK/T cell lymphoma is an aggressive disease and has a poor prognosis. Nasal NK/T cell lymphoma is refractory to conventional chemotherapy and has strong tendency of widespread relapse or dissemination into distant sites.MethodsWe immunohistochemically studied nasal NK/T-cell lymphoma to elucidate the unique characteristics of nasal NK/T-cell lymphoma, such as its higher metastatic tendency and its vast necrosis which leads to destruction of the involved tissues. The expression of P-glycoprotein and MMP-9 was evaluated in the 20 patients with nasal NK/T-cell lymphoma and 25 with nasal non-NK/T-cell lymphoma and the relationship between expression of these proteins and clinical results were analyzed in this report.ResultsOverall 5-year survival rates for patients with nasal NK/T cell lymphoma, and nasal non-NK/T cell lymphoma were 51%, and 84%. Distant involvement free 5-year survival rates for patients with nasal NK/T cell lymphoma, and nasal non-NK/T cell lymphoma were 53%, and 79%.Overall positivity for P-glycoprotein was observed in 10 of 19 patients with NTL and in 13 of 23 patients with non-NTL. When the overall survival rate was compared between patients with P-glycoprotein positive and negative, there was no difference between them.Sixteen of the 19 patients with nasal NK/T cell lymphoma expressed MMP-9. In contrast, only 8 of the 22 patients with nasal non-NK/T cell lymphoma expressed MMP-9. Distant involvement free 5-year survival rates for patients with MMP-9 negative, and MMP-9 positive were 92%, and 61%, respectively. The difference was statistically significant (p = 0.027).ConclusionPositive immunoreactivity for P-glycoprotein was not an independent prognostic factor in nasal NK/T-cell lymphomas, which stresses the importance of exploring other mechanisms of drug resistance. The strong expression of MMP-9 is uniquely characteristic of nasal NK/T cell lymphoma and may contribute to its strong tendency to disseminatate and the extensive necrosis which is always seen. However, our results are based on univariate comparisons, and as such, should be viewed with some caution.