Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502.

BACKGROUND: While adjuvant chemotherapy is preferable for high-risk colon cancer, treatment duration is controversial. Oral uracil and tegafur (UFT)/leucovorin (LV) is widely used as a standard adjuvant chemotherapy for colon cancer in Japan. We conducted a phase III trial to investigate the optimal duration of adjuvant chemotherapy for stage IIB/III colon cancer. PATIENTS AND METHODS: Patients with curatively resected stage IIB/III colon cancer were eligible for enrollment in this trial. Patients were registered within 6 weeks after surgery and were randomly assigned to receive UFT/LV for 28 of 35 days for 6 months in the control group or for 5 consecutive days per week for 18 months in the study group. The primary end point was the disease-free survival (DFS), and the secondary end points were overall survival (OS) and safety. RESULT: A total of 1071 patients were registered from 233 centers. A statistically significant difference in DFS was not observed between the study group and the control group; the 5-year DFS was 69% in the study group and 69% in the control group. The 5-year OS was 85% in the study group and 85% in the control group. CONCLUSION: Eighteen-month treatment with UFT/LV did not improve DFS or OS compared with 6-month UFT/LV treatment in patients with stage IIB/III colon cancer. The important finding from this study is that not 18 months but 6 months of treatment is enough for postoperative UFT/LV for stage IIB/III colon cancer. CLINICAL TRIAL NUMBER: UMIN-CTR C000000245.

Automation of etch pit analyses on solid-state nuclear track detectors with machine learning for laser-driven ion acceleration.

Solid-state nuclear track detectors (SSNTDs) are often used as ion detectors in laser-driven ion acceleration experiments and are considered to be the most reliable ion diagnostics since they are sensitive only to ions and measure ions one by one. However, ion pit analyses require tremendous time and effort in chemical etching, microscope scanning, and ion pit identification by eyes. From a laser-driven ion acceleration experiment, there are typically millions of microscopic images, and it is practically impossible to analyze all of them by hand. This research aims to improve the efficiency and automation of SSNTD analyses for laser-driven ion acceleration. We use two sets of data obtained from calibration experiments with a conventional accelerator where ions with known nuclides and energies are generated and from actual laser experiments using SSNTDs. After chemical etching and scanning the SSNTDs with an optical microscope, we use machine learning to distinguish the ion etch pits from noises. From the results of the calibration experiment, we confirm highly accurate etch-pit detection with machine learning. We are also able to detect etch pits with machine learning from the laser-driven ion acceleration experiment, which is much noisier than calibration experiments. By using machine learning, we successfully identify ion etch pits ∼105 from more than 10 000 microscopic images with a precision of ≳95%. A million microscopic images can be examined with a recent entry-level computer within a day with high precision. Machine learning tremendously reduces the time consumption on ion etch pit analyses detected on SSNTDs.

3D track extraction from a fluorescent nuclear track detector via machine learning and an application to diagnostics of laser-driven ions.

We have developed an ion diagnostic method for laser-driven ion acceleration experiments that uses fluorescent nuclear track detectors (FNTDs). An FNTD records the particle tracks as color centers and does not require chemical etching, unlike CR-39 track detectors. The color centers are observed using a confocal laser microscope, and 3D particle tracks can be obtained by changing its focal position. The intensity of the color centers corresponds to the energy deposited by the ions. The nuclides of the ions can be determined from the intensity distribution of the color centers as a function of depth and the distance between the stopping point and the surface of the detector. To extract the intensity distribution, we must track the same ion tracks in the depth-layered microscopic images from the surface to the stopping point, even if they overlap with those of other ions. In addition, since an FNTD is sensitive not only to ions but also to electrons and photons, we must identify ion tracks among those from the latter particles. To analyze a statistical number of ion tracks, it is necessary to automate these processes. We have thus developed a method for automated ion detection and 3D tracking that relies on a support vector classifier and a kernelized correlation filter. This method was tested on a laser ion acceleration experiment performed using the J-KAREN-P laser. The method automatically detects ion tracks on FNTDs and tracks them in the depth direction. The training data are sampled from the Heavy-Ion Medical Accelerator in Chiba.

