Gefitinib induction followed by chemoradiotherapy in EGFR-mutant, locally advanced non-small-cell lung cancer: LOGIK0902/OLCSG0905 phase II study.

BACKGROUND: The role of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) induction coupled with standard concurrent chemoradiotherapy (CRT) is unclear in unresectable, stage III, EGFR-mutant non-small-cell lung cancer (NSCLC). Therefore, a phase II trial was conducted to evaluate the efficacy and safety of gefitinib induction followed by CRT in this disease setting. PATIENTS AND METHODS: Patients with unresectable, EGFR-mutant, stage III NSCLC were administered gefitinib monotherapy (250 mg/day) for 8 weeks. Subsequently, patients without disease progression during induction therapy were administered cisplatin and docetaxel (40 mg/m2 each) on days 1, 8, 29, and 36 with concurrent radiotherapy at a total dose of 60 Gy. The primary endpoint was the 2-year overall survival (OS) rate, which was hypothesized to reach 85%, with a threshold of the lower limit of 60%. RESULTS: Twenty patients (median age: 66 years; male/female: 9/11; histology: 20 adenocarcinoma; stage IIIA/IIIB: 9/11; and exon 19/21: 10/10) were enrolled. The 2-year OS rate was 90% (90% confidence interval: 71.4% to 96.8%), indicating that this trial met the primary objective. The overall response rate and 1- and 2-year progression-free survival rates were 85.0%, 58.1%, and 36.9%, respectively. Grade ≥3 adverse events (>10%) included hepatic toxicity during the induction phase and neutropenia and febrile neutropenia in the CRT phase. Radiation pneumonitis grade ≥3 or treatment-related death did not occur. CONCLUSIONS: This is the first prospective study to demonstrate the favorable efficacy and safety of EGFR-TKI induction followed by standard CRT in EGFR-mutant, stage III NSCLC. Further confirmatory studies are needed.

Phase I/II clinical study of percutaneous vertebroplasty (PVP) as palliation for painful malignant vertebral compression fractures (PMVCF): JIVROSG-0202.

BACKGROUND: The safety and efficacy of percutaneous vertebroplasty (PVP), a new treatment modality for painful malignant vertebral compression fractures (PMVCF) using interventional radiology techniques, were evaluated prospectively. MATERIALS AND METHODS: After confirming the absence of safety issues in phase 1, a total of 33 cases were registered up to and including phase 2. Safety and efficacy were evaluated by National Cancer Institute-Common Toxicity Criteria version 2 and Visual Analogue Scale (VAS) at 1 week after PVP. Based on VAS score decreases, efficacy was classified into significantly effective (SE; > or = 5 or reached 0-2), moderately effective (ME; 2-4), or ineffective (NE; <2 or increase). RESULTS: Procedures were completed in all 33 patients (42 vertebrae). Thirty days after PVP, two patients died of primary disease progression, but no major adverse reactions (>grade 2) were observed. Response rate was 70% (95% confidence interval 54% to 83%) [61% (n = 20) with SE, 9% (n = 3) with ME, and 30% (n = 10) with NE] and increased to 83% at week 4. Median time to response was 1 day (mean 2.4). Median pain-mitigated survival period was 73 days. CONCLUSION: For PMVCF, PVP is a safe and effective treatment modality with immediate onset of action.

Computerized method for estimation of the location of a lung tumor on EPID cine images without implanted markers in stereotactic body radiotherapy.

The purpose of this study was to develop a computerized method for estimation of the location of a lung tumor in cine images on an electronic portal imaging device (EPID) without implanted markers during stereotactic body radiotherapy (SBRT). Each tumor region was segmented in the first EPID cine image, i.e., reference portal image, based on a multiple-gray level thresholding technique and a region growing technique, and then the image including the tumor region was cropped as a 'tumor template' image. The tumor location was determined as the position in which the tumor template image took the maximum cross-correlation value within each consecutive portal image, which was acquired in cine mode on the EPID in treatment. EPID images with 512 x 384 pixels (pixel size: 0.56 mm) were acquired at a sampling rate of 0.5 frame s(-1) by using energies of 4, 6 or 10 MV on linear accelerators. We applied our proposed method to EPID cine images (226 frames) of 12 clinical cases (ages: 51-83, mean: 72) with a non-small cell lung cancer. As a result, the average location error between tumor points obtained by our method and the manual method was 1.47 +/- 0.60 mm. This preliminary study suggests that our method based on the tumor template matching technique might be feasible for tracking the location of a lung tumor without implanted markers in SBRT.

