Junichi Maeda

Identification of postoperative adjuvant chemotherapy responders in non‐small cell lung cancer by novel biomarker

Cisplatin‐based (CDDP‐based) adjuvant chemotherapy of non‐small cell lung cancer (NSCLC) was reported to yield 5–15% improvement in 5‐year survival compared to complete resection alone. The importance of information concerning preselection of good responders has become increasingly evident. The purpose of our study is the establishment of a preselection of good responders for CDDP‐based adjuvant chemotherapy. We investigated protein expressions comparing intensity between parent strains (H69 and PC14 lung cancer cultured cells) and resistant strains against CDDP using 2‐dimensional polyacrylamide gel electrophoresis (2‐DE). Immunohistochemically, we evaluated the relationship between protein expression associated with CDDP‐resistance and the clinical effects of platinum‐based postoperative adjuvant chemotherapy using 126 surgically‐resected NCLC materials. We detected 2 kinds of polypeptides that changed expression levels on 2‐DE gels. The analyses of the amino acid sequence showed that these polypeptides were reticulocalbin (RCN) and glutathione‐S‐transferase‐π (GST‐π). The 2‐DE analysis showed decreased expression in RCN and overexpression in GST‐π with the acquisition of CDDP‐drug resistance. RCN‐transfectant of H69 CDDP‐resistant strain showed intermediate sensitivity between the parent strain and the CDDP‐resistant strain. RCN‐positive cases showed a statistically significant better disease‐free survival only in the cases receiving postoperative platinum‐based adjuvant chemotherapy after curative resection (p = 0.007). In addition, cases that were both RCN‐positive and GST‐π‐negative showed a statistically significantly better outcome (p = 0.0150). In the cases without postoperative adjuvant chemotherapy no relationship between the outcome and these expressions was seen. The evaluation of RCN and GST‐π might provide valuable information concerning postoperatively therapeutic strategy from the standpoint of individualized postoperative therapy.

Survival of a surgical series of lung cancer patients with synchronous multiple ground-glass opacities, and the management of their residual lesions

OBJECTIVES We reviewed the medical record of a series of patients with synchronous multiple lung cancers (SMLC), in an attempt to identify the optimal treatment strategy for multiple ground-glass opacities (GGOs). MATERIALS AND METHODS From 2004 to 2010, 1223 patients underwent complete resection of non-small cell lung cancer. Among these, there were 67 patients (5.5%) with SMLC with at least 1 of the nodules showing GGO appearance. SMLC was divided into the main cancer (MC) which was a main target based on its tumor size or radiological invasiveness and sub-nodules. According to consolidation/tumor ratio (CTR) on thin-section computed tomography, 67 cases were classified into GG-group (MC showing GGO-dominant lesion; CTR≤0.5) and GS-group (MC showing solid-dominant lesion; CTR>0.5). RESULTS There were 24 patients in the GG-group (36%) and 43 patients in the GS-group (64%). Surgical resections included 11 sublobar resections (SLs), 32 lobectomies, 19 lobectomy+SLs, and 4 bilobectomies. There were 39 patients with a total of 118 unresected GGOs after the initial surgery. Among them, the frequency of growth was 8% on a per-nodule basis with the median tumor doubling time of 1373 days, and new GGOs emerged in 15 patients (23%). Multivariate analysis demonstrated that larger size of MC and the GS-group was associated with poor prognosis, whereas growth of the residual GGOs, the development of new GGOs, or whether or not all GGOs were treated did not affect survival. The 5-year OS proportions were 95.8% for the GG-group and 68.0% for the GS-group (p=0.009), and 92.4% for a MC of ≤25 mm and 53.6% for a MC of >25 mm (p=0.008). CONCLUSION Survival of patients with multifocal GGOs is strongly affected by radiological findings of the MC. Strict surgical control for MC could be most important.

