Tomohisa Okuma

Radiofrequency Ablation in a Porcine Lung Model: Correlation Between CT and Histopathologic Findings

OBJECTIVE The objective of our study was to investigate the time course changes of the ablated lesion after radiofrequency ablation in the porcine lung and the correlation between CT and histopathologic findings. CONCLUSION Ground-glass attenuation on CT led to overestimation of the size of necrotic lesions. The layered structural findings on CT were consistent with the histopathologic findings. Although CT findings reflect the histopathologic findings, attention should be paid to the dissociation of ablated lesions and high-density areas in clinical interpretation of CT images.

Fluorine-18-fluorodeoxyglucose positron emission tomography for assessment of patients with unresectable recurrent or metastatic lung cancers after CT-guided radiofrequency ablation: Preliminary results

ObjectivesWe compared the diagnostic value of fluorine-18-fiuorodeoxyglucose positron emission tomography (FDG-PET) with that of computed tomography (CT) following radiofrequency ablation (RFA) of inoperable recurrent or metastatic cancers in the lung.MethodsTwelve patients (9 males and 3 females; 5 had recurrent lung cancer and the other 7 had metastatic nodules from a variety of primary cancers) were treated by RFA for 17 pulmonary nodules. FDG-PET was performed before and 2 months after RFA, and the mean standardized uptake value (SUV) was calculated. The response evaluation was based on the percent reduction relative to the baseline and the absolute values of SUV on FDG-PET performed at 2 months after RFA. We compared the response evaluations made based on findings of FDG-PET and CT at 2 and ≥6 months (mean 10.2) after RFA.ResultsThe percent reduction in uptake at 2 months was significantly lower in nodules considered progressive (69.6± 18.6%) than nonprogressive disease (38.7 ± 12.5%; p < 0.01) based on CT findings at >6 months after RFA. The absolute SUV at 2 months was significantly higher in nodules considered progressive (2.61 ±0.75) than nonprogressive disease (1.05 ±0.67; p<0.01) based on CT findings at ≥6 months post-RFA.ConclusionAlthough our pilot study comprised few cases of various histopathological types of cancers in the lung, the results suggest that FDG-PET could predict regrowth on subsequent follow-up CT. Regrowth could be diagnosed earlier by FDG-PET than by CT, and nodules with residual uptake and with <60% reduction of uptake relative to baseline on FDG-PET at 2 months after ablation might require additional therapy.

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Beyond Progressive Disease: A Retrospective Analysis for Japanese Patients with Activating EGFR Mutations

Introduction: It is not determined whether the continuous use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is reasonable for patients with activating EGFR mutations, who have progressed with the drug. Methods: We retrospectively analyzed the data from 2002 to 2010 of consecutive patients who had advanced non–small-cell lung cancer (NSCLC) harboring activating EGFR mutations and showed radiological disease progression after EGFR-TKI treatment as the first-line or second-line setting. We classified them into two groups: continuous EGFR-TKI and switching to chemotherapy, and compared the clinical outcomes. Multivariate analysis for survival was performed including age, sex, Eastern Cooperative Oncology Group performance status (0–1/ 2–4), brain metastasis, EGFR mutations (deletions in exon 19 versus L858R), continuous EGFR-TKI (yes/no), and initiation of EGFR-TKI (first versus second). Results: A total of 551 NSCLC patients were screened for EGFR mutations in the period, and 186 patients had activating EGFR mutations. To explore the potential use of EGFR-TKI beyond progressive disease (PD), 64 patients were selected and analyzed. There were 13 men and 51 women, and median age was 65.5 years (range, 42–86). Among them, 31 patients had deletions in exon 19, and 33 had point mutation of L858R in exon 21. Thirty-nine patients were continuing EGFR-TKI beyond PD; 25 patients were switched to cytotoxic chemotherapy alone. The median overall survival was 32.2 months in the patients continuing EGFR-TKI, and 23.0 months in the patients switching to chemotherapy, presenting a significant difference between the two groups (p = 0.005). Cox analysis showed that continuous EGFR-TKI after PD (hazards ratio 0.42, 95% confidence interval: 0.21–0.83, p = 0.013) was associated with improved survival. Conclusion: Continuous use of EGFR-TKI beyond PD may prolong overall survival compared with switching to cytotoxic chemotherapy in patients with activating EGFR mutations. A prospective study will be needed to confirm our results.