Radiation environment in high-altitude Antarctic plateau: Recent measurements and model studies.

Polar regions are the most exposed to secondary particles and radiation produced by primary cosmic rays in the atmosphere, because naturally they are with marginal geomagnetic shielding. In addition, the secondary particle flux contributing to the complex radiation field is enhanced at high-mountain altitudes compared to sea level because of the reduced atmospheric attenuation. At present, there are very few systematic experimental measurements of environmental dose at high southern latitudes, specifically at high-altitude region. Here, we report a campaign of measurements with different devices, that is passive and Liulin-type dosimeters, of the radiation background at high-mountain Antarctic station Vostok (3488 m above sea level, 78° 27' S; 106° 50' E). We compare the measurements with a Monte Carlo-based model for the propagation of the cosmic rays through the atmosphere and assessment of the radiation field in the atmosphere. We employed the model to estimate the radiation dose at Vostok station during the ground-level enhancement at 28 October 2021. As in previous studies by other teams, we show that the annual dose equivalent at high-altitude Antarctic facilities can significantly exceed the limit of 1 mSv established for the general population by the ICRP.

Mass-resolved ion measurement by particle counting analysis for characterizing relativistic ion beams driven by lasers.

Particle counting analysis is a possible way to characterize GeV-scale, multi-species ions produced in laser-driven experiments. We present a multi-layered scintillation detector to differentiate multi-species ions of different masses and energies. The proposed detector concept offers potential advantages over conventional diagnostics in terms of (1) high sensitivity to GeV ions, (2) realtime analysis, and (3) the ability to differentiate ions with the same charge-to-mass ratio. A novel choice of multiple scintillators with different ion stopping powers results in a significant difference in energy deposition between the scintillators, allowing accurate particle identification in the GeV range. Here, we report a successful demonstration of particle identification for heavy ions, performed at the Heavy Ion Medical Accelerator in Chiba. In the experiment, the proposed detector setup showed the ability to differentiate particles with similar atomic numbers, such as C6+ and O8+ ions, and provided an excellent energy resolution of 0.41%-1.2% (including relativistic effect, 0.51%--1.6%).

A multi-stage scintillation counter for GeV-scale multi-species ion spectroscopy in laser-driven particle acceleration experiments.

Particle counting analysis (PCA) with a multi-stage scintillation detector shows a new perspective on angularly resolved spectral characterization of GeV-scale, multi-species ion beams produced by high-power lasers. The diagnosis provides a mass-dependent ion energy spectrum based on time-of-flight and pulse-height analysis of single particle events detected through repetitive experiments. With a novel arrangement of multiple scintillators with different ions stopping powers, PCA offers potential advantages over commonly used diagnostic instruments (CR-39, radiochromic films, Thomson parabola, etc.) in terms of coverage solid angle, detection efficiency for GeV-ions, and real-time analysis during the experiment. The basic detector unit was tested using 230-MeV proton beam from a synchrotron facility, where we demonstrated its potential ability to discriminate major ion species accelerated in laser-plasma experiments (i.e., protons, deuterons, carbon, and oxygen ions) with excellent energy and mass resolution. The proposed diagnostic concept would be essential for a better understanding of laser-driven particle acceleration, which paves the way toward all-optical compact accelerators for a range of applications.

DISCRIMINATION METHOD FOR GAMMA RAY DOSES IN NEUTRON FIELDS USING AN IONIZATION CHAMBER WITH ATTENUATION FILTERS.

