Virtual Library

Background
The impact of primary procedure and procedure sequence has not been studied in combined application of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in lung cancer staging.

Methods
In a randomized controlled trial, 160 patients with histologically confirmed or strongly suspected potentially operable non-small cell lung cancer were enrolled (Group A, n=80, EBUS-centered; Group B, n=80, EUS-centered). In Groups A and B, EBUS-TBNA and EUS-FNA with ultrasound bronchoscope were used as the first procedure, respectively, and secondary procedures were added.

Results
Diagnostic values were evaluated in 148 patients (74 in each group). In Groups A and B, the diagnostic accuracy (93.2% vs. 97.3%, respectively, p=0.2454) and sensitivity (85.3% vs.92.0%, respectively, p=0.4312) in detecting mediastinal metastasis were not statistically different. In Group A, adding EUS-FNA to EBUS-TBNA did not significantly increase the accuracy (91.9% to 93.2%; p=0.7540) and sensitivity (82.4% to 85.3%; p=0.7419). In group B, adding EBUS-TBNA to EUS-FNA increased the accuracy (86.5% to 97.3%; p=0.0160) and sensitivity (60.0% to 92.0%; p=0.0081). There were no inter-group differences in procedure time, cardio-respiratory parameters during procedures, complications, or patient satisfaction.

Conclusion
In combination of EBUS-TBNA and EUS-FNA in mediastinal staging, diagnostic values and patient satisfaction were not different between EBUS-centered and EUS-centered group. However, the necessity of EBUS-TBNA following EUS suggests EBUS-TBNA is a better primary procedure in endoscopic mediastinal staging.

Background
Expert analysis of endobronchial ultrasound (EBUS) images obtained with the mini probe (MP) has established certain subjective criteria for predicting benign or malignant disease. Minimal data is available for objective analysis of these images. The aim of this study was to determine if greyscale texture analysis of EBUS-MP images could differentiate between benign and malignant peripheral lung lesions.

Methods
Digital EBUS-MP images with contrast set at 4 and gain set at 10 were included in this study. A region of interest (ROI) was mapped for each image and analysed in a prediction set. The ROIs were analysed for the following greyscale texture features in MATLAB (v7.8.0.347 (R2009a)); mean pixel value, difference between maximum and minimum pixel value, standard deviation of the mean pixel value, entropy, correlation, energy and homogeneity. Significant greyscale texture features were used to assess a validation set. Figure 1

Results
Eighty-five peripheral lung lesions were in the prediction set (47 malignant and 38 benign). Benign lesions had larger differences between maximum and minimum pixel values, larger standard deviations of the mean pixel values and a higher entropy than malignant lesions (p<0.0001 for all values). Eighty two peripheral lesions were in the validation set; 63/82 (76.8%) were correctly classified. Of these 45/49(91.8%) malignant lesions and 18/33 (54.5%) benign lesions were correctly classified. The negative predictive value for malignancy was 82% and the positive predictive value was 75%. Figure 1

Conclusion
Greyscale texture analysis of EBUS-MP images could assist in differentiating between benign and malignant peripheral lung lesions but tissue diagnosis is still important.

Background
Due to a widespread use of a CT there is recently increased incidence of smaller peripheral lung lesions. Because of an obvious need for a morphological verification new bronchoscopy methods for biopsy of such small peripheral lesions are needed. We have utilized two methods of spectroscopic detection in peripheral lung cancer. In vivo method- NIR spectroscopy of penetrating light and ex vivo method-Raman spectroscopy of biopsy specimens. Correlation of these two methods gives us the insight into molecular biology of in vivo spectroscopic measurement. In vivo NIR spectroscopy together with transbronchial biopsy under fluoroscopic guidance appears to be useful and reliable method for peripheral lung cancer diagnosis.

Methods
We have designed a simple instrument for measurement of a penetrated NIR light through the lung tissue. It consists of two fibres of 1 mm in diameter contained in one bundle covered with insulation sleeving. One of the fibres is a detector; the other is a source fibre. The indicator fibre is 1,5 cm longer than the source fibre and it is separately covered with insulation till its ending. The ending is cut in the angle of 60 degrees and titan coated in order to facilitate NIR light transmission toward detector fibre. The detector fibre is connected to NIR spectroscope and the source fibre to NIR source. The instrument for ex vivo Raman spectroscopy measurement has been derived from above described system. The endings of fibres have been grinded down perpendicularly in order to allow systematic Raman measurement.

