Pilot study on novel skin care method by augmentation with Staphylococcus epidermidis, an autologous skin microbe--A blinded randomized clinical trial.

BACKGROUND AND OBJECTIVE: Staphylococcus epidermidis is an autologous bacterium that is beneficial to skin health. Our goal was to develop a novel, personalized basic cosmetic that exploits this characteristic. METHODS: We conducted a double-blinded, randomized clinical trial on augmentation with S. epidermidis as a pilot study, in which S. epidermidis was collected from the subject, cultured for proliferation, and then continuously applied to the subject's own face before sleep twice per week for four weeks in order to increase colonization levels. RESULTS: The results showed that this treatment increased the lipid content of the skin and suppressed water evaporation, thereby markedly improving skin moisture retention. Moreover, augmentation with S. epidermidis maintained a low acidic condition on the skin surface. The low risk of undesirable effects induced by augmentation with S. epidermidis was also confirmed by measuring erythema and melanin levels. CONCLUSIONS: These results may serve as a driving force to accelerate the development of novel, personalized basic cosmetics.

Prognostic factors and the significance of treatment after recurrence in completely resected stage I non-small cell lung cancer.

OBJECTIVE: The objective of this study was to identify the clinicopathologic factors influencing postrecurrence survival (PRS) in and the effect of postrecurrence therapy (PRT) on patients with completely resected stage I non-small cell lung cancer (NSCLC). METHODS: We reviewed the data of 919 patients in whom complete resection of stage I NSCLC had been performed. RESULTS: Of the 919 patients, 170 (18.5%) had recurrent disease. Initial PRT was performed in 118 patients (69.1%) (surgery in eight, chemotherapy in 79, radiotherapy in 10, and chemoradiotherapy in 21). On multivariate analyses, PRT (hazard ratio [HR], 0.542; 95% CI, 0.344-0.853; P = .008), female sex (HR, 0.487; 95% CI, 0.297-0.801; P = .005), and differentiation (HR, 1.810; 95% CI, 1.194-2.743; P = .005) demonstrated a statistically significant association with favorable PRS. Bone metastasis (HR, 3.288; 95% CI, 1.783-6.062; P < .001), liver metastasis (HR, 4.518; 95% CI, 1.793-11.379; P = .001), chemotherapy (HR, 0.478; 95% CI, 0.236-0.975; P = .040), epidermal growth factor receptor-tyrosine kinase inhibitors treatment (EGFR-TKIs) (HR, 0.460; 95% CI, 0.245-0.862; P = .015), and nonadenocarcinoma (HR, 2.136; 95% CI, 1.273-3.585; P = .004) were independently and significantly associated with PRS in the 118 patients who underwent any PRT. Subgroup analysis with a combination of these five PRS factors in the patients who underwent any PRT revealed median PRS times of 42.4 months for 20 patients lacking all five risk factors and 18.8 months for 98 patients with at least one of these risk factors (P = .001). CONCLUSIONS: PRT, sex, and differentiation were independently associated with PRS. In the patients who underwent any PRT, PRS was related to EGFR-TKIs, chemotherapy, histology, and initial recurrence sites. One challenge for the future will be to create systematic treatment strategies for recurrent NSCLC according to the risk factor status of individual patients.

Retrospective analysis of nodal spread patterns according to tumor location in pathological N2 non-small cell lung cancer.

BACKGROUND: The purpose of the present study was to determine the nodal spread patterns of pN2 non-small cell lung cancer (NSCLC) according to tumor location, and to attempt to evaluate the possible indications of selective lymph node dissection (SLND). METHODS: We retrospectively analyzed nodal spread patterns in 207 patients with NSCLC of less than 5 cm with N2 involvement. RESULTS: The tumor location was right upper lobe (RUL) in 79, middle lobe in 12, right lower lobe (RLL) in 40, left upper division (LUD) in 41, lingular division in 11, and left lower lobe (LLL) in 24. Both RUL and LUD tumors showed a higher incidence of upper mediastinal (UM) involvement (96 and 100%, respectively) and a lower incidence of subcarinal involvement (15 and 10%, respectively) than lower lobe tumors (UM; RLL 60%, LLL 42%; subcarinal: RLL 60%, LLL 46%, respectively). Among the patients with 24 right UM-positive RLL and 10 left UM-positive LLL tumors, 2 showed negative hilar, subcarinal, and lower mediastinal involvement, and cT1, suggesting that UM dissection may be unnecessary in lower lobe tumors with no metastasis to hilar, subcarinal, and lower mediastinal nodes on frozen sections according to the preoperative T status. Among the patients with 12 subcarinal-positive RUL and 4 subcarinal-positive LUD tumors, one showed negative hilar or UM involvement, suggesting that subcarinal dissection may be unnecessary in RUL or LUD tumors with no metastasis to hilar and UM nodes on frozen sections. CONCLUSIONS: The present study appears to provide one of the supportive results regarding the treatment strategies for tumor location-specific SLND.