Usefulness of mini-tracheostomy and torque controlled insertion of applicator in fractionated endobronchial brachytherapy.

Endobronchial brachytherapy was developed as effective treatment of endobronchial cancer and fractionated schedule is applied to decrease late toxicity. However, repeated bronchofiberscopy is onerous to the patient and restricts the treatment schedule itself. We applied mini-tracheostomy for a ready access route, and a torque controlled technique for easy insertion of the endobronchial applicator. Eight patients with tracheobronchial cancer invasion were treated with endobronchial brachytherapy of 18-30 Gy/3-5 fractions/1.5-2.5 weeks (median 24 Gy/4 fractions/2 weeks) at reference points of 5 mm from the bronchial surface. The averaged individual irradiation and single session times were 4 min and 24 min, respectively. There were no procedure-related complications. These technical improvements may facilitate flexible fractionated dose prescriptions.

Acute toxicity of lipiodol infusion into the hepatic arteries of dogs.

RATIONALE AND OBJECTIVES: The authors studied the acute toxicity of percutaneous transcatheter hepatic artery infusion of iodized poppy oil fatty acid ester (Lipiodol, Laboratoire Guerbet, Aulnay-sous-Bois, France). METHODS: Lipiodol dosages of 0, 0.25, 0.5, 1.0, and 2.0 mL/kg were infused into the hepatic arteries of 10 beagles. Enzymatic and radiographic alterations were assessed. RESULTS: After the infusion of Lipiodol, the dogs showed body weight loss and hypoalbuminemia attributable to decreased food intake, transient elevation of the aspartate transaminase and alanine transaminase, and continuous increase in alkaline phosphatase. The controls did not show any significant change. The radiographs obtained immediately after and 2 weeks after the infusion showed dose-dependent accumulation of Lipiodol in the liver. After 2 weeks, histologic examination of livers and lungs showed dose-dependent (r = .9) retention of oily droplets in sinusoids and pulmonary capillaries. Interlobar pericholangitis was found in four dogs infused with Lipiodol. Pulmonary inflammatory reaction was observed with capillary oil embolism. Oil droplets also were found in the pancreas and the brain. CONCLUSIONS: Lipiodol infusion of the hepatic artery resulted in dose-dependent circulation and embolism of Lipiodol droplets via sinusoids and via pulmonary capillaries into the systemic circulation.

The high susceptibility of heterozygous p53(+/-) mice to malformation after foetal irradiation is related to sub-competent apoptosis.

PURPOSE: To investigate the relationship between the incidence of radiation-induced malformations and the extent of p53-dependent apoptosis. MATERIALS AND METHODS: Wild-type p53(+ / +) and heterozygous p53(+ / -) mice were exposed to X-rays at the mid-gestational period. The incidence of anomalies and prenatal deaths, the extent of apoptosis, and the levels of p53 protein were assessed. RESULTS: After X-irradiation with 2 Gy, the incidence of malformation (corrected for control levels) was 0 and 30%, respectively, for p53(+ / +) and p53(+ / -). After irradiation of p53(+ / +) foetuses with 3 Gy, the frequency (F) of apoptotic cells rapidly peaked at 80% at 4 h and fell close to the control level at 48 h. The relationship between F 4h after irradiation and dose (D) (1-3Gy) is accurately expressed by a single-hit equation, F= 1 -exp ( -(a + bD)¿, where the radiation-induced apoptosis rate, b, is 0.47 for the wild type and 0.22 for the heterozygous mice. The X-irradiated foetuses showed no increase in the levels of p53 protein. CONCLUSION: The higher susceptibility of irradiated p53(+ / -) foetuses to malformation is related to a twofold lower rate of apoptosis; competent removal by apoptosis of damaged cells from irradiated tissues is impaired dramatically if one of two wild-type p53 alleles is lost. The frequency of apoptotic cells in the wild type reached a maximum 4h after foetal irradiation with no measurable increase in the level of p53 protein, indicating that radiation-induced p53-mediated foetal apoptosis depends on non-transcriptional events.