Results
In vivo measurement: Measurements of a normal lung tissue at various areas of a lung tissue show characteristic peak at 735 nm which is not present during cancer tissue spectroscopy. In cancer tissue in addition all detected spectra have got fixed ratio (with minimal dispersion) of two standardized transmittance values at two chosen wavelengths (773 and 823 nm)- mirroring the source values with its mild modification by tissue auto fluorescence. By help of those findings we utilized endobronchial measurement of NIR transmittance spectra in attempt to improve sensitivity of trans bronchial biopsy under fluoroscopic guidance. Ex vivo measurement: Biopsy specimens has been immediately transferred to Raman spectroscope laboratory (within 10 minutes) on temperature 8-10°C. For tissue Raman studies we used excitation at 785 nm. Raman spectra in the 700-1,800 cm(-1) range from lung tissue biopsies were obtained within 10 sec. Raman Spectroscopy results from biopsy specimens taken from the in vivo spectroscopy pathological areas showed higher signals for nucleic acid, tryptophan and lower signals for phospholipids and proline, compared to normal tissue.

Conclusion
In vivo NIR spectroscopy together with transbronchial biopsy under fluoroscopic guidance appears to be useful and reliable method for peripheral lung cancer diagnosis. Ex vivo Raman spectroscopy confirmed diagnostics value of in vivo measurements. Such device or its modifications could be easily included for example into the examination by electromagnetic navigation.

Abstract not provided

Background
Adequate tumour samplings for biological analyses are currently of major importance in treating oncological patients. Obtaining histological samplings from the primary lung cancer can be a challenge due to tumour accessibility, small biopsies or tolerance to bronchoscopy such as bleeding or dyspnoea in case of limited airflow capacity. The ELCWP developed a multicentre prospective study searching for predictive factors for response to chemotherapy based on genomic analyses. We aim to analyse the capability in obtaining adequate tumour samplings from the primary non small cell lung cancer (NSCLC) for studying the transcriptome (miRNA and mRNAs) with high throughput techniques.

Methods
All patients presenting with a suspected lung cancer were proposed participating to the study. To be evaluable for the primary endpoint of the study, patients needed to have a confirmed diagnosis of NSCLC treated with chemotherapy and assessable for response. During the diagnostic bronchoscopy, 3 biopsies were collected from the primary tumour, with a control sample from normally appearing bronchial mucosa. One was formalin fixed and paraffin embedded for pathological diagnosis. A second was used for transcriptome analysis and the third one was frozen and stored in a tissue bank. We are presenting the flow chart of the patients screened for entry in the ELCWP study and the limitations for obtaining tumour samplings in assessable patients.

Results
From 1/04/2009 to 12/06/2013, 307 patients suspected to have NSCLC were prospectively registered. Eleven are under evaluation for pending histological confirmation leaving 296 patients evaluable for the present analysis. In 25 cases, no lung cancer confirmation was obtained (other tumour n = 12, no pathological confirmation at all n = 6, benign lesion n = 6, other reason n = 1) and 6 further patients withdrew their initial consent. Among 265 pathologically confirmed lung cancer (samples obtained during bronchoscopy or by another technique), 38 small cell lung cancers (SCLC) and 227 NSCLC were diagnosed. In addition to the diagnostic biopsy, further samplings for genomic analyses could be obtained during the same bronchoscopy in 30/38 SCLC (79%) and 116/227 NSCLC (51%). Among 227 NSCLC, 107 were presenting with an advanced disease treated with a cisplatin-based chemotherapy and were assessable for response to chemotherapy (primary study endpoint). Among these 107 patients, 59 adequate tumour samplings could be obtained for transcriptome analysis (20% from the initial cohort and 55% among assessable patients).

Conclusion
This analysis of a prospective multicentre study is showing the difficulties and limitations in obtaining adequate tumour samplings for biological analyses when conducting translational cooperative research in non-small cell lung cancer.