Pathological vascular invasion and tumor differentiation predict cancer recurrence in stage IA non-small-cell lung cancer after complete surgical resection.

INTRODUCTION: The appropriate therapeutic strategy and postoperative management for patients with stage IA non-small-cell lung cancer (NSCLC) still remain a matter of debate because of the prognostic heterogeneity of this population, including the risk of cancer recurrence. The objective of the current study was to identify the clinicopathological factors that affect overall prognosis and cancer recurrence of stage IA NSCLC. METHODS: We reviewed the data of 532 patients in whom complete resection of stage IA NSCLC had been performed. Overall survival and recurrence-free proportion (RFP) were estimated using the Kaplan-Meier method. RFP was estimated from the date of the primary tumor resection to the date of the first recurrence or last follow-up. We performed univariate and multivariate analyses to determine the independent prognostic factors. RESULTS: On multivariate analyses, three variables were shown to be independently significant recurrence risk factors: histological differentiation (hazard ratio [HR] = 1.925), blood-vessel invasion (HR = 1.712), and lymph-vessel invasion (HR = 1.751). On subgroup analyses combining these risk factors, the 5-year RFP was 91.3% for patients with no risk factors, 79.5% for those with either poorly differentiated carcinoma or vascular invasion, (p < 0.001 for both), and 62.9% for those with both poorly differentiated carcinoma and vascular invasion (p = 0.068). CONCLUSION: These results indicated that vascular invasion and tumor differentiation have a significant impact on the prediction of cancer recurrence in patients with stage IA NSCLC. Patients with these predictive factors of recurrence may be good candidates for adjuvant chemotherapy.

New aspects of photodynamic therapy for central type early stage lung cancer.

BACKGROUND: and Objective Photodynamic therapy (PDT) has come to be considered as the first choice of treatment for central type early stage lung cancer (CELC). Recent advances in the ability to diagnose CELC, and in photosensitizers, as well as sophisticated clinical management, may improve the therapeutic outcome and expand the indications of PDT. MATERIALS AND METHODS: We made the search for papers on PDT for lung cancer to select the most relevant articles. Based on this review and our recent data, we discussed the best available evidence for the diagnosis, the definition of indications, photosensitizers, and clinical management with regard to PDT. RESULTS: To obtain complete response (CR) by PDT, the selection of the indications is extremely important, including the extent of the tumor on the bronchial surface and the depth of invasion in the bronchial wall. The development of autofluorescence bronchoscopy (AFB) and endobronchial ultrasonography (EBUS) have had a large impact on diagnostic bronchoscopy for CELC. CELCs less than 1 cm in diameter showed a favorable cure rate by PDT, thus this is a good indication for PDT. The relatively newer photosensitizer NPe6, which has a stronger antitumor effect than Photofrin, showed similar treatment outcome even for large tumors >1.0 cm in diameter. Furthermore, comprehensive management including photodynamic diagnosis before and after PDT should be effective to minimize the possibility of local recurrence after PDT. CONCLUSION: The present guidelines of PDT for CELC were established based on the data obtained from studies in the 1980's. We postulate that comprehensive diagnosis and the new generation of photosensitizers may increase the CR rate and expand the indications of PDT for larger tumors.

Outcome of photodynamic therapy using NPe6 for bronchogenic carcinomas in central airways >1.0 cm in diameter.