Tumor volume determines the feasibility of cell‐free DNA sequencing for mutation detection in non–small cell lung cancer

Next‐generation sequencing (NGS) and digital PCR technologies allow analysis of the mutational profile of circulating cell‐free DNA (cfDNA) in individuals with advanced lung cancer. We have now evaluated the feasibility of cfDNA sequencing for mutation detection in patients with non‐small cell lung cancer at earlier stages. A total of 150 matched tumor and serum samples were collected from non‐small cell lung cancer patients at stages IA–IIIA. Amplicon sequencing with DNA extracted from tumor tissue detected frequent mutations in EGFR (37% of patients), TP53 (39%), and KRAS (10%), consistent with previous findings. In contrast, NGS of cfDNA identified only EGFR, TP53, and PIK3CA mutations in three, five, and one patient, respectively, even though adequate amounts of cfDNA were extracted (median of 4936 copies/mL serum). Next‐generation sequencing showed a high accuracy (98.8%) compared with droplet digital PCR for cfDNA mutation detection, suggesting that the low frequency of mutations in cfDNA was not due to a low assay sensitivity. Whereas the yield of cfDNA did not differ among tumor stages, the cfDNA mutations were detected in seven patients at stages IIA–IIIA and at T2b or T3. Tumor volume was significantly higher in the cfDNA mutation‐positive patients than in the negative patients at stages T2b–T4 (159.1 ± 58.0 vs. 52.5 ± 9.9 cm3, P = 0.014). Our results thus suggest that tumor volume is a determinant of the feasibility of mutation detection with cfDNA as the analyte.

The Frequency and Prognostic Impact of Pathological Microscopic Vascular Invasion According to Tumor Size in Non-Small Cell Lung Cancer

BACKGROUND Microscopic vascular invasion (MVI) in patients with non-small cell lung cancer (NSCLC) has been reported to be a strong predictor of poor outcomes but it has not been a descriptor of the TNM classification. The purposes of this study were to determine whether the presence of MVI is related to a predictor of poor outcomes and to explore the degree of MVI according to tumor size. METHODS A total of 1,884 patients with stage pT1-4N0-2 NSCLC who underwent complete resection comprised the study sample. Overall survival (OS) and recurrence-free proportion were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used to assess independent predictors of poor outcomes. RESULTS Of 1,884 patients, 1,097 (58.2%) had MVI. Multivariate analysis showed MVI was a significant independent predictor of unfavorable OS (hazard ratio, 1.666; P < .001) and recurrence (hazard ratio, 2.268; P < .001). The frequency of MVI varied according to tumor size, and in each cohort of tumor sizes ≤ 2 cm, > 2 to 3 cm, and > 3 to 5 cm, there were significant differences in survival outcome by MVI status. The proportions of patients with a 5-year recurrence-free period with tumor sizes ≤ 2 cm, > 2 to 3 cm, and > 3 to 5 cm between MVI (+) and MVI (-) were 93.0% and 72.5% (P < .001), 90.8% and 63.3% (P < .001), and 86.4% and 59.9% (P < .001), respectively. CONCLUSIONS This study demonstrated that MVI was a strong predictor of poor outcomes and that the effect is more prominent in patients with tumor sizes ≤ 5 cm. Further analysis of survival and MVI should be collected for future revision of the TNM system.

Recurrent squamous cell carcinoma of the breast with undifferentiated features: report of a case.