Background
Tumor localization and the precise evaluation of tumor invasion are most important for the management of central type early stage lung cancer (CELC) and Photodynamic therapy (PDT) has come to be considered as the first choice of treatment for CELC. The present guidelines of PDT for CELC were established based mainly on the data obtained from studies since 1980’s. CELCs less than 1 cm in diameter showed a favorable cure rate by PDT, thus this was a good standard to decide the indications of PDT. To obtain complete response (CR) by PDT, evaluation of each lesion is extremely important, including the extent of the tumor on the bronchial surface and the depth of invasion in the bronchial wall. We postulate that the combination of comprehensive diagnosis and the new generation of photosensitizers may increase the CR rate and expand the indications of PDT for larger tumors.

Methods
Autofluorescence bronchoscopy (AFB) has been used in the objective evaluation of the margin of the tumor before endoscopic treatment and Endobronchial ultrasonography (EBUS) has been employed to determine the depth of tumor invasion. Ooptical coherence tomography (OCT) has been investigated for clinical use as well. Also, the relatively newer photosensitizer NPe6, which has a stronger antitumor effect than Photofrin has been extensively used for PDT. We routinely used these diagnostic methodologies and NPe6 since 2004.

Results
A total of 122 consecutive CELCs were treated by PDT using NPe6 in Tokyo Medical University and CR was obtained in 115 lesions (CR rate 94.3%). Of the 122 lesions examined in this study, 78 had a diameter of ≦1.0 cm and the rest of the 44 cancer lesions were >1.0 cm in size. The CR rate of CELC ≦1.0 cm in diameter was 93.6% (73/78) and for those >1.0 cm in diameter, 95.5% (42/44), respectively. There was no significant difference between tumor size and clinical response. The CR rate to NPe6-PDT is higher than that of Photofrin-PDT in our previous studies. This early result suggests that PDT with NPe6 has a stronger antitumor effect than Photofrin therefore similar treatment outcome even for larger tumors >1.0 cm in diameter should be possible.

Conclusion
Objective evaluation by a comprehensive approach using AFB and EBUS enables to select the optimal therapeutic strategy for CELC. These results suggest that PDT with NPe6 may have a similar treatment outcome regardless of tumor size, as long sufficient laser illumination of the entire tumor is possible.

Background
The intra-operative diagnosis of pleural malignancy may facilitate surgical decision-making including the need for pleurodesis. A scanning laser confocal endomicroscopy device has been developed which allows histological-detail optical imaging of subsurface tissues in vivo. Confocal laser microscopy illuminates and detects light from a fixed point of a specimen which is scanned across a tissue plane and adjustable depths, providing a 3D structural view in a living body. Applied to screening of mucosal lesions in patients undergoing GI endoscopy, endomicroscopy obviates the need for many tissue biopsies and operators can rapidly learn to identify malignant tissues.

Methods
We performed the first intra-operative examination of pleural tissues using this equipment which is a thoracoscope-mounted endomicroscope device in patients administered iv fluorescein prior to imaging. Intra-operative endomicroscopic images were correlated with biopsies of pleural tissues.

Results
Sixteen patients were imaged: including mesothelioma 5 (2 biphasic) and pleural metastases from malignancies of lung 2, ovary 2 and one case each of breast, adenoidcystic (see figure), thyroid, colorectal, carcinoid and non-Hodgkin’s lymphoma, and also one benign case. We were able to image and identify normal mesothelium, sub-mesothelium, connective tissues and blood vessels (including RBC). Malignant cells and clusters of cells had a characteristic appearance including poor uptake of fluorescein and cellular pleomorphism. Appearances of mesothelioma correlated closely with histology. Glandular and papillary structures were identified in metastatic pleural tumour. In ovarian cancer calcification was readily identified as were psammoma bodies, while the typical cystic spaces surrounded by small dark cells mirrored closely the histological appearances of adenoidcystic carcinoma.

