Ikuno Nishibuchi

Stereotactic body radiotherapy for patients with small hepatocellular carcinoma ineligible for resection or ablation therapies

To evaluate the efficacy and safety of stereotactic body radiotherapy (SBRT) in patients with small hepatocellular carcinoma (HCC) who were ineligible for resection or ablation therapies.

Functional Image-Guided Radiotherapy Planning in Respiratory-Gated Intensity-Modulated Radiotherapy for Lung Cancer Patients With Chronic Obstructive Pulmonary Disease

PURPOSE To investigate the incorporation of functional lung image-derived low attenuation area (LAA) based on four-dimensional computed tomography (4D-CT) into respiratory-gated intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) in treatment planning for lung cancer patients with chronic obstructive pulmonary disease (COPD). METHODS AND MATERIALS Eight lung cancer patients with COPD were the subjects of this study. LAA was generated from 4D-CT data sets according to CT values of less than than -860 Hounsfield units (HU) as a threshold. The functional lung image was defined as the area where LAA was excluded from the image of the total lung. Two respiratory-gated radiotherapy plans (70 Gy/35 fractions) were designed and compared in each patient as follows: Plan A was an anatomical IMRT or VMAT plan based on the total lung; Plan F was a functional IMRT or VMAT plan based on the functional lung. Dosimetric parameters (percentage of total lung volume irradiated with ≥20 Gy [V20], and mean dose of total lung [MLD]) of the two plans were compared. RESULTS V20 was lower in Plan F than in Plan A (mean 1.5%, p = 0.025 in IMRT, mean 1.6%, p = 0.044 in VMAT) achieved by a reduction in MLD (mean 0.23 Gy, p = 0.083 in IMRT, mean 0.5 Gy, p = 0.042 in VMAT). No differences were noted in target volume coverage and organ-at-risk doses. CONCLUSIONS Functional IGRT planning based on LAA in respiratory-guided IMRT or VMAT appears to be effective in preserving a functional lung in lung cancer patients with COPD.

Reorganization of Damaged Chromatin by the Exchange of Histone Variant H2A.Z-2

PURPOSE The reorganization of damaged chromatin plays an important role in the regulation of the DNA damage response. A recent study revealed the presence of 2 vertebrate H2A.Z isoforms, H2A.Z-1 and H2A.Z-2. However, the roles of the vertebrate H2A.Z isoforms are still unclear. Thus, in this study we examined the roles of the vertebrate H2A.Z isoforms in chromatin reorganization after the induction of DNA double-strand breaks (DSBs). METHODS AND MATERIALS To examine the dynamics of H2A.Z isoforms at damaged sites, we constructed GM0637 cells stably expressing each of the green fluorescent protein (GFP)-labeled H2A.Z isoforms, and performed fluorescence recovery after photobleaching (FRAP) analysis and inverted FRAP analysis in combination with microirradiation. Immunofluorescence staining using an anti-RAD51 antibody was performed to study the kinetics of RAD51 foci formation after 2-Gy irradiation of wild-type (WT), H2A.Z-1- and H2A.Z-2-deficient DT40 cells. Colony-forming assays were also performed to compare the survival rates of WT, H2A.Z-1-, and H2A.Z-2-deficient DT40 cells with control, and H2A.Z-1- and H2A.Z-2-depleted U2OS cells after irradiation. RESULTS FRAP analysis revealed that H2A.Z-2 was incorporated into damaged chromatin just after the induction of DSBs, whereas H2A.Z-1 remained essentially unchanged. Inverted FRAP analysis showed that H2A.Z-2 was released from damaged chromatin. These findings indicated that H2A.Z-2 was exchanged at DSB sites immediately after the induction of DSBs. RAD51 focus formation after ionizing irradiation was disturbed in H2A.Z-2-deficient DT40 cells but not in H2A.Z-1-deficient cells. The survival rate of H2A.Z-2-deficient cells after irradiation was lower than those of WT and H2A.Z-1- DT40 cells. Similar to DT40 cells, H2A.Z-2-depleted U2OS cells were also radiation-sensitive compared to control and H2A.Z-1-depleted cells. CONCLUSIONS We found that vertebrate H2A.Z-2 is involved in the regulation of the DNA damage response at a very early stage, via the damaged chromatin reorganization required for RAD51 focus formation.

