Expression of fibroblast activation protein in intrathoracic solitary fibrous tumor.

PURPOSE: Fibroblast activation protein (FAP) is a serine integral membrane protease, the expression of which has been confirmed in various cancer types. Solitary fibrous tumors of the pleura (SFTP) are rare mesenchymal fibroblastic neoplasms. We present a case of 18F-labeled FAP inhibitor ([18F]FAPI-74) PET imaging and its correlation with histological FAP expression and review an SFTP series at our institution in relation to the extent of FAP expression. METHODS: This retrospective study included 13 patients who underwent surgery between March 2011 and December 2022 at our institute. One of the patients also underwent [18F]FAPI-74 PET imaging. We semi-quantitatively evaluated FAP expression in SFTPs using immunohistochemical staining and H-scores. RESULTS: Nine of the 13 patients were male, with a median age of 64 years (range, 28-79 years). The median tumor size was 6.6 cm (1.1, 16 cm). In the pathological findings, expression levels of Ki67 were 1-5% in 12 of 13 cases. Furthermore, FAP expression was observed in all patients, and the median H-score was 160 (range, 10-280). The H-score of FAP expression in two of the 13 patients was low (10 in both), and that in two of the 13 patients was high (240 and 280). The SUVmax value of [18F]FAPI-74 PET was 3.57 in a patient in whom the H-score of FAP expression was 180. CONCLUSIONS: SFTPs expressed FAP to varying degrees in different patients and the [18F]FAPI-74 PET results in one patient reflected FAP expression in the tumor tissue.

Singing Is a Risk Factor for Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Case-Control Study of Karaoke-Related Coronavirus Disease 2019 Outbreaks in 2 Cities in Hokkaido, Japan, Linked by Whole Genome Analysis.

Background: Singing in an indoor space may increase the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We conducted a case-control study of karaoke-related coronavirus disease 2019 (COVID-19) outbreaks to reveal the risk factors for SARS-CoV-2 infection among individuals who participate in karaoke. Methods: Cases were defined as people who enjoyed karaoke at a bar and who tested positive for SARS-CoV-2 by reverse-transcription polymerase chain reaction between 16 May and 3 July 2020. Controls were defined as people who enjoyed karaoke at the same bar during the same period as the cases and tested negative. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. ORs of key variables adjusted for each other were also estimated (aOR). Results: We identified 81 cases, the majority of whom were active elderly individuals (median age, 75 years). Six cases died (case fatality ratio, 7%). Among the cases, 68 (84%) were guests, 18 of whom had visited ≧2 karaoke bars. A genome analysis conducted in 30 cases showed 6 types of isolates within 4 single-nucleotide variation difference. The case-control study revealed that singing (aOR, 11.0 [95% CI, 1.2-101.0]), not wearing a mask (aOR, 3.7 [95% CI, 1.2-11.2]), and additional hour spent per visit (aOR, 1.7 [95% CI, 1.1-2.7]) were associated with COVID-19 infection. Conclusions: A karaoke-related COVID-19 outbreak that occurred in 2 different cities was confirmed by the results of genome analysis. Singing in less-ventilated, indoor and crowded environments increases the risk of acquiring SARS-CoV-2 infection. Wearing a mask and staying for only a short time can reduce the risk of infection during karaoke.

Surgical indication of pulmonary metastasis arising from osteosarcoma or soft tissue sarcoma.