Conclusion
Images obtained on scanning confocal endomicroscopy of pleural malignancy generally correlated well with the histological appearance on biopsies. We plan now to extend our experience of malignancy and also the ability to discriminate between benign disease and malignancy of the pleura. Supported by a Tumour Stream Grant from the Victorian Cancer Agency. Figure: Endomicroscopy image of pleural metastases from adenoidcystic carcinoma of the parotid. Figure 1

Abstract not provided

Abstract not provided

Abstract
In lung cancer field, the direction of treatment strategy is in the midst of great change since molecular-targeted-drug was introduced. One of the revolutionary drugs is EGFR-TKI for EGFR positive lung cancer. It contributes to the treatment not only of advanced lung cancer, but also resectable early lung cancer in stage II and III. Although it is common to conduct surgery as the standard of care for early-stage lung cancer treatment, Stage II and III cases show poor prognosis even though complete resection is done. According to Asamura et al, 5-year survival of stage IIA, IIB and IIIA Japanese patients are 61%, 47% and 32% respectively. In response to these results, many investigators have been trying neoadjuvant and adjuvant chemotherapy in combination with surgery. In many cases, relapse after standard resection is distant metastasis, thus it is suspected that in order to achieve better prognosis, possible micrometastasis in whole body needs to be eradicated. Currently combination therapy with platinum-doublet is commonly chosen as the strong treatment regimen for controlling the micrometastasis in advanced cancer cases. Gefitinib is an EGFR-TKI (tyrosine kinase inhibitor) approved for the treatment of unresectable or recurrent NSCLC. Since its approval in Japan in July 2002, it has been approved in about 70 countries and used as the therapeutic medication for advanced recurrent NSCLC (at the point of August 2010). When Gefitinib was initially released, 3 to 5% of drug-related ILD (Interstitial Lung Disease) and deaths were reported in Japan. After cohort study, it has been reported that those who are male, smoker, have the past illness of ILD and have low PS showed the higher ILD incidence rate than other cohorts. In 2004, it has been reported that Gefitinib shows the remarkably high response rate for EGFR positive patients, and subsequent studies demonstrated that EGFR mutation is an efficacy predictive biomarker.It is commonly known that Gefitinib induces apoptosis in EGFR positive patients. In fact, some clear anti-tumor effect have been observed in many clinical studies targeting on EGFR positive advanced NSCLC patients. The result of post-marketing Phase III clinical trial targeting on Asian patients untreated with chemotherapy (IPASS trial)was reported in September 2008. According to pre-planned subgroup analysis based on biomarker, in EGFR positive patient group Gefitinib cohort showed the significant prolongation of PFS (Progression Free Survival) compared to Carboplatin plus Paclitaxel cohort (HR 0.48, 95% CI 0.36～0.64, p<0.0001). In addition, Gefitinib cohort showed better efficacy, QOL, safety and tolerability. However, in terms of OS (Overall Survival), the difference was not observed in two cohorts (HR 1.00, 95% CI 0.76～1.33, p=0.990). On the other hand, in EGFR negative patient group, Carboplatin plus Paclitaxel cohort significantly prolonged PFS compared to Gefitinib cohort (HR 2.85, 95% CI 2.05～3.98, p<0.0001). It was reported from Japan that