Combined Ventilation and Perfusion Imaging Correlates With the Dosimetric Parameters of Radiation Pneumonitis in Radiation Therapy Planning for Lung Cancer

PURPOSE The purpose of this study was to prospectively investigate clinical correlations between dosimetric parameters associated with radiation pneumonitis (RP) and functional lung imaging. METHODS AND MATERIALS Functional lung imaging was performed using four-dimensional computed tomography (4D-CT) for ventilation imaging, single-photon emission computed tomography (SPECT) for perfusion imaging, or both (V/Q-matched region). Using 4D-CT, ventilation imaging was derived from a low attenuation area according to CT numbers below different thresholds (vent-860 and -910). Perfusion imaging at the 10th, 30th, 50th, and 70th percentile perfusion levels (F10-F70) were defined as the top 10%, 30%, 50%, and 70% hyperperfused normal lung, respectively. All imaging data were incorporated into a 3D planning system to evaluate correlations between RP dosimetric parameters (where fV20 is the percentage of functional lung volume irradiated with >20 Gy, or fMLD, the mean dose administered to functional lung) and the percentage of functional lung volume. Radiation pneumonitis was evaluated using Common Terminology Criteria for Adverse Events version 4.0. Statistical significance was defined as a P value of <.05. RESULTS Sixty patients who underwent curative radiation therapy were enrolled (48 patients for non-small cell lung cancer, and 12 patients for small cell lung cancer). Grades 1, 2, and ≥3 RP were observed in 16, 44, and 6 patients, respectively. Significant correlations were observed between the percentage of functional lung volume and fV20 (r=0.4475 in vent-860 and 0.3508 in F30) or fMLD (r=0.4701 in vent-860 and 0.3128 in F30) in patients with grade ≥2 RP. F30∩vent-860 results exhibited stronger correlations with fV20 and fMLD in patients with grade ≥2 (r=0.5509 in fV20 and 0.5320 in fMLD) and grade ≥3 RP (r=0.8770 in fV20 and 0.8518 in fMLD). CONCLUSIONS RP dosimetric parameters correlated significantly with functional lung imaging.

Dynamic computed tomography appearance of tumor response after stereotactic body radiation therapy for hepatocellular carcinoma: How should we evaluate treatment effects?

To evaluate the dynamic computed tomography (CT) appearance of tumor response after stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) and reconsider response evaluation criteria for SBRT that determine treatment outcomes.

The Time Course of Dynamic Computed Tomographic Appearance of Radiation Injury to the Cirrhotic Liver Following Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma

This study aimed to evaluate the dynamic computed tomographic (CT) appearance of focal radiation injury to cirrhotic liver tissue around the tumor following stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC). Seventy-seven patients with 92 HCCs were observed for >6 months. Sixty-four and 13 patients belonged to Child–Pugh class A and B, respectively. The median SBRT dose was 48 Gy/4fr. Dynamic CT scans were performed in non–enhanced, arterial, portal, and venous phases. The median follow-up period was 18 months. Dynamic CT appearances were classified into 3 types: type 1, hyperdensity in all enhanced phases; type 2, hypodensity in arterial and portal phases; type 3, isodensity in all enhanced phases. Half of the type 2 or 3 appearances significantly changed to type 1, particularly in patients belonging to Child–Pugh class A. After 3–6 months, Child–Pugh class B was a significant factor in type 3 patients. Thus, dynamic CT appearances were classified into 3 patterns and significantly changed over time into the enhancement group (type 1) in most patients belonging to Child–Pugh class A. Child–Pugh class B was a significant factor in the non–enhancement group (type 3).

