Yoko Harima

Bax and Bcl-2 expressions predict response to radiotherapy in human cervical cancer

AbstractPurpose: The ratio of Bcl-2 to Bax expression determines survival or death following an apoptotic stimulus. In order to establish a new predictor of the outcome of treatment for human cervical carcinoma, we investigated the relationship between the expressions of the Bax and Bcl-2 proteins and the response to radiotherapy after the administration of 10.8 Gy. Methods: A total of 44 patients with histologically proven carcinoma of the uterine cervix, including three with recurrent cervical stump carcinomas, were treated with definitive radiotherapy. The presence of mutations in exons 5–8 of the p53 gene was analyzed by a single-strand conformation polymorphism analysis and DNA sequencing. Results: Forty patients were found to have wild-type p53, and the remaining four had mutant p53. The Bax and Bcl-2 protein expressions prior to radiotherapy did not correlate with response and survival. However, the Bax and Bcl-2 protein expressions after radiotherapy correlated with both response and survival. Bax-positive tumors showed significantly better responses than the Bax-negative tumors after 10.8 Gy radiation (P = 0.0002). In contrast, the Bcl-2-positive tumors showed significantly poorer responses than the Bcl-2-negative tumors after radiation (P = 0.002). Increased Bax expression after the 10.8 Gy radiotherapy was found to be correlated with good survival (P = 0.04). In contrast, increased Bcl-2 expression after such radiotherapy was correlated with poor survival (P = 0.002). Conclusion: The levels of Bax and Bcl-2 expression after 10.8 Gy radiotherapy are useful prognostic markers in patients with human cervical carcinoma.

A multicentre randomised clinical trial of chemoradiotherapy plus hyperthermia versus chemoradiotherapy alone in patients with locally advanced cervical cancer

Abstract Purpose: To evaluate the effectiveness of whole-pelvic hyperthermia (HT) added to standard chemoradiotherapy (CRT) in locally advanced cervical cancer (CC), by investigating the clinical response and survival of patients treated with cisplatin-based CRT vs. CRT with HT (CRT + HT). Materials and methods: This study was conducted at five hospitals in Japan between September 2001 and March 2015 in patients with the International Federation of Gynecology and Obstetrics stage IB (bulky)–IVA CC undergoing definitive CRT. After giving a written informed consent, patients were randomly allocated to two treatment groups: CRT and CRT + HT group. Overall survival (OS), disease-free survival (DFS), local relapse-free survival (LRFS), complete response (CR) rate and tolerability were evaluated. Results: In total, 101 patients were treated. Patient characteristics, total dose of cisplatin and radiotherapy were similar for both groups. Although not statistically significant, the 5-year OS, DFS and LRFS in the CRT + HT group (77.8%, 70.8% and 80.1%, respectively) were better than those in the CRT group (64.8%, 60.6% and 71.0%, respectively). CR was significantly more likely to be achieved in patients in the CRT + HT group than in the CRT group (88% vs. 77.6%; adjusted odds ratio, 3.993; 95% confidence interval, 1.018–15.67; p = .047). CRT + HT was well tolerated and caused no additional acute or long-term toxicity compared with CRT alone. Conclusions: HT combined with CRT improved the CR rate of CRT in patients with locally advanced CC, however, could not improve survival outcomes. Further studies in larger samples are warranted.

Histopathological changes in rabbit uterus carcinoma after transcatheter arterial embolization using cisplatin

Abstract The effects of chemoembolization with cisplatin on gynecological malignancy were investigated using rabbit uterine tumors. A group of 20 rabbits were subjected to inoculation of the uterus with 5×107 VX2 carcinoma cells and 4 weeks later were divided into four groups, each consisting of five rabbits: an untreated control group, a group given cisplatin intraarterially (IA), a group subjected to transcatheter arterial embolization (TAE) with Gelfoam particles and a group subjected to transcatheter chemoembolization (TACE) with Gelfoam particles plus 1 mg/kg cisplatin. All groups were examined histologically 2 days after treatment. The untreated control group was further investigated 4 weeks after inoculation. In the untreated control group, the tumor cell nuclei varied in size and were irregular in form, and multiple nuclei and nuclear division were also observed. No necrotic zones were found up to 4 weeks after inoculation. The IA group showed no necrosis, but a few apoptotic cells were scattered throughout the tumor. In the TAE group, necrosis was observed in the center of the tumors, but proliferating cells persisted at the periphery. In the TACE group, necrosis was observed in the central part with many apoptotic cells surrounding the necrotic region in layers. The proliferating cell nuclear antigen (PCNA) index was 95.88% in the untreated control group, 86.6% in the IA group, and 8.62% in the TACE group, indicating a significant reduction in cell proliferation in the TACE group. These findings suggest that TACE results in more effective cytotoxicity than the other two treatments in uterine cancer tumor transplants.

Apolipoprotein C-II is a potential serum biomarker as a prognostic factor of locally advanced cervical cancer after chemoradiation therapy.