A novel positive detection system of in vivo mutations in rpsL (strA) transgenic mice.

To positively detect the in vivo mutations accumulated in different mouse organs, we have developed a transgenic mouse system. This transgenic mouse carried an Escherichia coli (E. coli) plasmid pML4 as a shuttle vector that consisted of a replication origin (ori), the kanamycin-resistant gene (KanR) and the rpsL+ gene (strAS) derived from E. coli. These E. coli elements were expected to be inert in the transgenic mouse system; thus, neutral mutations would be accumulated on the shuttle plasmid in the transgenic mice. The shuttle plasmid vector was recovered from the mouse genomic DNA and introduced into kanamycin-sensitive (KmS) and streptomycin-resistant (SmR) E. coli cells by using electroporation. The original pML4 shuttle plasmid transformed the host E. coli to KmR and SmS, since both the KanR and rpsL genes exhibited dominant traits of KmR and SmS, respectively. On the other hand, when the retrieved pML4 shuttle plasmid carried a mutated rpsL gene, it could be positively detected as both KmR and SmR. Based on this principle, we were able to positively detect the in vivo mutations accumulated in the rpsL transgene of the shuttle vector pML4 integrated into the mouse genome. The total number of rescued shuttle plasmids were counted on the plates containing Km alone, while only mutants were detected on the plates containing both Km and Sm. We have so far established 22 independent transgenic mouse lines that carried up to approx. 750 copies of the shuttle plasmid pML4 in a haploid genome. By using high-copy-number transgenic mouse lines which carried 350 copies or more of the shuttle vector, we also developed a simple and proficient method for retrieving the shuttle plasmid from various tissues of the transgenic mice. The background mutant frequency was approx. 5 x 10(-5). In order to validate the applicability of the positive-detection transgenic system for the induced mutagenicity assay, methylnitrosourea (MNU) was administered to the transgenic mice, and an increase in the number of mutant frequencies was seen in all tested organs including spleen, liver and brain. The rpsL transgenic mouse system was therefore considered to provide a quick-and-easy risk assessment test for in vivo tissue-specific mutagenicity, using positive detection by streptomycin.

Non-Hodgkin lymphoma and coexisting primary cancers: a retrospective clinical analysis of 10 patients.

The simultaneous occurrence of non-Hodgkin lymphoma (NHL) and primary cancers is rare, and the treatment strategy for both malignancies is unclear. The authors analyzed the clinical records of 10 patients with NHL and coexisting primary cancers. All patients initially had symptoms of NHL, and all carcinomas were found at the initial workup of NHL by chance. The most common primary sites of coexisting cancers were the stomach (six patients) and the colon (two). Histologically, the majority of NHLs were intermediate grade, and all lesions were B-cell type. All primary cancers were adenocarcinoma. Initially, NHL was treated with radiotherapy or chemotherapy. Six primary cancers were resected surgically or endoscopically after the remission of NHL. The remaining four patients received no treatment for primary cancers because of advanced stages or early relapse of NHL. Three patients died of NHL, one died of cancer, and six were still alive, five without evidence of disease and one with disease. The authors conclude that early detection of a coexisting cancer and appropriate treatment after the remission of NHL may increase the possibility of a cure.

Comparison between pancreatoduodenectomy and hepatopancreatoduodenectomy for bile duct cancer.

