Extensive proliferation of T cell lineage-restricted progenitors in the thymus: an essential process for clonal expression of diverse T cell receptor beta chains

For clonal diversification of TCR, a large number of T cell progenitors are required in which highly diverse TCRbeta chains are accommodated individually. In the present study, we examined the proliferative potential of thymic progenitors that have been defined to be T cell lineage restricted. We show that the earliest fetal thymus (FT) cells from Rag2(-/-) mice, when cultured individually in a thymic organ culture system, produced 150-1,800 CD25(+) cells. Since differentiation and proliferation of Rag2(-/-) thymocytes are arrested at the stage of TCRbeta chain gene rearrangement, the observed proliferation was considered to represent the proliferative potential of progenitors prior to the TCRbeta rearrangement. A comparable level of proliferation was revealed to occur by analyzing the Dbeta-Jbeta rearrangement profiles of T cells generated from single progenitors in the earliest population of FT from normal mice. The proliferative potential of progenitors declined along with the progression of developmental stages. Such an extensive proliferation of progenitors after the restriction to the T cell lineage may be an essential process ensuring the clonal diversification of TCRbeta chains.     

Effect of radioisotope sentinel node mapping in patients with cT1 N0 M0 lung cancer

BACKGROUND: Application of the sentinel node concept to lung cancer is still controversial. Patients with peripheral small lung cancers would gain the most benefit from this concept, if it were valid. We sought to determine whether it is possible to choose between limited lymph node sampling and systematic lymphadenectomy from the distribution of sentinel lymph nodes in patients with node-negative disease on the basis of imaging. METHODS: Sixty-five consecutive patients with cT1 N0 M0 non-small cell lung cancer were enrolled. A radioisotope tracer (4 mCi of technetium-99m tin colloid, 2.0 mL) was injected in the vicinity of the tumor before surgical intervention with computed tomographic guidance. The radioactivity of each resected lymph node was measured separately with a hand-held gamma probe after complete tumor resection. Sentinel nodes were identified, and the accuracy of sentinel node mapping was examined. Whether the location of the sentinel node depended on the site of the primary tumor was also examined. RESULTS: Of the 65 patients, 3 were excluded because of the final pathologic results. Successful radionuclide migration occurred in 39 (62.9%) of the 62 patients. There was 1 (2.6%) false-negative result among 39 patients with a sentinel node, and therefore the sensitivity was 90%, and the specificity was 100%. The most common sentinel lymph nodes were at level 12 (46.7%), followed by level 11 (18.3%), the mediastinum (16.7%), and level 10 (11.7%). CONCLUSION: The sentinel node concept is valid in patients with cT1 N0 M0 lung cancer. The lobar lymph nodes were identified as sentinel nodes more frequently than other lymph nodes. We need to make further efforts to increase the sentinel node identification rate. However, we believe that if sentinel nodes are identified, sentinel node mapping can allow the accurate intraoperative diagnosis of pathologic N0 status in patients with cT1 N0 M0 lung cancer.     

A prospective survey of delayed adverse reactions to iohexol in urography and computed tomography

We investigated 7505 inpatients who underwent intravenous urography or contrast-enhanced computed tomography to assess risk factors for delayed adverse drug reactions to iohexol, a non-ionic iodinated contrast medium. Focusing on delayed adverse reactions, all adverse events were prospectively investigated for 7 days after injection of iohexol. To explore the relevant risk factors, the relationship between occurrence of adverse reactions to iohexol and 17 different variables was evaluated by logistic regression analysis. To assess the influence of seasonal factors, adverse reactions were separately evaluated during two periods: February to April (the pollinosis period in Japan) and July to September (the non-pollinosis period). The prevalence of delayed adverse events and delayed adverse reactions was 3.5 and 2.8%, respectively, whereas the prevalence of adverse events and adverse reactions was 5.7 and 5.0%, respectively. Multivariate analysis showed that six parameters had a significant influence on delayed adverse reactions to iohexol, including (a) a history of allergy, (b) season, (c) radiographic procedure, (d) age, (e) concomitant surgery or other invasive procedures, and (f) concomitant medication. The prevalence of delayed reactions was lower than in previous large-scale studies. Significant risk factors included a history of allergy and performance of radiography during the pollinosis period, suggesting that allergy was involved in delayed adverse reactions. The type of radiographic procedure also had an influence. Electronic Publication     

Comparison of three tracers for detecting sentinel lymph nodes in patients with clinical N0 lung cancer