PURPOSE: Most centrally located early lung cancers (CLELC) <1.0 cm in diameter do not invade beyond the bronchial cartilage, and photodynamic therapy (PDT) with Photofrin is currently recommended as a treatment option for such lesions. NPe6 is a second-generation photosensitizer, and because it has a longer absorption band (664 nm) than Photofrin (630 nm), we hypothesized that NPe6-PDT would exert a strong antitumor effect against cancer lesions >1.0 cm in diameter, which are assumed to involve extracartilaginous invasion and to be unsuitable for treatment with Photofrin-PDT. EXPERIMENTAL DESIGN: Between June 2004 and December 2008, 75 patients (91 lesions) with CLELC underwent NPe6-PDT after the extent of their tumors had been assessed by fluorescence bronchoscopy for photodynamic diagnosis and tumor depth had been assessed by optical coherence tomography. RESULTS: Seventy cancer lesions < or =1.0 cm in diameter and 21 lesions >1.0 cm in diameter were identified, and the complete response rate was 94.0% (66 of 70) and 90.4% (19 of 21), respectively. After the mass of large tumors and deeply invasive tumors had been reduced by electrocautery, NPe6-PDT was capable of destroying the residual cancer lesions. CONCLUSION: NPe6-PDT has a strong antitumor effect against CLELCs >1.0 cm in diameter that have invaded beyond the bronchial cartilage, thereby enabling the destruction of residual cancer lesions after mass reduction of large nodular- or polypoid-type lung cancers by electrocautery. The PDT guidelines for lung cancers should therefore be revised because use of NPe6-PDT will enable expansion of the clinical indications for PDT.

Photodynamic therapy for lung cancers based on novel photodynamic diagnosis using talaporfin sodium (NPe6) and autofluorescence bronchoscopy.

BACKGROUND: We had previously developed the possibility of use of a photodynamic diagnosis (PDD) system using a tumor-selective photosensitizer and laser irradiation for the early detection and photodynamic therapy (PDT) for centrally located early lung cancers. Recently, we established the autofluorescence diagnosis system integrated into a videoendoscope (SAFE-3000) as a very useful technique for the early diagnosis of lung cancer. PATIENTS AND METHODS: Twenty-nine patients (38 lesions) with centrally located early lung cancer received PDD and PDT using the second-generation photosensitizer, talaporfin sodium (NPe6). Just before the PDT, we defined the tumor margin accurately using the novel PDD system SAFE-3000 with NPe6 and a diode laser (408nm). RESULTS: Red fluorescence emitted from the tumor by excitation of the photosensitizer by the diode laser (408nm) from SAFE-3000 allowed accurate determination of the tumor margin just before the PDT. The complete remission (CR) rate following NPe6-PDT in the cases with early lung cancer was 92.1% (35/38 lesions). We also confirmed the loss of red fluorescence from the tumors immediately after the PDT using SAFE-3000. We confirmed that all the NPe6 in the tumor had been excited and photobleached by the laser irradiation (664nm) and that no additional laser irradiation was needed for curative treatment. CONCLUSIONS: This novel PDD system using SAFE-3000 and NPe6 improved the quality and efficacy of PDT and avoided misjudgement of the dose of the photosensitizer or laser irradiation in PDT. PDT using NPe6 will become a standard option of treatments for centrally located early lung cancer.

Comprehensive diagnostic bronchoscopy of central type early stage lung cancer.

Due to advances in interventional bronchoscopy, curative treatment has become possible for central type lung cancer if it is detected in the early stage. However, expertise is required to diagnose the extent of tumor invasion and the depth of tumor involvement by conventional white light bronchoscopy alone, but judgement is still subjective. The development of autofluorescence bronchoscopy (AFB) and endobronchial ultrasonography (EBUS) has had a large impact on diagnostic bronchoscopy in the past decade and have been employed especially for the diagnosis of central type tumors. Objective evaluation by a comprehensive approach using AFB, EBUS and optical coherence tomography (OCT) enables selection of the optimal therapeutic strategy for central type early lung cancer (CELC).

Early detection of bronchial lesions using newly developed videoendoscopy-based autofluorescence bronchoscopy.