Frequency and Risk Factors of Various Complications After Computed Tomography–Guided Radiofrequency Ablation of Lung Tumors

ObjectiveTo retrospectively determine the frequency and risk factors of various side effects and complications after percutaneous computed tomography–guided radiofrequency (RF) ablation of lung tumors.MethodsWe reviewed and analyzed records of 112 treatment sessions in 57 of our patients (45 men and 12 women) with unresectable lung tumors treated by ablation. Risk factors, including sex, age, tumor diameter, tumor location, history of surgery, presence of pulmonary emphysema, electrode gauge, array diameter, patient position, maximum power output, ablation time, and minimum impedance during ablation, were analyzed using univariate and multivariate analyses.ResultsTotal rates of side effects and minor and major complications occurred in 17%, 50%, and 8% of treatment sessions, respectively. Side effects, including pain during ablation (46% of sessions) and pleural effusion (13% of sessions), occurred with RF ablation. Minor complications, including pneumothorax not requiring chest tube drainage (30% of sessions), subcutaneous emphysema (16% of sessions), and hemoptysis (9% of sessions) also occurred after the procedure. Regarding major complications, three patients developed fever >38.5°C; three patients developed abscesses; two patients developed pneumothorax requiring chest tube insertion; and one patient had air embolism and was discharged without neurologic deficit. Univariate and multivariate analyses suggested that a lesion located ≤1 cm of the chest wall was significantly related to pain (p < 0.01, hazard index 5.76). Risk factors for pneumothorax increased significantly with previous pulmonary surgery (p < 0.05, hazard index 6.1) and presence of emphysema (p <0.01, hazard index 13.6).ConclusionThe total complication rate for all treatment sessions was 58%, and 25% of patients did not have any complications after RF ablation. Although major complications can occur, RF ablation of lung tumors can be considered a safe and minimally invasive procedure.

Radiofrequency Ablated Lesion in the Normal Porcine Lung: Long-Term Follow-Up with MRI and Pathology

PurposeTo evaluate the effectiveness of magnetic resonance imaging (MRI) in reflecting histopathologic changes after radiofrequency ablation (RFA) to the lung and to assess accurately the extent of tissue necrosis for evaluating untreated lesions.MethodsPercutaneous RFA was performed on 72 lung regions in 12 pigs under computed tomographic guidance. After performing MRI, the animals were divided into three experimental phases: in the acute phase, 4 pigs were killed immediately after the procedure; in the subacute phase, 4 pigs were killed at 1 week; and in the chronic phases, 2 pigs were killed at 4 and 8 weeks after the procedure, respectively. MRI–histopathologic correlation was performed.ResultsIn the acute phase, the inner zone showed hypointensity on T2-weighted images and isointensity on T1-weighted images, with a lack of enhancement on contrast-enhanced T1-weighted images, representing early changes in coagulative necrosis on histopathologic examination. The outer zone showed hyperintensity on T2-weighted images and isointensity on T1-weighted images, with ring-like enhancement on contrast-enhanced T1-weighted images. The histopathologic section showed alveolar fluid collections and congestion. In the subacute phase the MR zone pattern was essentially similar to that of the acute phase, but the ablated lesion showed extensive coagulative necrosis with a fibrovascular rim on histopathologic examination. In the chronic phase, there was no change in the zone pattern on MRI. The lesions showed gradual resorption of coagulative necrosis. The area of coagulative necrosis correlated closely with the histopathologic size (p < 0.05).ConclusionsMRI effectively visualized the histopathologic changes after RFA and accurately determined the extent of the necrotic lesion. MRI is potentially a useful modality for evaluating therapeutic efficacy after RFA to the lung.