in the two Phase III controlled study targeting on EGFR positive advanced lung cancer patients untreated with chemotherapy, Gefitinibcohort showed better PFS (Hazard Ratio of less than 0.5) than standard chemotherapy cohort of Cisplatin plus Docetaxel (HR 0.489, 95% CI 0.336～0.710, p<0.0001) or Carboplatin plus Paclitaxel (HR 0.357, 95% CI 0.252～0.507, p<0.001) in both studies. However, the comparison of 2-year survival in the controlled study of Carboplatin plus Paclitaxel, there was no statistically significant difference (Gefitinib: 61.4%, Standard Chemotherapy of CBDCA plus PTX: 46.7%) (P=0.31). In addition, in two cohorts (Gefitinibvs CDDP plus DOC) there was no statistically significant difference in OS among them (HR 1.638, 95％CI 0.749～3.582, p=0.21), thus the superiority of Gefitinib was not demonstrated in terms of OS. In the above-mentioned three prospective controlled trial, it was demonstrated that Gefitinib dramatically prolongs PFS in EGFR positive NSCLC patients compared to standard chemotherapy, and shows high anti-tumor effect and improvement of QOL, but not in terms of OS. It is suspected this is partially because of the fact that in chemotherapy cohort many patients received Gefitinib after relapse. To sum up, Gefitinib shows higher anti-tumor effect than standard chemotherapy if the target patients are EGFR positive, and thus is an appropriate option as the adjuvant treatment regimen after complete resection. It was impliedfrom Phase I trial that Gefitinib shows anti-tumor effect for the solid tumor patients who did not benefit from standard of care or have no other treatment options and thus effective for various types of cancer. In Phase II monotherapy trial, Gefitinib showed clinically significant and continuous anti-tumor effect in locally-advanced or metastatic NSCLC patients previously treated with chemotherapy. Additionally, it improved the cancer symptoms in these patients. Orally administering 250mg or 500mg once per day showed the same level of efficacy. Although in Phase III monotherapy trial targeting on advanced NSCLC patients the efficacy of Gefitinib was demonstrated, there was no statistically significant difference in terms of OS, which is the primary endpoint. However, the response rate of Gefitinib cohort was higher than that of placebo cohort. In Phase III combination chemotherapy trial, standard chemotherapy (Gemcitabine/Cisplatin, Paclitaxel/Carboplatin) and Gefitinib 250mg per day or 500mg per day were evaluated. In this study however, statistically or clinically significant data superior to combination of standard chemotherapy with placebo was not observed. In conclusion, there are three reasons why patients with EGFR mutations should receive adjuvant EGFR-TKIs. Firstly, EGFR-TKI induces apoptosis and its exposition to EGFR positive patients potentially induces eradication of micrometastasis remaining after surgery. Secondly, for the EGFR positive patients, EGFR-TKI is superior to standard platinum-doublet in terms of safety and tolerability. Lastly, EGFR-TKI is the most potent anti-cancer drug for EGFR positive patients at the moment, which shows remarkable anti-tumor effect, prolongs PFS and improves QOL compared to platinum-doublet. Therefore, despite the issue of ILD remains, EGFR-TKI is to be considered as an appropriate treatment option in adjuvant setting for the EGFR positive patients. In order to prove this point, West Japan Oncology Group (WJOG) is currently conducting IMPACT trial, which is a prospective Phase III study.