Abstract.Squamous cell carcinoma of the breast is a rare type of cancer, the origin of which is still uncertain. We report a case of squamous cell carcinoma of the breast with a recurrent tumor that showed undifferentiated features. The patient was a 55-year-old woman who originally presented with a left breast mass in the upper outer quadrant. Echography showed a 46 × 29 × 23-mm mass with cavity formation, and aspiration cytology confirmed a diagnosis of squamous cell carcinoma. A modified radical mastectomy with level III lymph node dissection was performed. Pathologically, the tumor was composed of squamous cell carcinoma and noninvasive ductal carcinoma. A recurrent tumor showing undifferentiated features was detected in the left forechest 3 months after the operation, and tumorectomy with partial resection of the major and minor pectoralis muscles was performed. Despite intensive therapy including chemotherapy (CEF: cyclophosphamide, epirubicin, 5-fluorouracil) and irradiation (50 Gy), the patient died from pulmonary and skin metastases 20 months after her initial operation. The squamous cell carcinoma of the breast in this patient grew rapidly and her prognosis was poor. Immunohistochemical findings indicated the possibility that the squamous cell carcinoma developed from noninvasive ductal carcinoma of the comedo type, and that the undifferentiated cells from the site of recurrence developed from dedifferentiation of the squamous cell carcinoma.

Prognostic impact of the integration of volumetric quantification of the solid part of the tumor on 3DCT and FDG-PET imaging in clinical stage IA adenocarcinoma of the lung

OBJECTIVES The aim of this study was to conduct comparative analyses of the biological malignant potential of clinical stage IA adenocarcinoma using positron emission tomography/computed tomography (PET/CT), high-resolution CT (HRCT), and three-dimensional CT (3DCT). The predictive performance of these parameters was evaluated in terms of clinical outcomes and pathological invasiveness (positive lymphatic permeation, blood-vessel invasion, pleural invasion, and lymph-node metastasis). MATERIALS AND METHODS We enrolled 170 patients with c-IA adenocarcinoma who underwent PET/CT, HRCT, and 3D reconstruction of lung structures using the Synapse Vincent system (Fujifilm Corporation, Tokyo, Japan) followed by complete resection. Maximum standardized uptake values (SUVmax) of F18-fluorodeoxyglucose and the size and volume of the solid part of the tumor were quantified and analyzed in relation to surgical outcomes. RESULTS Univariate analysis demonstrated that all the three parameters and whole-tumor volume were associated with unfavorable disease-free survival (DFS), while the volume of the solid part was the independent predictor on multivariate analysis (p < .001). The receiver operating characteristic curves for pathological invasiveness, determined using the variables dichotomized at each cut-off level (SUVmax 2.4; solid-part size 1.23 cm; solid-part volume 779 mm3), showed that all were significantly correlated with pathological invasiveness and prognosis, whereas the combination of SUVmax and the solid-part volume was the most powerful predictor of survival and pathological invasiveness compared to any other parameters: the 4-year DFS and proportion of pathological invasiveness in patients with SUVmax > 2.4 and solid-part volume > 779 mm3 versus those with SUVmax ≤ 2.4 or solid-part volume ≤779 mm3 were 81.2% versus 98.3% (p < .001) and 84.3% versus 15.1% (p < .001), respectively. CONCLUSION In c-IA adenocarcinoma, the volume of the solid part of the tumor was the independent predictor for unfavorable DFS, and the integration of the volume of the solid part and SUVmax was highly beneficial for the prediction of survival and pathological invasiveness.

Maximizing Use of Robot-Arm No. 3 in Da Vinci–Assisted Thoracic Surgery

We have previously reported on the importance of appropriate robot-arm settings and replacement of instrument ports in robot-assisted thoracic surgery, because the thoracic cavity requires a large space to access all lesions in various areas of the thoracic cavity from the apex to the diaphragm and mediastinum and the chest wall. (1 - 3) Moreover, it can be difficult to manipulate the da Vinci Surgical System using only arms No. 1 and No. 2 depending on the tumor location. However, arm No. 3 is usually positioned on the same side as arm No. 2, and sometimes it is only used as an assisting-arm to avoid conflict with other arms ( Fig. 1 ). In this report, we show how robot-arm No. 3 can be used with maximum effectiveness in da Vinci-assisted thoracic surgery. [Figure: see text].

