Mitsuharu Sougawa

Is whole-brain irradiation necessary for primary central nervous system lymphoma?: Patterns of recurrence after partial-brain irradiation

Neurotoxicity after whole‐brain irradiation remains a major problem in the treatment of primary central nervous system lymphoma (PCNSL). To clarify whether whole‐brain radiation is necessary for PCNSL, the authors retrospectively analyzed the outcome of patients treated with partial‐brain irradiation.

HUMAN PAPILLOMA VIRUS (HPV) DNA ASSOCIATED WITH PROGNOSIS OF CERVICAL CANCER AFTER RADIOTHERAPY

PURPOSE The importance of human papilloma virus (HPV) infection in the outcome of cervical cancer after radiotherapy remains unknown. Our study explored whether the HPV status of tumors is associated with the outcome of radiotherapy in patients with cervical cancer. METHODS AND MATERIALS A total of 84 patients with cervical cancer (6 Stage I, 10 Stage II, 49 Stage III, and 19 Stage IV) who underwent definitive radiotherapy between January 1995 and June 2000 were included in this study. Tumor samples were obtained from all patients by punch biopsy before radiotherapy. The presence of HPV and its type were analyzed by polymerase chain reaction (PCR) based assay using the consensus primers for E6 and L1 regions. Actuarial methods were used to calculate overall survival and disease-free survival. RESULTS A total of 42 patients (50%) had cancer recurrence after radiotherapy. HPV-positive tumors were found in 76.2% (64 cases) of patients. HPV-negative patients survived for significantly shorter time periods compared to the HPV-positive patients in the overall survival (p = 0.007) and the disease-free survival (p = 0.005). According to multivariate analysis, HPV status is a significant predictor of both overall (p = 0.02) and disease-free survival time (p = 0.005). CONCLUSION The results of this study suggest that HPV-negative patients with cervical carcinoma have a significantly poorer prognosis after radiotherapy, and HPV status may be used as a marker to optimize the treatment of patients with this type of cancer.

Expression of Ku80 in cervical cancer correlates with response to radiotherapy and survival.

To reveal the genes relevant for prediction of cervical cancer after radiotherapy, we previously carried out cDNA microarray experiments on primary cervical cancer comparing patients with a complete response (CR) and those with no change (NC). Some of these genes had already been associated with the radiation response, such as x-ray repair cross-complementing 5 (XRCC5), which was found more in radioresistant tumors than in radiosensitive ones. The aim of this study was to confirm the possible roles of XRCC5 mRNA levels by a real-time polymerase chain reaction method in 20 cervical cancers, and Ku80 protein, which is the gene product of XRCC5, using a histopathologic method of formalin-fixed sections of tumor biopsies in determining tumor response to radiotherapy and survival in 89 patients with cervical cancer. The levels of XRCC5 mRNA were 104.82 ± 100.2 copies/&mgr;g total RNA in tumor tissues in the CR group (mean ± standard deviation) and 104.95 ± 100.32 copies/&mgr;g total RNA in those in the NC group. The levels of XRCC5 mRNA were not significantly different between the CR and NC groups. Histopathologic methods revealed 29.2% (26 of 89) of the patients to be Ku80-negative, with Ku80-positive findings in 70.8% (63 of 89). Of the Ku80-negative patients, 19 had CR, 3 had a partial response (PR), and 4 had NC. Of the Ku80-positive patients, 25 had CR, 22 had PR, and 16 had NC. Ku80-negative tumors showed significantly better responses than Ku80-positive ones, comparing CR and PR/NC responses (p = 0.01). In addition, overall survival was significantly better in the Ku80-negative patients as compared with those who were Ku80-positive (p = 0.04). The results of this study suggest that a low expression of Ku80 protein leads to radiosensitivity in cervical cancer and that Ku80 might play a role in treatment outcome.

Chromosome 6p21.2, 18q21.2 and human papilloma virus (HPV) DNA can predict prognosis of cervical cancer after radiotherapy.