Neutron fields produced by an accelerator-driven neutron source are generally mixed radiation fields that consist of fast neutrons and gamma rays. To estimate the biological effects of fast neutrons precisely, the gamma ray dose contamination must be evaluated in neutron fields. In this work, we developed a discrimination technique for absorbed doses (60Co gamma-ray equivalent) of fast neutrons and gamma rays using an ionization chamber. The filter thickness dependences of the absorbed doses of fast neutrons and gamma rays are different for a given filter material. Thus, the absorbed doses of each type of radiation were distinguished by fitting the dose attenuation curve, which was measured with an ionization chamber and attenuation filters, with a two-component exponential function. The absorbed dose of fast neutrons and gamma rays with no attenuation filter was evaluated from the y-intercept of the fitting function. This technique was demonstrated in two neutron fields produced by 4 MeV proton and deuteron bombardment of a 9Be target. The thicknesses of the polyethylene attenuation filters were 0-350 mm. The dose attenuation coefficients of fast neutrons obtained by the two-component exponential fitting function for the 9Be(p,n)9 and 9Be(d,n) reactions showed differences of 1.5 and 1.7%, respectively, from the reference measurements using a CR-39 plastic nuclear track detector. The absorbed dose contributions of gamma rays in neutrons fields of the 9Be(p,n)9B and 9Be(d,n) reactions were evaluated as 30.2 ± 3.24% and 20.4 ± 5.16%, respectively, without polyethylene filters.

IMAGING URANIUM DISTRIBUTION ON RAT KIDNEY SECTIONS THROUGH DETECTION OF ALPHA TRACKS USING CR-39 PLASTIC NUCLEAR TRACK DETECTOR.

Uranium is renowned as a global contaminant, and attracts major concern with regards to the health risks involved because its nephrotoxicity. This paper discusses the development of a simple method to identify accumulated regions or localized sites of uranium within kidneys using the CR-39 plastic nuclear track detector. To demonstrate the proposed method, renal cryo-sections (5 µm-t) from Wistar male rats, subcutaneously administered with uranyl acetate (2 mg/kg), were prepared on day one after administration. Concerned sections were subsequently placed on CR-39, stored for 1.25 years, and then etched in a 7 M NaOH solution at 70°C for 3 h. α-tracks were then detected in the form of etch pits, corresponding to uranium, and also the tissue shape and structure were transferred as a roughness on the surface of CR-39. As observed, the proposed method served to facilitate simultaneous detection and identification of localized regions of uranium accumulation within kidneys.

Cost-effectiveness of adjuvant chemotherapy with uracil-tegafur for curatively resected stage III rectal cancer.

Recently, the National Surgical Adjuvant Study of Colorectal Cancer in Japan, a randomised controlled trial of oral uracil-tegafur (UFT) adjuvant therapy for stage III rectal cancer, showed remarkable survival gains, compared with surgery alone. To evaluate value for money of adjuvant UFT therapy, cost-effective analysis was carried out. Cost-effectiveness analysis of adjuvant UFT therapy was carried out from a payer's perspective, compared with surgery alone. Overall survival and relapse-free survival were estimated by Kaplan-Meier method, up to 5.6 years from randomisation. Costs were estimated from trial data during observation. Quality-adjusted life-years (QALYs) were calculated using utility score from literature. Beyond observation period, they were simulated by the Boag model combined with the competing risk model. For 5.6-year observation, 10-year follow-up and over lifetime, adjuvant UFT therapy gained 0.50, 0.96 and 2.28 QALYs, and reduced costs by $2457, $1771 and $1843 per person compared with surgery alone, respectively (3% discount rate for both effect and costs). Cost-effectiveness acceptability and net monetary benefit analyses showed the robustness of these results. Economic evaluation of adjuvant UFT therapy showed that this therapy is cost saving and can be considered as a cost-effective treatment universally accepted for wide use in Japan.

MEASUREMENT OF DIFFERENT COMPONENTS OF SECONDARY RADIATION ONBOARD INTERNATIONAL SPACE STATION BY MEANS OF PASSIVE DETECTORS.

The evaluation of different components of secondary radiation (charged fragments and neutrons) onboard ISS is described. Solid-state nuclear track detectors CR-39™ were applied for the measurements of short-range nuclear fragments, while the measurements of neutrons were carried out by means of thermo-luminescent dosimeters with various concentrations of 6Li and 7Li. The flux of charged secondaries and the gamma-equivalent neutron dose are presented in function of the low-LET dose in various modules of the Russian segment of ISS.

Expression of carbohydrate antigen 19-9 and stage-specific embryonic antigen 1 in nontumorous and tumorous epithelia of the human colon and rectum.