PURPOSE To determine pretreatment serum protein levels for generally applicable measurement to predict chemoradiation treatment outcomes in patients with locally advanced squamous cell cervical carcinoma (CC). METHODS AND MATERIALS In a screening study, measurements were conducted twice. At first, 6 serum samples from CC patients (3 with no evidence of disease [NED] and 3 with cancer-caused death [CD]) and 2 from healthy controls were tested. Next, 12 serum samples from different CC patients (8 NED, 4 CD) and 4 from healthy controls were examined. Subsequently, 28 different CC patients (18 NED, 10 CD) and 9 controls were analyzed in the validation study. Protein chips were treated with the sample sera, and the serum protein pattern was detected by surface-enhanced laser desorption and ionization-time-of-flight mass spectrometry (SELDI-TOF MS). Then, single MS-based peptide mass fingerprinting (PMF) and tandem MS (MS/MS)-based peptide/protein identification methods, were used to identify protein corresponding to the detected peak. And then, turbidimetric assay was used to measure the levels of a protein that indicated the best match with this peptide peak. RESULTS The same peak 8918 m/z was identified in both screening studies. Neither the screening study nor the validation study had significant differences in the appearance of this peak in the controls and NED. However, the intensity of the peak in CD was significantly lower than that of controls and NED in both pilot studies (P=.02, P=.04) and validation study (P=.01, P=.001). The protein indicated the best match with this peptide peak at 8918 m/z was identified as apolipoprotein C-II (ApoC-II) using PMF and MS/MS methods. Turbidimetric assay showed that the mean serum levels of ApoC-II tended to decrease in CD group when compared with NED group (P=.078). CONCLUSION ApoC-II could be used as a biomarker for detection in predicting and estimating the radiation treatment outcome of patients with CC.

Interhospital network system using the worldwide web and the common gateway interface.

We constructed an interhospital network system using the worldwide web (WWW) and the Common Gateway Interface (CGI). Original clinical images are digitized and stored as a database for educational and research purposes. Personal computers (PCs) are available for data treatment and browsing. Our system is simple, as digitized images are stored into a Unix server machine. Images of important and interesting clinical cases are selected and registered into the image database using CGI. The main image format is 8- or 12-bit Joint Photographic Experts Group (JPEG) image. Original clinical images are finally stored in CD-ROM using a CD recorder. The image viewer can browse all of the images for one case at once as thumbnail pictures; image quality can be selected depending on the user’s purpose. Using the network system, clinical images of interesting cases can be rapidly transmitted and discussed with other related hospitals. Data transmission from relational hospitals takes 1 to 2 minutes per 500 Kbyte of data. More distant hospitals (eg, Rakusai Hospital, Kyoto) takes 1 minute more. The mean number of accesses our image database in a recent 3-month period was 470. There is a total about 200 cases in our image database, acquired over the past 2 years. Our system is useful for communication and image treatment between hospitals and we will describe the elements of our system and image database.

Transcatheter arterial embolization therapy in cases of recurrent and advanced gynecologic cancer.

Transcatheter internal iliac arterial embolization therapy (TAE) using Gelfoam particles was performed in 24 patients with recurrent gynecologic cancer and ten patients with advanced gynecologic cancer who had previously undergone radiotherapy. The tumor showed complete response (CR) to the therapy in six patients, partial response (PR) in 12, minor response (MR) in three, and no changes (NC) in 13 patients, with the response rate (CR + PR) of 52.9% (18 of 34). No serious or prolonged side effects were encountered except for vesicovaginal fistula in three patients and renal failure in one. The median duration of survival was 299 days, and the 1‐year cumulative survival rate was 32.5%. The factors that were associated with favorable outcome after TAE were good general condition, no distant metastases, tumors <5 cm in diameter, and responses to the therapy of PR or better. Thus, TAE appears useful for the treatment of recurrent and advanced gynecologic malignancies.

Relationships between thermal dose parameters and the efficacy of definitive chemoradiotherapy plus regional hyperthermia in the treatment of locally advanced cervical cancer: data from a multicentre randomised clinical trial

Abstract Purpose: To evaluate the contribution of the thermal dose parameters during regional hyperthermia (HT) treatment to the clinical outcomes in patients with cervical carcinoma (CC) who received chemoradiotherapy (CRT) plus HT. Materials and methods: Data from a multicentre randomised clinical trial of concurrent CRT + HT vs. CRT alone were used to evaluate the efficacy and safety of this combination therapy in the CC patients. The intrarectal temperatures of patients undergoing HT were recorded. The complete thermal data of 47 (92%) of the 51 patients in the CRT + HT group were available for the thermal analysis. Thus, 47 patients who received CRT + HT were included in the present study. Results: Among the patients who received CRT + HT, a higher CEM43T90 (≥1 min) value (a thermal dose parameter) was significantly associated with better local relapse-free survival in both univariate (p = 0.024) and multivariate (p = 0.0097) analyses. The disease-free survival of the patients with higher CEM43T90 (≥1 min) values tended to be better in comparison to patients with lower CEM43T90 (<1 min) value (p = 0.071). A complete response tended to be associated with the CEM43T90 (p = 0.056). Disease-free survival, local relapse-free survival and complete response rate for patients with higher CEM43T90 (≥1) were significantly better than those for patients with CRT alone (p = 0.036, p = 0.036 and p = 0.048). Conclusions: Dose-effect relationships between thermal dose parameters and clinical outcomes were confirmed in the CC patients treated with a combination of CRT + HT. This study also confirmed that HT with lower CEM43T90 is insufficient to achieve a significant hyperthermic sensitisation to CRT.

