Naofumi Shinagawa

Virtual bronchoscopic navigation combined with endobronchial ultrasound to diagnose small peripheral pulmonary lesions: a randomised trial

Background Bronchoscopy using endobronchial ultrasound (EBUS) can help to diagnose small peripheral pulmonary lesions. However, although biopsy sites can be confirmed, a bronchoscope cannot be guided in EBUS. Virtual bronchoscopic navigation (VBN) can guide a bronchoscope with virtual images, but its value has not been confirmed. Methods This prospective multicentre study examines the value of VBN-assisted EBUS for diagnosing small peripheral pulmonary lesions. 199 patients with small peripheral pulmonary lesions (diameter ≤30 mm) were randomly assigned to VBN-assisted (VBNA) or non-VBN-assisted (NVBNA) groups. A bronchoscope was introduced into the target bronchus of the VBNA group using the VBN system. Sites of specimen sampling were verified using EBUS with a guide sheath under fluoroscopy. Results The diagnostic yield was higher for the VBNA than for the NVBNA group (80.4% vs 67.0%; p=0.032). The duration of the examination and time elapsed until the start of sample collection were reduced in the VBNA compared with the NVBNA group (median (range), 24.0 (8.7–47.0) vs 26.2 (11.6–58.6) min, p=0.016) and 8.1 (2.8–39.2) vs 9.8 (2.3–42.3) min, p=0.045, respectively). The only adverse event was mild pneumothorax in a patient from the NVBNA group. Conclusions The diagnostic yield for small peripheral pulmonary lesions is increased when VBN is combined with EBUS. Clinical trial number UMIN000000569.

Anti‐OX40 monoclonal antibody therapy in combination with radiotherapy results in therapeutic antitumor immunity to murine lung cancer

The therapeutic effect of agonistic anti‐OX40 (CD134) monoclonal antibody (mAb) in combination with radiotherapy was evaluated in a murine lung cancer model. After intradermal transplantation of ovalbumin (OVA)‐transfected Lewis lung carcinoma, C57BL/6 mice were irradiated locally with a single dose of 20 Gy in combination with an intratumoral injection of anti‐OX40 mAb at 50 µg on day 4 after transplantation, which is when the major axis of the inoculated tumor reached a diameter of 7–9 mm. On days 8, 11, and 14, the tumor‐bearing mice were further treated with the same dose of anti‐OX40 mAb. Anti‐OX40 mAb in combination with radiotherapy prolonged survival and provided greater efficacy than either single treatment against well‐established tumors. An in vivo depletion study suggested that therapeutic immunity was mainly CD8+ T‐cell dependent. OX40+CD8+ T cells were augmented in draining lymph nodes obtained from irradiated mice compared with those from non‐irradiated mice. OVA‐major histocompatibility complex tetramer+ CD8+ T cells had been strongly recruited to the draining lymph nodes obtained from mice treated with anti‐OX40 mAb in combination with radiotherapy, and strong antigen‐specific cytotoxicity was confirmed by a 51Cr‐release assay. Moreover, a tumor‐rechallenge model indicated that this combination therapy induced durable tumor immunity. Thus, anti‐OX40 mAb in combination with radiotherapy may potentially help the management of patients with lung cancer. (Cancer Sci 2008; 99: 361–367)

Virtual Bronchoscopic Navigation Combined with Ultrathin Bronchoscopy. A Randomized Clinical Trial