The expression of carbohydrate antigen 19-9 (CA 19-9) and stage-specific embryonic antigen 1 (SSEA-1) in various human colorectal epithelia was examined by an immunohistochemical method. In mucosa remote from the carcinoma, CA 19-9 was not expressed, whereas SSEA-1 was only faintly expressed in lower crypts in all cases. In mucosa adjacent to the carcinoma, CA 19-9 was weakly expressed in upper crypts in 20% of the cases, whereas SSEA-1 was expressed not only in lower crypts in all cases but also in upper crypts in 93.3% of the cases. In adenoma, CA 19-9 was expressed in 80.6% of the cases, and SSEA-1 was expressed in all cases. The expression of both antigens was to some extent related to the degree of cellular atypia. In focal carcinoma in adenoma, CA 19-9 was strongly and diffusely expressed in 50% of the cases, and SSEA-1 was strongly and diffusely expressed in all cases. In advanced carcinoma, CA 19-9 was homogeneously or heterogeneously expressed in 82.2% of the cases, and SSEA-1 was homogeneously or heterogeneously expressed in all cases, but lower intensity of SSEA-1 staining was associated with a decrease in the degree of carcinoma differentiation. These results show that the expression of both CA 19-9 and SSEA-1 changes along with neoplastic transformation and progression in the colon and rectum. Immunohistochemical studies of SSEA-1 in flat colorectal mucosa might be a useful approach for detecting foci with preneoplastic change in the general population, whereas those of SSEA-1 and CA 19-9 could be a useful method for detecting focal carcinoma in adenoma.

Selection of a monoclonal antibody reactive with a high-molecular-weight glycoprotein circulating in the body fluid of gastrointestinal cancer patients.

The monoclonal antibody NCC-CO-450 (IgM kappa) was selected by screening of reactivity with high-molecular-weight antigens (Mr greater than 10(6] isolated from ascitic fluid of a colon cancer patient. This antibody detected heterogeneous but predominantly high-molecular-weight antigens in 4 of 6 ascitic fluid samples from gastrointestinal cancer patients by immunoblotting analysis. A sandwich radioimmunoassay was developed in order to examine the serum level of this antigen, and the cutoff value was defined as the mean plus 2 SD of values obtained with sera from normal donors. While 97% (93 of 96) of sera had a negative antigen value in normal donors, 56% (14 of 25) of patients with colorectal carcinoma and 40% (8 of 20) of patients with gastric carcinoma showed a positive antigen value. The distribution of the antigen in sera of patients with various cancers did not show any correlation with the distribution of carcinoembryonic antigen or CA 19-9. From immunohistochemical and biochemical analyses, NCC-CO-450 antigen was characterized as a mucin-like glycoprotein abundant in normal colonic epithelium as well as in carcinomas of the colon, stomach, and pancreas. The immunohistochemical reactivity of NCC-CO-450 was distinct from that of other monoclonal antibodies reported to be useful for serological diagnosis. The epitope recognized by NCC-CO-450 is considered to be an O-linked carbohydrate chain without terminal sialic acid but is different from the known carbohydrate chains, i.e., Lea, Lex, LeY, Tn, sialyl-Lea, and sialyl sugar chain defined by NCC-ST-439 in a competitive binding inhibition assay of monoclonal antibodies. This newly defined antigen is a good example of a normal antigen shed from cancer cells that can be used successfully as a serum tumor marker.

Note: Application of CR-39 plastic nuclear track detectors for quality assurance of mixed oxide fuel pellets.

A CR-39 plastic nuclear track detector was used for quality assurance of mixed oxide fuel pellets for next-generation nuclear power plants. Plutonium (Pu) spot sizes and concentrations in the pellets are significant parameters for safe use in the plants. We developed an automatic Pu detection system based on dense α-radiation tracks in the CR-39 detectors. This system would greatly improve image processing time and measurement accuracy, and will be a powerful tool for rapid pellet quality assurance screening.

The basic fibroblast growth factor and its receptor in pulmonary adenocarcinomas: an investigation of their expression as prognostic markers.