OBJECTIVES: Metastasectomy is often the local treatment for pulmonary metastases arising from osteosarcoma or soft tissue sarcoma. However, there have been few investigations on the outcomes of patients who undergo this procedure. In this study, we identified prognostic factors in patients with pulmonary metastases arising from osteosarcoma and soft tissue sarcoma to determine more appropriate eligibility criteria for metastasectomy. METHODS: We retrospectively examined 37 patients who underwent metastasectomy of pulmonary nodules arising from osteosarcomas or soft tissue sarcomas at our institute between 2005 and 2020. Overall and recurrence-free survival intervals were determined using univariate and multivariate analyses. RESULTS: A tumor doubling time > 1 month and a primary tumor histological type of osteosarcoma were independent predictors of longer overall survival on multivariate analysis (hazard ratios: 3.618 and 2.979, p = 0.00986 and 0.0373, respectively). Moreover, a > 1-month tumor doubling time and > 10-cm diameter of the primary tumor were independent predictors of longer recurrence-free survival (hazard ratios: 3.293 and 2.67, p = 0.0121 and 0.0134, respectively). Patients who underwent repeat pulmonary metastasectomy after complete resection of sarcoma-derived pulmonary metastases had significantly longer overall survival than those who did not (median: 5.91 years vs. 0.81 years, p < 0.0001). CONCLUSIONS: Tumor doubling time is a significant predictor of clinical outcomes in patients who undergo resection of pulmonary metastases originating from sarcomas. The surgical indication for this procedure should be decided carefully, particularly for patients with metastatic lesion doubling times ≤ 1 month.

[Dealing with Pleural Adhesion in Video-assisted Thoracoscopic Surgery].

The adhesion between the visceral and parietal pleura makes video-assisted thoracoscopic surgery (VATS) difficult or impossible. When performing VATS without conversion to thoracotomy due to pleural adhesion, it is important to( ⅰ) evaluate the presence and extent of the adhesion preoperatively, (ⅱ) carefully perform detachment, and( ⅲ) adequately repair the injured visceral pleura. We evaluate visceral sliding with the help of chest ultrasonography and plan the best approach to make utility inci-sions, camera port, and third-port incisions. Considering the difficulty in repairing the injured visceral pleura under VATS, we perform extra-pleural detachment of adhesions around the injured visceral pleura, which can facilitate the repair of the pleural injury. For repairing pleural injury, we use free mediastinal fat tissue as biological pledgets to support suturing. In this report, we present the approaches and techniques we follow to perform VATS for patients with pleural adhesion.

Novel imprint cytological classification is correlated with tumor spread through air spaces in lung adenocarcinoma.

OBJECTIVES: Spread through air spaces (STAS) is a risk factor for local recurrence after sublobar resection in lung cancer patients. We recently proposed the novel Nakayama-Higashiyama imprint cytological classification (N-H classification) based on small-sized lung adenocarcinoma surgical specimens, which correlated with histological patterns and nodal involvement. This study aimed to evaluate the correlation between STAS and the N-H classification and to validate the N-H classification as an intraoperative predictor of the presence of STAS. MATERIALS AND METHODS: We retrospectively analyzed 164 intraoperative imprint cytologies and their paired histologic specimens from patients undergoing surgical resection for lung adenocarcinoma in our institute in 2017-2019. Using the NH classification, imprint cytological findings were classified into 5 groups (Groups I to V) based on cell cluster shape, cell and nucleus size, and the existence of necrosis. We examined the characteristics of imprint cytology and STAS in the resected tissues and analyzed the relationship between them. RESULTS: Tumor STAS was observed in 29 (17.7 %) cases. The presence of STAS was significantly associated with the NH classification (P < 0.0001). STAS was present in 6 of 57 cases (10.5 %) in NH classification Group II, 11 of 42 cases (26.2 %) in Group III, and 12 of 28 cases (42.9 %) in Group IV/V; STAS was not observed in any case in Group I. Logistic regression analysis revealed that tumors with a ground glass opacity rate of <50 % on computed tomography (P = 0.00867) and Groups III-V of the NH classification (P = 0.00201) were significant independent predictors for STAS. CONCLUSION: Intraoperative imprint cytology with the N-H classification for lung adenocarcinoma is well correlated with the STAS status of the tumor and might have applications as an intraoperative predictive marker of STAS. This classification may be useful for intraoperative detection of STAS and in the decision-making process for the surgical procedure.