RATIONALE In bronchoscopy, an ultrathin bronchoscope can be advanced to more peripheral bronchi. Because virtual bronchoscopic navigation (VBN) is a method to guide a bronchoscope under direct observation using VB images, VBN may be particularly useful when combined with ultrathin bronchoscopy. OBJECTIVES This prospective multicenter study evaluated the value of VBN-assisted ultrathin bronchoscopy for diagnosing peripheral pulmonary lesions. METHODS We randomly assigned 350 patients with peripheral pulmonary lesions (diameter, ≤30 mm) to VBN-assisted or non-VBN-assisted groups. An ultrathin bronchoscope (outer diameter, 2.8 mm) was introduced to the target bronchus using a VBN system in the VBN-assisted group, whereas only computed tomography axial images were referred to in the non-VBN-assisted group. Specimen sampling sites were verified using X-ray fluoroscopy. MEASUREMENTS AND MAIN RESULTS Subjects for analysis included 334 patients. There was no significant difference in the diagnostic yield between the VBN-assisted group (67.1%) and the non-VBN-assisted group (59.9%; P = 0.173). The subgroup analysis showed that the diagnostic yield was significantly higher in the VBN-assisted group than in the non-VBN-assisted group for right upper lobe lesions (81.3% vs. 53.2%; P = 0.004); lesions invisible on posterior-anterior radiographs (63.2% vs. 40.5%; P = 0.043); and lesions in the peripheral third of the lung field (64.7% vs. 52.1%; P = 0.047). CONCLUSIONS VBN-assisted ultrathin bronchoscopy does not improve the diagnostic yield for peripheral pulmonary lesions. However, the method improves the diagnostic yield for lesions in the subcategories (right upper lobe, invisible, peripheral third), warranting further study. Clinical trial registered with www.umin.ac.jp/ctr/ (UMIN 000001536).

Stereotactic body radiotherapy using gated radiotherapy with real-time tumor-tracking for stage I non-small cell lung cancer

BackgroundTo clarify the clinical outcomes of two dose schedule of stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC) using a real-time tumor-tracking radiation therapy (RTRT) system in single institution.MethodsUsing a superposition algorithm, we administered 48 Gy in 4 fractions at the isocenter in 2005–2006 and 40 Gy in 4 fractions to the 95% volume of PTV in 2007–2010 with a treatment period of 4 to 7 days. Target volume margins were fixed irrespective of the tumor amplitude.ResultsIn total, 109 patients (79 T1N0M0 and 30 T2N0M0). With a median follow-up period of 25 months (range, 4 to 72 months), the 5-year local control rate (LC) was 78% and the 5-year overall survival rate (OS) was 64%. Grade 2, 3, 4, and 5 radiation pneumonitis (RP) was experienced by 15 (13.8%), 3 (2.8%), 0, and 0 patients, respectively. The mean lung dose (MLD) and the volume of lung receiving 20 Gy (V20) were significantly higher in patients with RP Grade 2/3 than in those with RP Grade 0/1 (MLD p = 0.002, V20 p = 0.003). There was no correlation between larger maximum amplitude of marker movement and larger PTV (r = 0.137), MLD (r = 0.046), or V20 (r = 0.158).ConclusionsSBRT using the RTRT system achieved LC and OS comparable to other SBRT studies with very low incidence of RP, which was consistent with the small MLD and V20 irrespective of tumor amplitude. For stage I NSCLC, SBRT using RTRT was suggested to be reliable and effective, especially for patients with large amplitude of tumor movement.

Endobronchial Ultrasonography with a Guide Sheath for Pure or Mixed Ground-Glass Opacity Lesions

Background: Ground-glass opacity (GGO) lesions are difficult to diagnose by transbronchial biopsy (TBB). Objectives: We attempted to diagnose solitary peripheral GGO predominant-type lesions by TBB using endobronchial ultrasonography with a guide sheath (EBUS-GS) under X-ray fluoroscopic guidance, and to evaluate several factors associated with diagnostic yield. Methods: The medical records of 67 patients with GGO predominant-type lesions who underwent TBB using EBUS-GS under X-ray fluoroscopic guidance were retrospectively reviewed. Results: Of the 67 lesions, 38 (57%) were successfully diagnosed by EBUS-GS (5/11 pure GGO lesions and 33/56 mixed GGO lesions). The diagnosable lesions were significantly larger than the nondiagnosable lesions (24 vs. 17 mm, respectively; p < 0.01). Regarding the diagnostic yield by signs on computed tomography, the lesions with a bronchus leading directly to a lesion had a significantly higher diagnostic yield than the others (p < 0.05). When GGO lesions were confirmed under X-ray fluoroscopic guidance, the diagnostic yield was 79% (vs. 40% in lesions not visible on X-ray fluoroscopy; p < 0.05). Conclusions: EBUS-GS is a useful and valuable diagnostic modality, even for GGO predominant-type lesions located at the lung periphery.