Preoperative prediction of a pathologic complete response of esophageal squamous cell carcinoma to neoadjuvant chemoradiotherapy

Background: The accurate prediction of a pathologic complete response (ypT0N0M [LYM] 0 ypStage 0) before operation is essential for selecting appropriate strategies for treating esophageal cancer after neoadjuvant chemoradiotherapy. Methods: We reviewed 130 consecutive patients with esophageal squamous cell carcinoma who were evaluated preoperatively using upper gastrointestinal endoscopy, computed tomography, and 18F‐fluorodeoxyglucose‐positron emission tomography after neoadjuvant chemoradiotherapy and subsequently underwent esophagectomy. Our aim was to determine the diagnostic abilities of computed tomography, 18F‐fluorodeoxyglucose‐positron emission tomography, and endoscopy to predict preoperatively a pathologic complete response of the primary site of the locally advanced esophageal squamous cell carcinoma and associated lymph nodes to trimodal neoadjuvant chemoradiotherapy. Associations between clinical complete response (ycT0N0M [LYM] 0 ycStage 0) and pathologic complete response were investigated preoperatively. Results: Twenty‐nine (22.3%) and 43 (33.1%) patients, respectively, achieved clinical complete response and pathologic complete response, which were associated (P = .001). The sensitivity and specificity, as well as the positive and negative predictive values of clinical complete response to define pathologic complete response were 39.5%, 86.2%, 58.6%, and 74.3%, respectively. Univariate and multivariate analyses selected clinical complete response as the sole independent preoperative predictor of pathologic complete response (clinical complete responses versus non–clinical complete responses: odds ratio: 0.26, 95% confidence interval, 0.10–0.65, P = .004). Recurrence‐free and overall survival (OS) rates were better in patients with than in those without clinical complete response (5‐year recurrence‐free and overall survival: 69.0% vs 41.4% and 75.9% vs 45.0%, respectively, both P = .02). Furthermore, clinical complete response was an independent preoperative predictor of recurrence‐free survival (clinical complete response versus nonclinical complete response: hazard ratio: 2.20, 95% confidence interval, 1.08–4.45, P = .03). Conclusion: Although pathologic complete response was predictable preoperatively to some extent, the accuracy was somewhat low. Considerable caution should be exercised when selecting the watch‐and‐wait approach with operation as needed and omitting planned operative intervention even for patients who achieve clinical complete response after neoadjuvant chemoradiotherapy.

Functional image guided radiation therapy planning in volumetric modulated arc therapy for patients with malignant pleural mesothelioma

Purpose To investigate the incorporation of functional lung image-derived low-attenuation area (LAA) based on 4-dimensional computed tomography (4D-CT) in volumetric modulated arc therapy (VMAT) planning for patients with malignant pleural mesothelioma (MPM) after extrapleural pneumonectomy. Methods and materials Twelve patients with MPM after extrapleural pneumonectomy were included. The primarily affected side was the right in 6 patients and the left in 6 patients. LAA was generated from 4D-CT data according to CT values with a threshold of less than –860 Hounsfield units (HU). Functional lung image was defined as the area where LAA was excluded from contralateral lung image. Two radiation therapy plans were designed: (1) Plan C, conventional VMAT and (2) Plan F, functional VMAT plan based on the functional lung. Both plans were compared in each patient with respect to the following dosimetric parameters: fV20, V20, fV10, V10, fV5, and V5, the percentages of functional or contralateral lung volumes irradiated with >20 Gy, 10 Gy, or 5 Gy, respectively; functional mean lung dose (fMLD) and mean lung dose (MLD), the mean dose to the functional or contralateral lung, respectively; maximum dose to the cord; mean doses to the liver and heart; and planning target volume homogeneity index. Results fV5 and MLD were significantly lower in Plan F (fV5, median 57.5% in Plan C vs 38.5% in Plan F, P < .01; MLD, median 7.0 Gy in Plan C vs 6.4 Gy in Plan F, P = .04). fV10, V5, and fMLD were also significantly lower in Plan F. Compared with Plan C, planning target volume homogeneity index and liver, heart, and cord doses were not significantly elevated in Plan F. Conclusions Significant reductions in fV5, fV10, fMLD, V5, and MLD were achieved with the functional image guided VMAT plan without negative effects on other factors. LAA-based functional image guided radiation therapy planning in VMAT is a feasible method to spare the functional lung in patients with MPM.