Loss of heterozygosity (LOH) is one of the most important mechanisms for inactivation of tumor‐suppressor genes. Studies of LOH in patients with cervical carcinoma have reported a high frequency of LOH on 3p21.3, 6p21.2, 17p13.1, and 18q21.2. Our study explored whether p53 status, human papilloma virus (HPV), and LOH on chromosome 3p21.3, 6p21.2, 17p13.1, and 18q21.2 are associated with treatment outcome in 65 patients with cervical cancer after radiotherapy. Tumors and normal DNA were analyzed by polymerase chain reaction (PCR) for genetic losses at 10 polymorphic microsatellite loci. The presence of HPV and its type were analyzed by PCR‐based assay using the consensus primers for E6, E7, and L1 region. Mutations of the p53 gene were identified by a single‐strand conformation polymorphism analysis. Chromosomes 3p21.3, 6p21.2, 17p13.1, and 18q21.2 were involved in the LOH in 23.1%, 41.5%%, 33.8%, and 23.1% of the tumors in our study, respectively. HPV‐positive tumors were found in 73.8% of the patients and p53 mutation in 10.8%. The patients with LOH on chromosome 6p21.2 and 18q21.2 survived significantly shorter compared with those without LOH on chromosome 6p21.2 and 18q21.2 in both the overall survival (P = 0.006 and P = 0.007) and the disease‐free survival (P = 0.005 and P = 0.008). The HPV‐negative patients survived significantly shorter compared with the HPV‐positive patients in both the overall survival (P = 0.01) and the disease‐free survival (P = 0.04). According to multivariate analysis, HPV status (P = 0.0004, P = 0.01), LOH on 6p21.2 (P = 0.006, P = 0.02), and LOH on 18q21.2 (in both P = 0.01) is a significant predictor of both overall and disease‐free survival time. The results of our study suggest that absence of HPV infection, LOH on 6p21.2, and LOH on 18q21.2 are the most important determinants of outcome of patients with cervical carcinoma after radiotherapy.

Enhancement of radiation effects by acyclovir

Acyclovir (ACV), a new antiviral drug, was used to investigate its effect of radiosensitivity in tumors in vivo. In in vivo experiments with Sarcoma-180 transplanted into the ICR mouse and FM3A transplanted into the C3H mouse, ACV enhanced the radiosensitivity of both tumors. In S-180, radiation effects were enhanced by treatment with 100 mg/kg of ACV from 30 min before to 60 min after irradiation. In S-180 treated by 400 mg/kg of ACV, the enhancement ratio was approximately 2.0, as evaluated by the growth delay method. In the FM3A tumor treated by 20 mg/kg of ACV, the enhancement ratio was approximately 1.3, as evaluated by tumor cure (TCD50 assay). ACV is already clinically used as an antiviral drug. Its ability to radiosensitize tumors could therefore have clinical potential when combined with radiotherapy.

A new liquid embolic material for liver tumors: An animal experimental study using Onyx

Purpose: To evaluate the feasibility of a new liquid embolic material, Onyx, for treating liver tumors. Material and Methods: Onyx is a mixture of 6% (w/v) ethylene-vinyl-alcohol copolymer dissolved in anhydrous dimethyl sulfoxide (DMSO) with 28% (w/v) tantalum powder. In addition to 6% Onyx, we also tried 4%, 2% and 1% solutions, prepared by adjusting the amount of DMSO. We used 15 white rabbits with liver tumors created by percutaneous injection of VX2 tumor cells. In 4 groups with 3 rabbits in each, the liver arteries were embolized with 6%, 4%, 2% and 1% Onyx, respectively, and in 3 rabbits DMSO alone was injected. The injections were performed just proximal to the bifurcation of the proper hepatic artery, followed by celiac arteriography. Post mortem, the livers were examined by soft-tissue radiography, and liver-tissue section microscopy. Results: The maximum number of arterial branching points passed by embolic material in either the right or left hepatic arteries was 11, 15 and 16, for 6%, 4% and 2% Onyx, respectively, but was non-measurable for 1% Onyx. Minimum diameters of arteries reached by 6%, 4%, 2% and 1% Onyx in tumorous areas were 40 μm, 35 μm, 20 μm and 10 μm, respectively, and in non-tumorous areas 35 μm, 5 μm, 5 μm and 5 μm, respectively. Conclusion: This study suggests that Onyx may be feasible for treatment of hepatic tumors.

Extravasation of Tc-99m sodium pertechnetate detected on Meckel's cine scintigraphy in hemorrhagic diverticulum.

Meckels diverticulum scintigraphy using Tc-99m sodium pertechnetate usually shows persistent focal uptake in the midabdomen. The authors describe a patient with a hemorrhagic diverticulum demonstrating active, intermittent intraluminal tracer extravasation on Meckels scintigraphy, a pattern mimicking gastrointestinal bleeding scintigraphy using Tc-99m red blood cells or Tc-99m human serum albumin. Cine scintigraphy was helpful in the evaluation of the intraluminal hemorrhage.

Stenting of the superior mesenteric artery as a preoperative treatment for total pancreatectomy.

The patient was a 58-year-old male with mucinous cyst adenocarcinoma of the pancreas. Prior to total pancreatectomy, preoperative CT and angiography showed a high-grade arteriosclerotic stenosis of about 1.0 cm in length in the ostium of the superior mesenteric artery (SMA), as well as the development of collateral vessels in the area around the head of the pancreas. A stent was placed in the SMA stenosis to preserve the intestinal blood flow in the SMA region after total pancreatectomy, which was performed 25 days after stent placement. The postoperative SMA blood flow was favorable, with no postoperative intestinal ischemia, and the patient had an uneventful postoperative course.