Endobronchial Ultrasonography With a Guide Sheath in the Diagnosis of Benign Peripheral Diseases

BACKGROUND For appropriate treatment, such as the selection of antibiotics or initiation of steroid therapy, correctly diagnosing benign pulmonary diseases located at the periphery is vital. This study assessed the usefulness of bronchoscopy using endobronchial ultrasonography with a guide sheath (EBUS-GS) in the diagnosis of benign pulmonary diseases, especially those presenting peripheral nodular lesions. METHODS We retrospectively reviewed 159 patients with 171 peripheral pulmonary lesions (PPLs) that were subsequently diagnosed as benign diseases. To examine the role of bronchoscopy with EBUS-GS, the contribution of bronchoscopy was classified into 4 categories. We also retrospectively reviewed 24 patients with 25 PPLs that were subsequently diagnosed as benign diseases by bronchoscopy without EBUS-GS (historical control). RESULTS The ultimate diagnosis of 171 PPLs included 45 cases of mycobacteriosis, 45 cases of bronchiolitis obliterans organizing pneumonia/chronic organized pneumonia (BOOP), 23 cases of bacterial pneumonia, 13 abscesses, 11 cases of sarcoidosis, and 34 other benign diseases. Among them, a definitive diagnosis was obtained by bronchoscopy with EBUS-GS in 99 lesions (58%). Lesions in which the probe was positioned within the lesion had a higher diagnostic yield (64%) than did lesions in which the probe was positioned adjacent to the lesion (52%) or outside the lesion (20%; P=0.01). The diagnostic yield of bronchoscopy with EBUS-GS was higher compared with that of the historical control (58% versus 28%; P=0.04). CONCLUSIONS Bronchoscopy using EBUS-GS is a reasonable option as a diagnostic procedure for PPLs, even if they are suspected to be benign in nature.

Combining transbronchial biopsy using endobronchial ultrasonography with a guide sheath and positron emission tomography for the diagnosis of small peripheral pulmonary lesions

To evaluate the combination of transbronchial biopsy (TBB) using endobronchial ultrasonography with a guide sheath (EBUS-GS) and positron emission tomography with fluorodeoxyglucose (FDG-PET) for the diagnosis of small peripheral pulmonary lesions (PPLs) < or = 30 mm in mean diameter. A total of 74 PPLs (69.2%) were diagnosed by TBB using EBUS-GS with X-ray fluoroscopy. Diagnostic yield by FDG-PET was 78.5% for the 107 PPLs examined. Diagnostic yield with the combination of TBB using EBUS-GS and FDG-PET (90.7%) was significantly higher compared with that for each procedure alone. A significant increment in diagnostic yield with this combination was seen for PPLs >20mm and < or = 30 mm and for malignant lesions. Combination of TBB using EBUS-GS and FDG-PET is useful for the diagnosis of small PPLs.

Granulocyte-Macrophage Colony-Stimulating Factor Gene-Transduced Tumor Cells Combined with Tumor-Derived gp96 Inhibit Tumor Growth in Mice

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-based cancer cell vaccines have been shown to be potent inducers of antitumor immunity in several murine models, but the antitumor effects on established tumors have been minimal. Conversely, the major role of the heat shock protein gp96, localized in the endoplasmic reticulum (ER), is to act as a molecular chaperone to assist the folding of nascent polypeptide chains in the ER. gp96 derived from tumor cells elicits specific protective immunity against parental tumors, presumably through the transport of tumor-specific peptides to antigen-presenting cells and the maturation of dendritic cells (DCs). However, the therapeutic effects of tumor-derived gp96 on established tumors have not been promising. The present study analyzes the therapeutic effects of GM-CSF gene-transduced Lewis lung cancer (LLC/GM) cells combined with LLC-derived gp96 on established wild-type LLC tumors in immunocompetent C57BL/6 mice. Therapy with either irradiated LLC/GM cells or LLC-derived gp96 barely affected established LLC tumor growth. The antitumor effect was significantly enhanced when 1 microg of LLC-derived gp96 was administered together with 1 x 10(6) irradiated LLC/GM cells (p < 0.05). The antitumor effects of irradiated LLC/GM cells and LLC-derived gp96 required mainly CD8(+) T cells. Spleen cells obtained from mice vaccinated with irradiated LLC/GM cells and LLC-derived gp96 showed specific CD8 cytotoxic activities against LLC cells (specific lysis rate of approximately 28%). This antibody response was not associated with a synergic effect of the combination therapy. Moreover, draining lymph nodes from mice immunized with irradiated LLC/GM cells and LLC-derived gp96 contained more migrating mature CD11c(+) cells (higher levels of CD86 and major histocompatibility complex [MHC] class II molecules) compared with those from any other immunization protocols. These results suggest that the combination of irradiated LLC/GM cells and tumor-derived gp96 has potential as a new immunogene therapeutic strategy against lung cancer.