P3.09-23 Accuracy and Reproducibility of Touch Imprint Cytology in Resected Lung Cancer

uniformity, and variant call accuracy from FFPE TNA and DNA. For example, a single pool of 8 RNA and 16 DNA libraries yielded >500,000 reads for each library, with RNA fusions called with 189 to 11,274 reads and DNA mutations detected down to 5% variant allele frequency. Variant calls were 100% concordant with independent results and included mutations in EGFR, RAS, PIK3CA, and BRAF, along with fusions in ALK, RET, and NRG1 and skipped METex14. Conclusion: The co-detection strategy generated reliable quantitative information from low-input tumor FFPE DNA and TNA within three days. The simplicity and speed of the approach, coupled with a standardized workflow, has the potential to increase the accessibility of NGS analysis and accelerate the return of results for NSCLC patients.

Clinical applications of virtual navigation bronchial intervention

Background In patients with bronchial tumors, we frequently consider endoscopic treatment as the first treatment of choice. All computed tomography (CT) must satisfy several conditions necessary to analyze images by Synapse Vincent. To select safer and more precise approaches for patients with bronchial tumors, we determined the indications and efficacy of virtual navigation intervention for the treatment of bronchial tumors. Methods We examined the efficacy of virtual navigation bronchial intervention for the treatment of bronchial tumors located at a variety of sites in the tracheobronchial tree using a high-speed 3-dimensional (3D) image analysis system, Synapse Vincent. Constructed images can be utilized to decide on the simulation and interventional strategy as well as for navigation during interventional manipulation in two cases. Results Synapse Vincent was used to determine the optimal planning of virtual navigation bronchial intervention. Moreover, this system can detect tumor location and alsodepict surrounding tissues, quickly, accurately, and safely. The feasibility and safety of Synapse Vincent in performing useful preoperative simulation and navigation of surgical procedures can lead to safer, more precise, and less invasion for the patient, and makes it easy to construct an image, depending on the purpose, in 5-10 minutes using Synapse Vincent. Moreover, if the lesion is in the parenchyma or sub-bronchial lumen, it helps to perform simulation with virtual skeletal subtraction to estimate potential lesion movement. By using virtual navigation system for simulation, bronchial intervention was performed with no complications safely and precisely. Conclusions Preoperative simulation using virtual navigation bronchial intervention reduces the surgeons stress levels, particularly when highly skilled techniques are needed to operate on lesions. This task, including both preoperative simulation and intraoperative navigation, leads to greater safety and precision. These technological instruments are helpful for bronchial intervention procedures, and are also excellent devices for educational training.

Skin fluorescence following photodynamic therapy with NPe6 photosensitizer

BACKGROUND The second-generation photosensitizer NPe6 has strong anti-tumor effects with a much shorter photosensitive period than the first-generation photosensitizer Photofrin. Although photosensitive period has been reduced, skin photosensitivity is still a major side effect of photodynamic therapy (PDT). Therefore, we conducted a prospective study to investigate whether the NPe6 fluorescence intensity in skin after PDT could be measured effectively in human patients to improve the management of a patients photosensitive period. METHODS The NPe6 fluorescence measurements using a constructed fluorescence sensing system at the inside of the arm were acquired prior to and 5 and 10min after NPe6 administration as well as at the time of PDT (4-5h after administration), at discharge (2 or 3days after PDT), and at 1 or 2 weeks after PDT. Participants were interviewed as to whether they had any complications at 2 weeks after PDT. RESULTS Nine male patients and one female patient entered this study. Nine patients were inpatients and one patient was an outpatient. All of the measurements of NPe6 fluorescence in the skin could be obtained without any complications. The spectral peak was detected at the time of discharge (2-3days after administration) in most cases and it decreased at 1 or 2 weeks after PDT. CONCLUSIONS The fluorescence of NPe6 in the skin could be detected feasibly using the fluorescence sensing system in human patients. Measuring the relative concentration of NPe6 in the skin indirectly by measuring fluorescence intensity might be useful to predict the period of skin photosensitivity after PDT.