The expression of basic fibroblast growth factor (bFGF) and its receptor, the high-affinity type I basic fibroblast growth factor receptor (FGFR-1): were immunohistologically studied in tissues specimens from 167 patients with a pulmonary adenocarcinoma. Of the 167 specimens, 82 (49%) expressed bFGF and 104 (62%) expressed FGFR-1, bFGF and FGFR-1 were simultaneously expressed in 72 (43%). It was also found that many patients who showed intensely positive staining for bFGF were also positive for FGFR-1, and that the expression of bFGF or FGFR-1 or both was associated with p-stage, T and N factors. The overall prognosis was significantly poorer in the bFGF-positive or FGFR-1-positive patients than in negative patients (P < 0.01). The prognosis was also significantly poorer in all patients positive for both bFGF and FGFR-1 than in those negative for both (P < 0.01); this was also true for stage I patients (P < 0.05). Multivariate analysis showed that bFGF had a significant affect on prognosis, whereas FGFR-1 did not. As FGFR-1 is significantly linked with the bFGF expression, it may be that FGFR-1 interferes with the bFGF effect on survival. These findings suggest that bFGF and FGFR-1 play important roles in tumour progression, and that bFGF expression may be a useful prognostic marker for pulmonary adenocarcinomas.

Induction of hyporesponsiveness to fully allogeneic cardiac grafts by intratracheal delivery of alloantigen.

BACKGROUND: Soluble protein delivered through the mucosal surface can induce immunological unresponsiveness. The purpose of this study was to determine if prior exposure to alloantigen via the trachea could modulate the immune response to subsequent cardiac allografts. METHODS: Hearts from C57BL/10(H2b) mice were transplanted into CBA(H2k) recipients. Recipient mice were given donor 1x10(7) splenocytes into the trachea with or without antibody specific for mouse CD80 (1G10) and/or CD86 (GL1) (100 microg each) 7 days before transplantation. RESULTS: All grafts survived in recipients treated with intratracheal delivery of alloantigen for over 35 days (mean survival time [MST], 56 days), whereas naive control mice and mice treated with syngeneic antigen rejected grafts acutely (MST, 8 and 7 days, respectively). Interestingly, when 1G10, GL1, or both of them were combined with the protocol, the majority of grafts were rejected within 21 days after grafting (MST, 7, 15, and 17 days, respectively). CONCLUSION: Intratracheal delivery of alloantigen induced significantly prolonged survival of fully mismatched cardiac allografts and the effect was abrogated by the blockade CD80 and/or CD86 pathway.

Pulmonary adenocarcinoma angiogenesis.

The basic fibroblast growth factor (bFGF), the transforming growth factor (TGF)-beta 1, and the vascular endothelial growth factor (VEGF) expressions have been studied individually and in combinations with the factor 8-related antigen (F8RA) in relation to the microvascular density and prognosis of a pulmonary adenocarcinoma. The findings have revealed that the bFGF, TGF-beta 1 and VEGF expressions all correlated with microvascular density and the prognosis. A reduced expression of all three angiogenic factors correlated with-less tumor angiogenesis and a better prognosis. A multivariate analysis of the three prognostic factors also revealed that the the bFGF expression correlated with survival. These findings indicate that bFGF, TGF-beta 1, and VEGF expressions play important roles in tumor angiogenesis, and that the bFGF expression is a useful prognostic marker for assessing the outcome bf a pulmonary adenocarcinoma.

Clinical significance of tissue blood flow during esophagectomy by laser Doppler flowmetry.