Relationship between sentinel lymph nodes and postoperative tangential fields in early breast cancer, evaluated using SPECT/CT.

Single-photon emission computed tomography/computed tomography (SPECT/CT) demonstrates the precise location of the sentinel lymph nodes (SLNs) in patients with breast cancer. We evaluated the relationship between SLNs and postoperative tangential fields by using SPECT/CT images. Subjects included 72 patients with early breast cancer who underwent SPECT/CT of the SLNs and received whole-breast irradiation with tangential fields after partial mastectomy. The SLN locations evaluated by using SPECT/CT images were entered into the treatment-planning CT image with a 5-mm-diameter sphere. A 15-mm-diameter sphere including the 5-mm treatment margin around the SLNs was defined as PTV-SLN. The PTV-SLN doses with tangential irradiation were evaluated and expressed as the percentage of the prescribed dose. In 69 patients, SLNs were detected by using SPECT/CT; 68 SLNs were located at axillary lymph node Level I, and one was located at Level II. A total of 62 SLNs (90%) were determined to be located inside the tangential fields on the digitally reconstructed radiography (DRR) images. The median doses of SLN center, mean PTV-SLN dose, and PTV-SLN D95 (the minimum dose delivered to 95% of the volume) were 94.1% (range, 15.3–101.9%), 93.7% (range, 29.3–104.0%) and 84.8% (range, 6.8–99.8%). The D95 for the SLNs with treatment margins were ≤90% of the prescribed doses in more than half of the cases. Modification of the individual treatment fields seemed to be necessary to ensure coverage of the SLNs in whole-breast irradiation.

Time-Adjusted Internal Target Volume: A Novel Approach Focusing on Heterogeneity of Tumor Motion Based on 4-Dimensional Computed Tomography Imaging for Radiation Therapy Planning of Lung Cancer

PURPOSE To consider nonuniform tumor motion within the internal target volume (ITV) by defining time-adjusted ITV (TTV), a volume designed to include heterogeneity of tumor existence on the basis of 4-dimensional computed tomography (4D-CT). METHODS AND MATERIALS We evaluated 30 lung cancer patients. Breath-hold CT (BH-CT) and free-breathing 4D-CT scans were acquired for each patient. The tumors were manually delineated using a lung CT window setting (window, 1600 HU; level, -300 HU). Tumor in BH-CT images was defined as gross tumor volume (GTV), and the sum of tumors in 4D-CT images was defined as ITV-4D. The TTV images were generated from the 4D-CT datasets, and the tumor existence probability within ITV-4D was calculated. We calculated the TTV80 value, which is the percentage of the volume with a tumor existence probability that exceeded 80% on ITV-4D. Several factors that affected the TTV80 value, such as the ITV-4D/GTV ratio or tumor centroid deviation, were evaluated. RESULTS Time-adjusted ITV images were acquired for all patients, and tumor respiratory motion heterogeneity was visualized. The median (range) ITV-4D/GTV ratio and median tumor centroid deviation were 1.6 (1.0-4.1) and 6.3 mm (0.1-30.3 mm), respectively. The median TTV80 value was 43.3% (2.9-98.7%). Strong correlations were observed between the TTV80 value and the ITV-4D/GTV ratio (R=-0.71) and tumor centroid deviation (R=-0.72). The TTV images revealed the tumor motion pattern features within ITV. CONCLUSIONS The TTV images reflected nonuniform tumor motion, and they revealed the tumor motion pattern features, suggesting that the TTV concept may facilitate various aspects of radiation therapy planning of lung cancer while incorporating respiratory motion in the future.