The combination of white light and autofluorescence bronchoscopy has been reported to show better sensitivity in detecting dysplasia and cancer of the bronchus than white light alone. However, fiberoptic bronchoscopy has been replaced by videoendoscopy at most leading facilities for over a decade. To avoid interruption of the videoendoscopy examination to perform fiberscopy-based autofluorescence examination as well as enhancing the sensitivity of intraepithelial lesions, autofluorescence diagnosis system integrated into a videoendoscope (SAFE 3000, Pentax, Tokyo) was created. A total of 154 consecutive patients were studied using this system, containing 83 known or suspected lung cancer cases, 46 of the cases with abnormal sputum cytology findings, 10 follow up cases following lung cancer operations, and 15 heavy smokers with respiratory symptoms. Abnormal findings were recognized by white light and/or SAFE 3000 at 166 sites and biopsies were taken to evaluate the relationship between endoscopic findings and pathology results. The sensitivity of the system for CIS+dysplasia was 65% in white light and 90% in SAFE. This videoendoscopy-based autofluorescence system had significantly higher sensitivity for intraepithelial lesions than white light videoendoscopy alone.

Photodynamic therapy (PDT) for lung cancers.

Photodynamic therapy (PDT), a treatment for cancer, uses a photosensitizer and laser irradiation to produce reactive oxygen in cells. In Japan, the United States, and many other countries, PDT is a treatment option for stage 0 (TisN0M0) and stage I (T1N0M0) centrally located early stage lung cancer. PDT can preserve lung function, can be repeated, and can be combined with other therapeutic modalities such as chemotherapy. Recently, mono-l-aspartyl chlorine e6 (NPe6, Laserphyrin), a second-generation photosensitizer with lower photosensitivity than Photofrin (porfimer sodium), was approved by the Japanese government and a phase II clinical study using NPe6 with a new diode laser demonstrated an excellent antitumor effect and low skin photosensitivity. We expect PDT to be widely employed in many fields and the applications of PDT to be extended because of the decreasing cost of laser equipment and lower systemic photosensitivity induced by the photosensitizer. The purpose of this review is to introduce not only recent clinical trials of PDT for centrally located early lung cancer, but also new applications of PDT for cases of peripheral-type, early-stage lung cancers. We also discuss the applications of PDT for advanced lung cancer and combined therapy using PDT and other treatments for lung cancer.

The Val158Met polymorphism of the catechol-O-methyltransferase gene is associated with the PSA-progression-free survival in prostate cancer patients treated with estramustine phosphate.

OBJECTIVE: The aim of our study is to find out the good responders for estramustine phosphate (EMP) therapy in patients with prostate cancer. We have focused on the metabolism of EMP and studied the association between a functional single-nucleotide polymorphism in the catechol-O-methyltransferase gene (Val158Met of COMT) and PSA-progression-free survival in Japanese patients with prostate cancer treated by EMP. METHODS: Seventy-two Japanese patients with previously untreated prostate cancer who were found to be eligible for low-dose EMP therapy were enrolled in the study. Genotyping of the Val158Met polymorphism of COMT was conducted by both the polymerase chain reaction-based restriction fragment length polymorphism method and TaqMan assay. RESULTS: Patients with the Val/Val genotype of COMT had a significantly higher PSA-progression-free rate as compared to those with the Val/Met or Met/Met genotype (p=0.027). The adjusted hazard ratio of biochemical PSA failure for the Val158Met genotype of COMT was 2.164 (95% CI, 1.111 to 5.525). CONCLUSIONS: The Val158Met polymorphism of COMT is associated with the PSA-progression-free rate of EMP-treated patients in prostate cancer.

Optical coherence tomography in the diagnosis of bronchial lesions.

PURPOSE: Optical coherence tomography (OCT) can obtain high-resolution, cross-sectional microscopic images of tissue, potentially enabling optical biopsy to substitute for conventional excisional biopsy. We sought to investigate the capability of OCT to image the microstructure of normal and abnormal bronchial tissue. EQUIPMENT: The OCT system was produced by Light Lab Imaging (Boston, U.S.A.) and Pentax. (Tokyo, Japan). Preliminary examination: the OCT system was used to image-resected lung specimens from patients who had given written informed consent for this study. We inserted the OCT catheter via the working channel of the bronchoscope to evaluate the bronchial lumen. The catheter delivers a radial OCT beam and scans circumferentially to generate a transluminal image. We collected OCT images of normal bronchus, primary tumors and alveoli. All images were saved and labeled according to the patient and type of tissue imaged for later correlation with histologic studies. Clinical examination: five other patients, all of whom had given written informed consent, were examined with the OCT system under local anesthesia. The OCT catheter was inserted into the working channel of the bronchoscope for evaluation of the bronchial lumen. We collected OCT images of the normal bronchus and tumors in vivo. RESULTS: (1) Normal bronchus: the bronchial mucosal and submucosal layers appear homogeneous in OCT images. The submucosal layer is relatively reflective due to the presence of an extracellular matrix. A membrane can be seen between the submucosal and the smooth muscle layer, and areas of cartilage show high levels of scattering. (2) Alveoli: OCT images show the uniform appearance of the bronchial wall and the structure of air-containing alveoli. (3) Central type lung cancers: in preliminary and clinical examinations, the tumors showed unevenly distributed high backscattering areas and resultant loss of the normal layer structure. CONCLUSIONS: This study was the first report of the endobronchial OCT for lung cancer in clinical practice. Layers of the bronchial wall were distinctly observed in the normal bronchus on the OCT images, as opposed to bronchial tumors which lacked a layered structure. The ability of OCT to identify abnormal areas may well revise present methods for early diagnosis endoscopically.