Abstract
Adjuvant therapies are required to prevent disease recurrence and improve patient survival after surgery in early stage (stage I–IIIA) non-small cell lung cancer (NSCLC). In advanced disease, patients whose tumours have activating EGFR mutations have an approximately 60%-75% response rate to EGFR tyrosine kinase inhibitors (TKIs) treatment as first-line therapy and a progression-free survival that is significantly superior to standard chemotherapy. Although adjuvant TKI therapy is an appealing treatment strategy, can the remarkable efficacy of EGFR TKI in advanced EGFR-mutant NSCLC be extrapolated to stage I-IIIA disease? While adjuvant cisplatin-based chemotherapy prolongs survival with just 3-4 months of treatment, no trial to date has studied the value of a few months of adjuvant EGFR TKI. The phase III BR.19 trial by the National Cancer Institute of Canada designed to study 1,160 patients with fully resected stage IB, II and IIIA NSCLC randomised to receive 2 years of adjuvant gefitinib at 250 mg daily or 2 years of adjuvant placebo was greatly underpowered because enrolment was stopped prematurely when, in 2008, the SWOG 0023 investigators reported a worse overall median survival with maintenance gefitinib after definitive chemoradiation in a patient population not enriched for the presence of EGFR mutations with inoperable stage III NSCLC. EGFR mutation status was tested post-hoc in two thirds of 537 patients enrolled. There was no overall survival (OS) benefit for adjuvant gefitinib over placebo (HR 1.58; 95% CI, 0.83 - 3.0; P = 0.16) in 76 patients with EGFR mutant tumours. Despite an underpowered study, the negative finding should caution us about recommending adjuvant EGFR TKI therapy outside of a protocol setting. The phase III Randomized, Double-Blind Trial in Adjuvant NSCLC with Tarceva (RADIANT) compares 2 years of adjuvant erlotinib, at 150 mg orally per day, to 2 years of placebo following complete resection of stage I-IIIA NSCLC in 945 patients who were selected based on having either EGFR protein expression by immunohistochemistry or increased EGFR gene copy number by FISH. At the 2009 ASCO meeting, the RADIANT investigators presented the results of the biomarker analyses from the first 655 patients enrolled which showed an EGFR mutation-positive rate of 12%, which suggests that in the final result there will be approximately 38 EGFR mutation-positive patients on the placebo arm and about 76 on the erlotinib arm. This study is unlikely to provide sufficient power to a draw a firm conclusion about genotype-directed adjuvant therapy for patients with EGFR mutations. Investigators from the Memorial-Sloan Kettering Cancer Center reported a retrospective series of 167 patients at their centre with resected stages I-III NSCLC which were EGFR mutation-positive, among whom 32% received adjuvant EGFR TKI therapy. An improved 2-year disease-free survival (DFS) was observed in patients who received adjuvant TKI therapy compared to those who did not (89% vs 72%) (HR, 0.53; 95% CI, 0.28 - 1.03; P = 0.06). A trend toward more favorable 2-year OS in recipients of EGFR TKI therapy was also seen (96% vs 90%; HR 0.62, CI 0.26-1.51, P = 0.296). When the number of patients with resected EGFR mutant lung cancers was increased to 222, the same investigators in a more recent publication, showed treatment with adjuvant erlotinib or gefitinib was associated with a lower risk of recurrence or death, DFS HR 0.43 (95% CI: 0.26-0.72, P = 0.001), and a trend toward improved OS. The phase II SELECT (Surgically resected EGFR-mutant Lung cancer with adjuvant Erlotinib Cancer Treatment) trial is a single-arm, prospective study of two years of adjuvant erlotinib in 100 patients with resected, state IA to IIIA EGFR mutation positive NSCLC. Preliminary results presented at the 2012 ASCO meeting for the first 36 patients showed a DFS of 94% compared to a historical control of 70% with a median follow-up of 2.7 months. The answer provided by the SELECT trial is also unlikely to be definitive. The phase II/III Tailored Post-Surgical Therapy in Early Stage NSCLC (TASTE) trial by the French Collaborative Intergroup compares 4 cycles of standard cisplatin/pemetrexed (CP) adjuvant chemotherapy (arm A, n = 74) with customised adjuvant treatment (arm B, n = 76) based on EGFR and ERCC1 status in patients with completely resected stage IIA, IIB or IIIA (non-N2) (6[th] TNM edition) nonsquamous NSCLC. In the experimental arm, EGFR mutated patients received erlotinib 150 mg for one year. ERCC1 negative pts received four cycles of CP. EGFR mutation was identified in only 10 patients (3 in arm A, 7 in arm B). All 7 patients with EGFR mutation in arm B received erlotinib for a median duration of 276 days. The phase III was cancelled due to the unexpected unreliability of the ERCC1 immunohistochemistry read-out. Two randomised studies comparing gefitinib 250 mg daily for 2 years with adjuvant chemotherapy (4 cycles of cisplatin/vinorelbine) in patients with surgically resected stage IIA, IIB and IIIA EGFR mutation-positive adenocarcinoma are ongoing in Japan and in China (ADJUVANT CTONG 1104). In conclusion, it remains unclear whether targeted therapies improve outcomes over traditional chemotherapy in the adjuvant setting in NSCLC, and it is premature to recommend adjuvant EGFR TKI therapy outside well-designed clinical trials as there is currently no conclusive data on its role in early- and locally advanced NSCLC harbouring EGFR mutations. Given the consistent development of acquired resistance to EGFR TKI therapy in patients with metastatic NSCLC, there is good reason to question whether it is advisable to use EGFR TKI for adjuvant therapy in patients who have no evidence of disease and who can develop resistance to an otherwise effective treatment. Furthermore, the optimal duration of adjuvant therapy is yet to be defined and it is unknown whether EGFR TKI is merely by suppressing the growth of residual disease after surgery rather than eradicating minimal residual disease. Given the fact that adjuvant therapy needs to be given post-operatively for a prolonged period, the quality of life of patients while on therapy and the financial cost involved also need to be considered.

Abstract not provided