Recommendations for high-risk clinical target volume definition with computed tomography for three-dimensional image-guided brachytherapy in cervical cancer patients

Abstract Our purpose was to develop recommendations for contouring the computed tomography (CT)-based high-risk clinical target volume (CTVHR) for 3D image-guided brachytherapy (3D-IGBT) for cervical cancer. A 15-member Japanese Radiation Oncology Study Group (JROSG) committee with expertise in gynecological radiation oncology initiated guideline development for CT-based CTVHR (based on a comprehensive literature review as well as clinical experience) in July 2014. Extensive discussions occurred during four face-to-face meetings and frequent email communication until a consensus was reached. The CT-based CTVHR boundaries were defined by each anatomical plane (cranial–caudal, lateral, or anterior–posterior) with or without tumor progression beyond the uterine cervix at diagnosis. Since the availability of magnetic resonance imaging (MRI) with applicator insertion for 3D planning is currently limited, T2-weighted MRI obtained at diagnosis and just before brachytherapy without applicator insertion was used as a reference for accurately estimating the tumor size and topography. Furthermore, utilizing information from clinical examinations performed both at diagnosis and brachytherapy is strongly recommended. In conclusion, these recommendations will serve as a brachytherapy protocol to be used at institutions with limited availability of MRI for 3D treatment planning.

Radiation dose of nurses during IR procedures: a controlled trial evaluating operator alerts before nursing tasks.

PURPOSE To compare radiation exposure of nurses when performing nursing tasks associated with interventional procedures depending on whether or not the nurses called out to the operator before approaching the patient. MATERIALS AND METHODS In a prospective study, 93 interventional radiology procedures were randomly divided into a call group and a no-call group; there were 50 procedures in the call group and 43 procedures in the no-call group. Two monitoring badges were used to calculate effective dose of nurses. In the call group, the nurse first told the operator she was going to approach the patient each time she was about to do so. In the no-call group, the nurse did not say anything to the operator when she was about to approach the patient. RESULTS In all the nursing tasks, the equivalent dose at the umbilical level inside the lead apron was below the detectable limit. The equivalent dose at the sternal level outside the lead apron was 0.16 μSv ± 0.41 per procedure in the call group and 0.51 μSv ± 1.17 per procedure in the no-call group. The effective dose was 0.018 μSv ± 0.04 per procedure in the call group and 0.056 μSv ± 0.129 per procedure in the no-call group. The call group had a significantly lower radiation dose (P = .034). CONCLUSIONS Radiation doses of nurses were lower in the group in which the nurse called to the operator before she approached the patient.

Treatment outcomes of patients with FIGO Stage I/II uterine cervical cancer treated with definitive radiotherapy: a multi-institutional retrospective research study

The purpose of this study was to analyze the patterns of care and outcomes of patients with FIGO Stage I/II cervical cancer who underwent definitive radiotherapy (RT) at multiple Japanese institutions. The Japanese Radiation Oncology Study Group (JROSG) performed a questionnaire-based survey of their cervical cancer patients who were treated with definitive RT between January 2000 and December 2005. A total of 667 patients were entered in this study. Although half of the patients were considered suitable for definitive RT based on the clinical features of the tumor, about one-third of the patients were prescribed RT instead of surgery because of poor medical status. The RT schedule most frequently utilized was whole-pelvic field irradiation (WP) of 30 Gy/15 fractions followed by WP with midline block of 20 Gy/10 fractions, and high-dose-rate intracavitary brachytherapy (HDR-ICBT) of 24 Gy/4 fractions prescribed at point A. Chemotherapy was administered to 306 patients (46%). The most frequent regimen contained cisplatin (CDDP). The median follow-up time for all patients was 65 months (range, 2–135 months). The 5-year overall survival (OS), pelvic control (PC) and disease-free survival (DFS) rates for all patients were 78%, 90% and 69%, respectively. Tumor diameter and nodal status were significant prognostic indicators for OS, PC and DFS. Chemotherapy has potential for improving the OS and DFS of patients with bulky tumors, but not for non-bulky tumors. This study found that definitive RT for patients with Stage I/II cervical cancer achieved good survival outcomes.