Predictors of the clinical effects of pirfenidone on idiopathic pulmonary fibrosis

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with a poor prognosis. Recently, pirfenidone was reported to slow the rate of decline in vital capacity and improve progression-free survival in IPF. The purpose of this study was to clarify the factors that predicted a good response to pirfenidone, as well as its adverse effects. METHODS Forty-one IPF cases, treated with pirfenidone from January 2009 to January 2011, were enrolled in this investigation. Disease severity was classified into grades I-IV, as defined by the Japanese Respiratory Society (JRS). Short-term responsiveness to pirfenidone was evaluated by the modified criteria of the JRS. Predictors of nausea, anorexia, or both that represented important adverse effects were examined by multivariate Cox proportional hazard analyses. Predictors of short-time responsiveness were examined by multivariate logistic regression analyses. RESULTS Diagnosed by a surgical lung biopsy (SLB), the mild cases of grade I/II were predictors of good, short-term responsiveness. Patients taking acid-secretion inhibitors, including proton pump inhibitors and histamine H2-receptor antagonists, showed less anorexia, nausea, or both. Only 1 case was administered drugs to activate gastrointestinal motility. CONCLUSIONS We concluded that IPF patients with a mild disease, diagnosis by SLB, or both showed indications of a good response to pirfenidone. In addition, acid-secretion inhibitors may reduce the frequency of anorexia, nausea, or both from pirfenidone.

Long-term follow-up high-resolution CT findings in non-specific interstitial pneumonia

Background The aims of this study were to retrospectively assess the change in findings on follow-up CT scans of patients with non-specific interstitial pneumonia (NSIP; median, 72 months; range, 3–216 months) and to clarify the correlation between the baseline CT findings and mortality. Methods The study included 50 patients with a histologic diagnosis of NSIP. Two observers evaluated the high-resolution CT (HRCT) findings independently and classified each case into one of the following three categories: (1) compatible with NSIP, (2) compatible with UIP or (3) suggestive of alternative diagnosis. The correlation between the HRCT findings and mortality was evaluated using the Kaplan–Meier method and the log-rank test, as well as Cox proportional hazards regression models. Results Ground-glass opacity and consolidation decreased, whereas coarseness of fibrosis and traction bronchiectasis increased on the follow-up HRCT scans, however, in 78% of cases the overall extent of parenchymal abnormalities had no change or decreased. Patients with HRCT diagnosed compatible with NSIP had a longer survival than those with HRCT findings more compatible UIP or an alternative diagnosis. On multivariate analysis, the coarseness of fibrosis alone was associated with prognosis (HR: 1.480; 95% CIs 1.100 to 1.990). Conclusions The HRCT patterns seen in patients with a histopathologic diagnosis of NSIP progress in a variable manner. Overall disease extent may decrease over time in some, while fibrosis may progress in others. The initial HRCT diagnosis may impact survival in this group of patients.

Continued treatment with gefitinib beyond progressive disease benefits patients with activating EGFR mutations.

BACKGROUND Gefitinib is an effective treatment for patients with non-small cell lung cancer who harbor activating epidermal growth factor receptor (EGFR) mutations. However, no optimal strategy has been established for these patients after gefitinib fails. The aim of this retrospective study was to assess the survival benefit of continued gefitinib treatment in these cases. PATIENTS AND METHODS We analyzed gefitinib responders with activating EGFR mutations who developed progressive disease (PD) during the course of therapy. Prognostic variables were analyzed using a Cox proportional-hazards model. RESULTS A total of 134 patients were retrospectively reviewed. Exon-19 deletion mutations and L858R point mutations were detected in 71 and 63 patients, respectively. Median survival time after PD with gefitinib was 14.3 months (95% confidence interval: 11.7-16.9). The median duration of continued gefitinib therapy beyond PD was 3.2 months. Statistical analysis showed that good performance status (0-1) (hazard ratio [HR]: 0.6), progression of a previously evaluated lesion (HR: 0.6), and at least 3 months of continued treatment (HR: 0.4) were independent prognostic factors. CONCLUSION Continuation of gefitinib beyond PD is an effective optional treatment in EGFR-mutated patients.