OBJECTIVES: We sought to investigate the effect of tissue blood flow on the incidence of anastomotic leakage during esophagectomy. METHODS: Reconstruction was done with a gastric tube, and all cases involved cervical anastomosis. Tissue blood flow of 43 patients was measured with a laser Doppler flowmeter before emplacement and after anastomosis during surgical intervention. The reconstruction route and tissue blood flow before emplacement and that after anastomosis were analyzed as possible factors influencing anastomotic leakage. RESULTS: Tissue blood flow after anastomosis with leakage was 9.1 +/- 2.0 mL/min per 100 g, and that without leakage was 13.7 +/- 2.9 mL/min per 100 g. Tissue blood flow with leakage was significantly lower than that without leakage (P <.01, unpaired t test). Twenty-one patients had tissue blood flow after anastomosis of greater than 13 mL/min per 100 g, and none of them had leakage, whereas 5 patients had blood flow of less than 10 mL/min per 100 g, and all 5 had leakage. CONCLUSION: Tissue blood flow can be an important and useful indicator of the presence of current anastomotic leakage. Low tissue blood flow after anastomosis may mediate for appropriate surgical or pharmacologic interventions to detect, localize, and counteract leakage.

Transforming growth factor beta 1 as a prognostic factor in pulmonary adenocarcinoma.

AIMS: To evaluate the efficacy of transforming growth factor beta (TGF-beta) for the prognosis of pulmonary adenocarcinoma. METHODS: TGF-beta was detected immunohistochemically using the avidin-biotin-peroxidase complex technique in resected pulmonary adenocarcinomas from 88 patients. RESULTS: Of the 88 patients, 39 were TGF-beta negative and 45 TGF-beta positive. The five year survival rate was 56% for the TGF-beta negative and 16% for the TGF-beta positive group. CONCLUSIONS: TGF-beta can be used as a prognostic factor in pulmonary adenocarcinoma.

Overexpression of heme oxygenase-1 protects allogeneic thyroid grafts from rejection in naive mice.

BACKGROUND: Endocrine allografts are an option for the treatment of endocrine failure. METHODS: One lobe of the thyroid was transplanted under the kidney capsule. RESULTS: C57BL/10 (H2(b)) thyroids were rejected in naive CBA (H2(k)) mice within 14 days after transplantation. When mice were treated with anti-CD4 monoclonal antibodies (mAb), all grafts survived for more than 60 days. The first grafts still survived after second C57BL/10 or Balb/c (H2(d)) thyroid grafts that were transplanted into the same recipients were rejected acutely, which suggests that the primary grafts were modified under anti-CD4 mAb treatment. To confirm this hypothesis, C57BL/10 thyroid grafts from anti-CD4 mAb-treated mice were retransplanted. All grafts survived in naive mice; this correlated with the overexpression of heme oxygenase-1 (HO-1) in the grafts. Next, an inhibitor of HO-1 (zinc protoporphyrin) or control compound (copper protoporphyrin) was injected intraperitoneally after transplantation of C57BL/10 thyroid grafts into the primary CBA recipients that had been treated with anti-CD4 mAb. The grafts in mice that had been treated with zinc protoporphyrin, but not copper protoporphyrin, were rejected when retransplanted to naive recipients. CONCLUSIONS: Overexpression of HO-1 correlated with the protection of fully allogeneic thyroid grafts from rejection when retransplanted into naive recipients.

Association between preoperative plasma CEA levels and the prognosis of gastric cancer following curative resection. Tumor Marker Committee, Japanese Foundation for Multidisciplinary Treatment of Cancer, Tokyo, Japan.

A large-scale retrospective study was undertaken to evaluate the association between preoperative plasma carcinoembryonic antigen (CEA) levels and the prognosis of 2768 gastric cancer patients who underwent curative gastrectomy between 1983 and 1984 at 66 leading medical institutions in Japan Postoperative follow-up was at least 5 years. Preoperative plasma CEA levels were also analysed against other prognostic factors. Preoperative plasma CEA levels showed strong correlations to the degree of lymph node metastasis (P < 0.001), TNM stage (P = 0.004) and the histopathology of the gastric cancer (P < 0.001). Preoperative CEA levels were also evaluated against survival, after being adjusted for the effect of clinically important factors by multivariate analysis. Patients with lower preoperative plasma CEA levels survived significantly longer than patients with higher CEA levels (P = 0.0001). This analysis demonstrates that curatively resected gastric cancer patients with higher preoperative plasma CEA levels have a poorer prognosis than those with lower levels, despite the adjustment for the effects of major prognostic factors.