Virtual Bronchoscopic Navigation Improves the Diagnostic Yield of Radial-Endobronchial Ultrasound for Peripheral Pulmonary Lesions with Involved Bronchi on CT

OBJECTIVE Bronchoscopy using radial-endobronchial ultrasound (R-EBUS) and virtual bronchoscopic navigation (VBN) is a promising method for diagnosing peripheral pulmonary lesions. We previously performed a randomized comparative trial (RCT) (i.e., VBN combined with EBUS RCT) involving patients with 30-mm or smaller peripheral pulmonary lesions and found that the addition of VBN to R-EBUS improved the diagnostic yield. In the present study, we performed a retrospective subanalysis in order to identify patients for whom VBN is useful. METHODS The per-protocol population (194 cases) of the VBN combined with EBUS RCT was divided into subgroups based on the lesion size, lung lobe containing the lesion, lesion location, presence or absence of involved bronchi (bronchus sign) on thin-section CT and whether the lesion was detected on posterior-anterior (P-A) radiographs. The difference in the diagnostic yield between the VBN-assisted (VBNA) and non-VBN-assisted (NVBNA) groups was investigated. RESULTS Within the bronchus sign-positive subgroup, the diagnostic yield in the VBNA and NVBNA groups was 94.4% (68/72) and 77.8% (56/72), respectively, showing a significantly higher yield in the VBNA group (p=0.004; odds ratio: 4.9). The yield was particularly high for lesions smaller than 20 mm (94.6% vs. 70.7%; p=0.006), lesions located in the peripheral third of the lung field (95.1% vs. 71.4%; p=0.005) and lesions invisible on P-A radiographs (90.0% vs. 41.7%; p=0.026). CONCLUSION VBN improves the diagnostic yield when combined with R-EBUS to assess lesions exhibiting involved bronchi on CT images.

Susceptibility to oxygen desaturation during bronchoscopy in elderly patients with pulmonary fibrosis

Background: Fiber-optic flexible bronchoscopy (FFB) is a frequently performed procedure for the diagnosis and treatment of pulmonary disorders. However, hypoxemia occasionally occurs during FFB. Objectives: We attempted to examine the causes of arterial oxygen desaturation during FFB. Methods: We studied 336 patients who underwent FFB without intervention between June 1, 2001 and September 30, 2002. Arterial oxygen saturation (SpO2) was continuously monitored using oximetry with a recording system. We analyzed the relationship between a reduction in SpO2 during FFB and various clinical parameters or background lung diseases. Results: Of the 336 patients, 73 (22%) had an episode of oxygen desaturation (SpO2 <90% over 10 s). Of patients over 80 years old, 55% had an episode of oxygen desaturation, which was significantly higher than 27% observed in the patients of 80 and less than 80 years old (p < 0.05). Patients with pulmonary fibrosis had a higher risk of desaturation (55%) compared to patients with other complications or patients without any complication (p < 0.05). Multivariable analysis revealed that both age and pulmonary fibrosis were independent predictors of oxygen desaturation. However, the majority of the patients (94%) did not require routine oxygen supplementation. Conclusion: Although FFB is safe and does not require oxygen supplementation in most cases, age over 80 years and pulmonary fibrosis are high risk factors for significant oxygen desaturation during FFB.