The goal of this pilot study was to compare three tracers for the detection of sentinel nodes in patients with lung cancer. Forty-eight patients with clinical N0 non-small cell lung cancer were enrolled. Indocyanine green (n=16) or isosulfan blue (n=18) was injected around the tumor intraoperatively, or technetium tin colloid was injected preoperatively under CT guidance (n=14). Sentinel nodes were detected in 6.3% of patients injected with indocyanine green, 50.0% of patients injected with isosulfan blue, and 64.3% of patients injected with technetium tin colloid. The detection rate achieved with indocyanine green was significantly lower than with the other two tracers. A false-negative sentinel node was seen in 1 patient using isosulfan blue. Both isosulfan blue and technetium tin colloid seem to be suitable for intraoperative sentinel node mapping in patients with lung cancer.     

Radiographic pulmonary and pleural changes after carbon ion irradiation

PURPOSE: For the treatment of Stage I non-small-cell lung cancers, a Phase I/II study of carbon ion irradiation was undertaken. In the present study, we focus on posttreatment radiographic lung damage: specifically, its timing, features, and relation to dose-volume factors. MATERIALS AND METHODS: Forty-three patients with 44 Stage I non-small-cell lung cancers were treated with carbon ion irradiation ranging from 59.4 to 95.4 photon Gy equivalent dose (GyE) in 18 fractions over 6 weeks, according to our dose escalation protocols. Primary lesions were irradiated by 2-4 portals. Follow-up evaluation with computed tomography (CT) was sequentially performed to assess changes in the lung. CT findings were classified into two categories: pulmonary reaction and pleural reaction. A dose-volume histogram for each patient was calculated, using a three-dimensional CT planning system. Statistical analysis was conducted using Spearman's rank test. RESULTS: The median appearance period of pulmonary reactions was 3 months after the start of carbon ion irradiation, whereas the maximum period was 6 months. The severity of pulmonary reactions statistically correlated with lung volumes irradiated no less than 20 GyE (vol. 20) and 40 GyE (vol. 40) (p = 0.017 and p = 0.0089). Geometrically unique findings in the irradiated fields were observed in 7 patients (16%). The median appearance period of pleural reactions was 4 months after the start of carbon ion irradiation. The occurrence of pleural reactions significantly correlated with planning target volume (p = 0.000098), vol. 20 (p = 0.00011), and vol. 40 (p = 0.00097). CONCLUSIONS: Lung damage after carbon ion irradiation was observed in the parenchyma and in the pleura. The severity of pulmonary reactions was correlated with dose-volume factors. These findings might provide useful information in the planning and management of carbon ion irradiation.     

Three-dimensional treatment planning using electrocardiographically gated multi-detector row CT

PURPOSE: Information concerning the amount and nature of target motion is essential for the determination of internal margin size. However, there are few published reports outlining the motion with heart and aortic pulsation. We introduce a method for three-dimensional radiation treatment planning (3D-RTP) by using electrocardiographically (ECG) gated spiral scanning with a four-section CT system. We describe a new approach to visualize internal organ motion resulting from cardiac motion with ECG gated multidetector row CT. MATERIALS AND METHODS: Five patients with lung or liver tumors were studied with a multidetector row CT system under shallow inspiration breath-holding. With retrospective ECG gating, only data acquired within a predefined interval of the cardiac cycle are used for image reconstruction. All reconstructed image data at diastolic and systolic phases of the cardiac cycle were transferred to the 3D-RTP system. The shift of the internal organs between the cardiac cycles was evaluated. RESULTS: Cardiac contraction influences anterior thorax, pulmonary peripheral vessels, and liver position, in addition to locations near the heart. Apparent movements more than 5 mm between diastolic and systolic phases were observed in the left ventricle, right atrium, and superior vena cava. Two-phase imaging was useful for showing the movement of internal organs during cardiac contraction under breath-holding. CONCLUSIONS: Spatial information using ECG-gated CT has the potential to determine the planning target volume of moving lung and liver tumors more precisely than conventional CT planning.     