Radiofrequency Ablation and Immunostimulant OK-432: Combination Therapy Enhances Systemic Antitumor Immunity for Treatment of VX2 Lung Tumors in Rabbits

PURPOSE To evaluate whether antitumor immunity is enhanced systemically by combining radiofrequency ablation (RFA) and local injection of an immunostimulant, OK-432. MATERIALS AND METHODS Experiments were approved by the institutional animal care committee. Experimental Japanese rabbits inoculated with VX2 tumors in the lung and the auricle were randomized into four groups of eight: control (supportive care), RFA (RFA of lung tumor), OK-432 (direct injection of OK-432 into lung tumor), and combination therapy (lung RFA and direct OK-432 injection into lung tumor). All procedures were performed 1 week after implantation of VX2 tumors (week 1). In addition, a VX2 tumor rechallenge test was performed in the RFA and combination therapy groups. Survival time was evaluated by means of the Kaplan-Meier method and by using the log-rank test for intergroup comparison. Mean auricle tumor volumes were calculated every week. Specific growth rates (SGRs) were calculated and compared by using the Mann-Whitney test. RESULTS The median survival times of the control, RFA, OK-432, and combination therapy groups were 23, 36.5, 46.5, and 105 days, respectively. Survival was significantly prolonged in the combination therapy group when compared with the other three groups (P <.05). The mean auricle tumor volume decreased only in the combination therapy group. The mean auricle tumor volumes of the combination therapy group from week 1 to week 7 were 205, 339, 264, 227, 143, 127, and 115 mm(3). SGR in the combination therapy group became significantly smaller than those in the other three groups (P < .05). In the rechallenge test, the volume of all reimplanted tumors decreased. CONCLUSION Combining RFA with local injection of immunostimulant OK-432 may lead to indirectly activation of systemic antitumor immunity.

FDG-MicroPET and Diffusion-Weighted MR Image Evaluation of Early Changes After Radiofrequency Ablation in Implanted VX2 Tumors in Rabbits

The objective of this study was to evaluate the early changes after radiofrequency ablation (RFA) in VX2 rabbit tumors implanted into the back muscles by diffusion-weighted magnetic resonance (MR) imaging and 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET). Percutaneous CT-guided RFA was conducted in seven rabbits with implanted VX2 tumors. VX2 tumors on the other side were untreated and served as the control. MR imaging was performed with a clinical 1.5-T instrument 2 days after RFA, and FDG-PET, using a high-resolution PET scanner for small animals, was obtained 3 days after the procedure. The mean apparent diffusion coefficient (ADC) values and radioactivity count of untreated and ablated tumors were calculated. Untreated VX2 tumors showed hyperintensity on T1-, T2-, and diffusion-weighted MR images, ring-enhanced on contrast-enhanced T1-weighted imaging, and ring-shaped FDG accumulation on FDG-PET. Ablated VX2 tumors showed slight hyperintensity on T1-, T2-, and diffusion-weighed images, slight enhancement on contrast-enhanced T1-weighted images, and low accumulation on FDG-PET. The ADC value of ablated VX2 tumors (1.52 ± 0.24 × 10−3 mm2/s) was significantly higher than that of untreated tumors (1.09 ± 0.12 × 10−3; p < 0.05). The tumor/muscle ratio of ablated tumors (0.5 ± 0.3) was significantly lower than that of untreated tumors (11.6 ± 3.2; p < 0.05). Histopathological examination confirmed the lack of viable tumor cells in the ablated lesions. The results indicate that both ADC value and FDG-PET are potentially useful markers for monitoring the early effects of RFA.