Histopathological evaluation of fluorescence bronchoscopy using resected lungs in cases of lung cancer.

Objective evaluation of the performance of autofluorescence bronchoscopy based on analysis of thin sections of the bronchus of resected lungs was performed and compared with the results of preoperative autofluorescence bronchoscopy. Conventional bronchoscopy and autofluorescence bronchoscopy were performed prior to surgery for lung cancer. Thin sections of the bronchus were obtained from the resected specimens. The thin sections were pathologically analyzed and the diagnostic accuracy of endoscopy was calculated. The subjects were 30 consecutive operable lung cancer cases who received white light and autofluorescence bronchoscopy before operation. A total of 163 thin sections of the bronchi in the resected lungs were made. The sensitivity of white light bronchoscopy for cancer was 90 and 31% for dysplasia. The respective figures for autofluorescence bronchoscopy were 97 and 50% for cancer and dysplasia. The specificity of white light and autofluorescence was 88 and 84%, respectively. The diagnostic accuracy of autofluorescence bronchoscopy was objectively confirmed. Autofluorescence examination showed better sensitivity for cancerous/precancerous lesions and the evaluation of the extent of cancer invasion was accurate.

[Chemoprevention of lung cancer].

Since a high concentration of beta-carotene in blood reduces the risk of lung cancer, a large-scale intervention examination containing beta-carotene was conducted, mainly by the National Cancer Institute. The results showed that the risk of lung cancer increased with administration of beta-carotene. This result demonstrates that continuation of smoking is an important factor in the increased risk, and not smoking is confirmed to be the most important prevention method. The authors examined the treatment effect of raising the concentration of folic acid and vitamin B12 in blood on bronchial dysplasia as a pre-cancerous lesion. A significant medical treatment effect was see in the folic acid and vitamin B12 medication groups, which seems promising for the chemoprevention of lung cancer.

Telomerase activity during carcinogenesis in the bronchus.

Telomerase is a ribonucleoprotein reverse transcriptase that synthesizes telomeric DNA onto chromosome ends, and is not detected in most normal cells. It has been clarified that some bronchial squamous cell carcinomas may arise through the metaplasia and dysplasia sequence accompanied by accumulation of genetic mutations in metaplastic cells. Recently a highly sensitive polymerase chain reaction (PCR)-based telomerase assay (TRAP assay) was developed for the detection of telomerase activity. Telomerase activity has been found in most malignant neoplasms, including lung cancer. The objective of this study was to determine whether telomerase RNA might increase in precancerous lesions of the bronchi. Bronchial-brushing extracts were analyzed for telomerase activity (F-TRAP) and in situ telomerase activity using a fluorescence-based TRAP assay (in situ TRAP) and compared to cytological features. The fluorescence-based semi-quantitative TRAP assay detected telomerase activity in 8 out of 12 lung cancer cases (66.7%). In squamous cell carcinoma, 6 out of 9 cases (66.7%) showed telomerase activity. On the other hand, in normal and precancerous lesions of the bronchi, telomerase activity was not detected using either the F-TRAP method or in situ TRAP method. We concluded that dysplastic cells might not contain immortalized cells, and that the increase of telomerase activity is a relatively late event during the bronchial carcinogenesis. It is difficult to distinguish between dysplasia and in situ carcinoma of the bronchus morphologically, but the measurement of telomerase activity is clinically valuable for the determination of treatment.