BACKGROUND/AIMS: Pancreatoduodenectomy has been accepted as a standard operative procedure for distal bile duct cancer with low operative mortality. However, hepatopancreatoduodenectomy has not been accepted as a standard treatment modality for diffuse bile duct cancer. METHODOLOGY: From December 12, 1992 to December 15, 2000, 37 patients with the diagnosis of extrahepatic bile duct adenocarcinoma (cholangiocarcinoma) underwent pancreatoduodenectomy or hepatopancreatoduodenectomy, at the department of surgery, Ibaraki Prefectural Central Hospital and the Cancer Center. The differences in indications and results of both operative procedures were investigated retrospectively. RESULTS: Thirty-day operative mortality was 0% after either pancreatoduodenectomy or hepatopancreatoduodenectomy. One- to 5-year cumulative survival rates for the 24 patients after pancreatoduodenectomy were 76.3%, 41.5%, 41.5%, 41.5%, 41.5%, respectively. One- to 4-year cumulative survival rates for the 13 patients after hepatopancreatoduodenectomy were 48.0%, 32.0%, 32.0%, 16.0%, respectively. There were no statistically significant differences between cumulative survival rates after pancreatoduodenectomy and hepatopancreatoduodenectomy either in all the patients or in patients with UICC stage IV. CONCLUSIONS: Hepatopancreatoduodenectomy should be tried for patients with diffuse bile duct cancer, because only hepatopancreatoduodenectomy has the possibility of a cure at this time.

Relapsed non-Hodgkin's lymphoma: detection and treatment.

PURPOSE: To evaluate the optimal management strategy during clinical remission and after relapse in patients with non-Hodgkin's lymphoma (NHL). METHODS: Sixty-six patients with relapse of NHL from a state of clinical remission between 1987 and 1997 were analyzed retrospectively. The pattern of relapses, diagnostic methods used for relapses, and clinical outcome of salvage treatment were analyzed with attention to time after the achievement of clinical remission. RESULTS: Thirty-three relapses (50%) occurred within 12 months, and the remainder occurred gradually from 12-48 months after the first remission. Diagnosis of relapse in 61 of the 66 patients (93%) was made at unscheduled evaluations prompted by symptoms, on physical examinations, or because of high LDH levels. The 1- and 5-year cause-specific survival rates after relapse were 56.7% and 39.4%, respectively. The 1- and 5-year relapse-free survival rates were 50.1% and 35.0%, respectively. The 5-year relapse-free survival rate in patients with late relapse (49.5%) was significantly better than in those with early relapse (21.2%) (p<0.01). CONCLUSION: Time to relapse may be a useful factor to determine optimal management strategy in NHL patients.

Radiotherapy for localized relapse in patients with non-Hodgkin's lymphoma: a preliminary report.

PURPOSE: To evaluate the usefulness of radiotherapy for relapse of non-Hodgkin's lymphoma (NHL) at a localized site. METHODS: Of 79 patients with relapsed intermediate- or high-grade NHL, 13 patients (16.5%) with a localized relapse were analyzed retrospectively. RESULTS: Five patients were treated with radiotherapy alone and eight were treated with radiotherapy plus conventional chemotherapy (CHOP or other combinations). Radiotherapy was delivered to the involved field to a mean total dose of 34.1 Gy (range, 21-51 Gy). The 5-year overall and disease-free survival rates were 80.2% and 76.2%, respectively. Four patients relapsed subsequently. After further salvage therapy, two patients died of NHL and two were alive without active disease. CONCLUSION: Radiotherapy may be an important component of treatment for selected patients with NHL who relapse at a localized site.

Transvaginal fallopian tube catheterization--diagnostic and therapeutic usefulness.

Fifty-two patients with 84 proximal Fallopian tube obstructions underwent Fallopian tube recanalization (FTR). The successful catheterization rate for Fallopian tubal ostia was 100%, and the successful recanalization rate was 64%. After FTR, hysterosalpingography or selective tubography showed no evidence of adhesion (without adhesion) in 31 tubes, perifimbrial adhesion in 17 tubes, hydrosalpinx in six tubes, and intratubal adhesion in 30 tubes (unsuccessful recanalization). Six patients (11%) achieved intrauterine pregnancies and two had extrauterine pregnancies. Follow-up studies in seven patients without adhesion showed patency in one patient and reocclusion in six patients who obtained repatency after a second FTR. Fallopian tube catheterization was useful for the exact diagnosis of Fallopian tube occlusion. The higher incidence of adhesion in patients' background caused the low incidence of pregnancy.