Prospective trial of combined transcatheter arterial chemoembolization and three-dimensional conformal radiotherapy for portal vein tumor thrombus in patients with unresectable hepatocellular carcinoma

PURPOSE: We conducted a prospective trial of combined transarterial chemoembolization (TACE) and three-dimensional conformal radiotherapy (3D-CRT) for portal vein tumor thrombus (PVTT) in unresectable hepatocellular carcinoma (HCC). The aim of the present study was to investigate the efficacy and toxicity of this trial regime. METHODS AND MATERIALS: Patients with unresectable HCC complicated with tumor thrombus in the first branch of portal vein were selected as eligible for this study. TACE was performed using Lipiodol, epirubicin hydrochloride, and mitomycin, followed by gelatin sponge cubes. The 3D-CRT was performed targeting the clinical target volume (CTV) defined as PVTT only to a total dose of 60 Gy using 10-MV accelerator. RESULTS: A total of 19 patients were enrolled in this study. Survival rates at 1 and 2 years were 40.6% and 10.2%, respectively. The median survival time was 7.0 months. An objective response was observed in 11 of 19 cases (57.9%). Recanalization of the first portal branches was not observed; however, the protrusion of PVTT into the main portal trunk decreased in all cases. Growth of intrahepatic metastasis outside the 3D-CRT field was observed in 12 cases (63%). Deterioration of the Child-Pugh Score was observed in 5 of 6 cases with the percent volume of the total liver receiving a dose exceeding 30 Gy (V(30)) > or =40%, vs. 2 of 13 cases with a V(30) <40% (p < 0.01). CONCLUSION: This combined therapy was feasible. Our results indicate that V(30) was a predictive test for deterioration of liver function. Further investigation of treatment modalities is needed to prevent the growth of intrahepatic metastasis.     

Tumor response to chemotherapy: the validity and reproducibility of RECIST guidelines in NSCLC patients

We investigated the validity and inter-criteria reproducibility between RECIST (Response Evaluation Criteria in Solid Tumors) guidelines and WHO (World Health Organization) criteria, considering the decrease in patient numbers resulting from inclusion of the minimum lesion size criterion introduced in RECIST guidelines. RECIST guidelines are based on unidimensional measurement and exclusion of small lesions from measurement. The aims of the study were to examine: (1) the effect of the minimum lesion size criterion, (2) the validity of unidimensional and bidimensional measurements, i.e., their relationship with tumor volume, (3) the inter-criteria reproducibility between current RECIST guidelines and previous WHO criteria. One hundred and twenty patients with non-small cell lung cancer (NSCLC) in clinical trials were evaluated. By applying the minimum lesion size criterion, six cases became ineligible without any influence on precision of tumor volume measurement. In the validity study, actual tumor volume was regarded as the gold standard. Although the unidimensional measurement had a lower correlation with tumor volume value than the bidimensional measurement, both the unidimensional measurement and bidimensional measurement correlated sufficiently well with tumor volume changes and the assessed tumor volume response. In the inter-criteria reproducibility study between RECIST guidelines and WHO criteria, the response rate assessed by RECIST guidelines (19.3%) was almost the same as that assessed by WHO criteria (20.0%). In conclusion, RECIST guidelines are adequate for evaluating tumor response to chemotherapy in terms of both validity in relation to tumor volume and inter-criteria reproducibility with the WHO criteria.     

Radioisotope marking under CT guidance and localization using a handheld gamma probe for small or indistinct pulmonary lesions

STUDY OBJECTIVES: A new marking technique was developed to localize small or indistinct pulmonary lesions, involving preoperative radioisotope injection and intraoperative detection with a handheld gamma probe. SETTING: National hospital for respiratory disease. METHODS: and patients: A technetium suspension (either (99m)Tc tin colloid [2 to 4 mCi, 0.5 to 2.5 mL] or (99m)Tc phytate [2 mCi, 2.0 mL]) was injected preoperatively in the vicinity of the lesion under CT guidance in 25 patients with small or indistinct pulmonary lesions. A handheld gamma probe (Navigator GPS; Tyco Healthcare Japan; Tokyo, Japan) was used to detect the hot spot where radioactivity was localized during surgery. The lesion marked by the radioisotope then was thoracoscopically resected using endostaplers. RESULTS: The preoperative marking procedure took approximately 30 min. A small pneumothorax and mild intrapulmonary bleeding were observed in two patients and one patient, respectively, but no additional treatment was needed for these complications. The lesion was resected soon after the marking procedure in 21 patients, and on the next day in 4 patients. All lesions were easily identified during surgery as radioactive hot spots detected by the handheld gamma probe. Thoracoscopic wedge resection was successfully performed in all patients without complications. CONCLUSION: This new marking technique for small or indistinct pulmonary lesions (radioisotope injection under CT guidance and intraoperative detection with a handheld gamma probe) seems to be safe, reliable, and convenient.