Clear cell sarcoma of the kidney in an adult.

A 25-year-old woman with clear cell sarcoma of the kidney (CCSK) underwent computed tomography (CT), angiography, and a surgical operation. The clear cell sarcoma showed a cystic lesion with solid components on CT and a hypovascular tumor and rat-tail occlusion of the left renal artery on angiography. These findings in our adult case of CCSK corresponded with those of CCSK in childhood.

[Usefulness of ventilation and perfusion scans in patients with collagen-vascular diseases].

We studied 32 patients with collagen-vascular diseases with Xe-133 ventilation scans (V) and Tc-99m MAA perfusion scans (Q). Five patients underwent sequential studies at intervals of more than 3 months. Mean transit time (MTT) was calculated from the Xe-133 wash-out curve. V, Q images and MTT were compared with chest X-ray films and the values of %DLco. Of 32 patients, 17 had no abnormal finding on the chest X-ray films. Of the 17 patients, however, V and/or Q abnormalities were found in 10 (59%), 14 patients (82%), respectively. Every patient with abnormal findings on the chest X-ray film showed both V and Q abnormalities. Overall, Q abnormality was more frequent and severer than V one. Of the 5 patients with the sequential studies, 3 showed prolongation of MTT in concordance with deterioration of pulmonary fibrosis. V and Q abnormalities were not necessarily relevant to %DLco. In conclusion, ventilation and perfusion studies are useful in assessing the regional pulmonary function in patients with collagen-vascular diseases.

[Arterial stasis chemotherapy].

"Arterial stasis chemotherapy" is a concept which summarizes administration methods of anticancer agents under the temporary blockade of the blood flow by any means. The drugs so infused is hardly diluted by blood flow, reaching the tumor tissue in high concentration and staying there much longer than that of administered by simple arterial infusion. "Arterial stasis chemotherapy" contains TAE (transcatheter arterial embolization) with gelatin sponge. TAE with ethiodol, TAE with microencapsulated anticancer drug, BOAI (balloon occluded arterial infusion), arterial administration of SMANCS/Lipiodol, intra-arterial administration of DSM (degradable starch microsphere) and so on. The authors confirmed that anticancer agents, which were soaked in gelatin sponge particles, densely stayed in the tumor for twenty hours after TAE using CT and iodinated contrast media. And we also confirmed a high level of the drug was present selectively in the tumor tissue for a longer time when it was given by BOAI than SAI using scintillation camera and Xe. After these basic studies, we applied TAE and BOAI on the patients with malignant tumors and got much better therapeutic effects than previous reports. We believe therapies based on the concept of "Arterial stasis chemotherapy" will prevail from now on.

[Comparison of Gore-tex covered Ultraflex stent and bare Ultraflex stent: preliminary clinical results].

We clinically compared the covered Ultraflex stent and the bare Ultraflex stent for malignant esophageal strictures. Materials were 6 cases with esophageal carcinomas. We placed the Gore-tex covered stents (A group) in 4 cases including 2 cases of esophagorespiratory fistulae, and the bare stents (B group) in 2 cases. The stents were well-expanded in all cases. After stenting, dysphagia was improved in all cases. Fistulae were obstructed by the cover in 2 cases in A group. Mean survival term was 123 days in A group and 45 days in B group. Complications were fistulation of bare portion of the covered stent in one case in A group, and tumor bleeding in one case in B group. Considering of the risk of fistula or tumor bleeding, the cover is necessary to increase the safety and efficacy of the esophageal stent.

Can a belly board reduce respiratory-induced prostate motion in the prone position?--assessed by cine-magnetic resonance imaging.

The purpose of this study is to evaluate the real-time respiratory motion of the prostate and surrounding tissues/organs in the supine and prone positions and to investigate, using cine-MRI, whether a belly board can reduce respiratory-induced motion in the prone position. Cine-MRI scans were made of 13 volunteers in the supine and prone positions on a flat board and in two different prone positions using a belly board. Images in cine mode were recorded for 20 seconds. For each session, the points of interest (POIs) were located at the apex, base, mid-anterior surface and mid-posterior surface of the prostate; the tip of the seminal vesicle; the pubic symphysis; and the sacrum. The maximum range and standard deviation (SD) of the displacement from the mean value were calculated. The SDs for each of the four different positions were compared using a paired t-test. Respiratory-induced prostate motion was significantly larger in the prone position than in the supine position. However, when a belly board was used in the prone position, motion in the prostate and surrounding tissues/organs was significantly reduced. There were no significant differences between the two different positions using a belly board in any of the POIs.

TU-E-BRB-01: Similar-Case-Based Optimization of Beam Arrangements in Stereotactic Body Radiation Therapy.

PURPOSE: The quality of a treatment plan for stereotactic body radiotherapy (SBRT) depends on an experience of each treatment planner. Therefore, the treatment plans are subjectively determined by comparison of several treatment plans developed by time consuming iterative manners, while considering the benefit to a tumor and the risk to the surrounding normal tissues. The aim of our study was to develop an automated optimization method for beam arrangements based on similar cases in a database including plans designed by senior experienced treatment planners. METHODS: Our proposed method consists of three steps. First, similar cases were automatically selected based on image features from the treatment planning point of view. We defined four types of image features relevant to planning target volume (PTV) location, PTV shape, lung size, and spinal cord positional features. Second, the beam angles of the similar case were registered to the objective case with respect to lung regions using a linear registration technique. Third, the beam direction of the objective case was locally optimized based on the cost function considering radiation absorption in normal tissues and organs at risk. The proposed method was evaluated with 10 test cases and a treatment planning database including 81 cases by using eight planning evaluation indices such as D95, lung V20, and maximum spinal cord dose. RESULTS: The proposed method may provide usable beam directions, which have no statistically significant differences with the original beam directions (P > 0.05) in terms of the seven planning evaluation indices. Moreover, the mean value of D95 for 10 test cases was improved with a statistically significant difference by using the proposed method, compared with the original beam directions (P = 0.03). CONCLUSIONS: The proposed method could be used as a computer-assisted treatment planning tool for determination of beam directions in SBRT.

WE-G-BRCD-04: Development of Automated Determination Method of Robust Beam Directions against Patient Setup Errors Based on Spatial Distribution of Electron Density in Particle Therapy.

PURPOSE: The three-dimensional (3D) dose distribution covering a tumor region tends to be more breakable if the beam's eye view (BEV) of the 3D electron density (ED) map in a beam direction changes more abruptly with large fluctuations. Our aim of this study was to develop an automated determination method of robust beam directions against the patient setup error based on the ED-based BEV in the beam direction in the particle therapy. METHODS: The basic idea of our proposed method was to find the robust beam directions, whose the ED-based BEV has the spatial fluctuations with low special frequency and small amplitude. For evaluation of the spatial fluctuation in the ED-based BEV in a beam direction, we obtained power spectra of the ED-based BEVs in all directions, i.e., 0 to 355 degree, with an interval of 5 degree. It was assumed that as the average spatial frequency and amplitude of the fluctuation in the ED-based BEV in a beam direction is lower and smaller, respectively, the absolute value of a gradient of the power spectrum becomes larger. Therefore the gradient of the power spectrum was calculated for determination of the robust beam direction. The ED-based BEV was produced by projecting a 3D electron density map derived from the computed tomography (CT) image from a beam source to the distal end of a planning target volume (PTV). Four cases of head and neck cancer patients were selected for evaluation of the proposed method. RESULTS: As a preliminary result, radiation oncologists agreed with most beam directions, which seem to be robust against patient setup errors, suggested by the proposed method. CONCLUSIONS: Our proposed method could be feasible to suggest the robust beam directions against patient setup errors in hadron particle therapy.