Number of metastatic lymph nodes and zones as prognostic factors in non-small-cell lung cancer.

OBJECTIVES: Characterizing pathological nodes (pNs) by location alone is sometimes inadequate as patients with pN1 or pN2 non-small-cell lung cancer (NSCLC) show prognostic heterogeneity. We aimed to assess the relationship of the number of metastatic lymph nodes (LNs) and zones with prognosis in NSCLC patients. METHODS: We analysed 1393 patients who underwent lobectomy with mediastinal LN dissection for NSCLC at the Osaka International Cancer Institute between January 2006 and December 2015. Patients were classified into 3 groups according to the number of LNs: n1-3, n4-6 and n7-. We investigated the relationship of prognosis with the number of metastatic LNs and metastatic zones. RESULTS: In the multivariable analyses, the number of metastatic LNs and zones were not independent factors for overall survival or recurrence-free survival in patients with pN1 disease after adjustment for age, sex, tumour histology and tumour diameter. However, n4-6 (ref. n1-3) was an independent prognostic factor for overall survival [hazard ratio (HR) 4.148, P < 0.001] in those with pN2 disease. There were no significant differences in overall survival and recurrence-free survival between pN1 (HR 0.674, P = 0.175) and pN2n1-3 disease (HR 1.056, P = 0.808). Moreover, patients with pN2 disease with a higher number of metastatic zones had a poor prognosis for recurrence-free survival [3 zones (ref. 1): HR 1.774, P = 0.051, and 4 zones (ref. 1): HR 2.173, P < 0.047]. CONCLUSIONS: The number of metastatic LNs and metastatic zones were useful prognostic factors in NSCLC patients. The findings could help in establishing a new pN classification.

Aggressive cribriform-morular variant of papillary thyroid carcinoma: Report of an unusual case with pulmonary metastasis displaying poorly differentiated features.

The cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) is a rare morphologic entity in which metastasis rarely occurs. Until now, only three cases of metastasis by CMV-PTC have been reported. We present a rare sporadic case of CMV-PTC with multiple lung metastases in a 28-year-old female, 3 years after total thyroidectomy. The lung tumor was not encapsulated but well-circumscribed and showed a mixture of cribriform, papillary, and solid patterns of growth with necrosis. The tall columnar carcinoma cells did not display the typical nuclear features of PTC. Carcinoma cells were positive for thyroid transcription factor 1, paired-box gene 8, estrogen receptor, progesterone receptor, and adenomatous polyposis coli, and showed positive nuclear and cytoplasmic staining for ß-catenin. Carcinoma cells were negative for thyroglobulin and CDX-2, and the Ki-67 labeling index was 22.1%. This immunoprofile suggests a pathological diagnosis of metastasis by a CMV-PTC displaying poorly differentiated features. To the best of our knowledge, our case is the first report of CMV-PTC with pulmonary metastasis that was confirmed by histological and immunohistochemical examinations. The present case suggests that CMV-PTC with a high Ki-67 labeling index may cause visceral metastasis.

Survey to Identify Substandard and Falsified Tablets in Several Asian Countries with Pharmacopeial Quality Control Tests and Principal Component Analysis of Handheld Raman Spectroscopy.

The World Health Organization has warned that substandard and falsified medical products (SFs) can harm patients and fail to treat the diseases for which they were intended, and they affect every region of the world, leading to loss of confidence in medicines, health-care providers, and health systems. Therefore, development of analytical procedures to detect SFs is extremely important. In this study, we investigated the quality of pharmaceutical tablets containing the antihypertensive candesartan cilexetil, collected in China, Indonesia, Japan, and Myanmar, using the Japanese pharmacopeial analytical procedures for quality control, together with principal component analysis (PCA) of Raman spectrum obtained with handheld Raman spectrometer. Some samples showed delayed dissolution and failed to meet the pharmacopeial specification, whereas others failed the assay test. These products appeared to be substandard. Principal component analysis showed that all Raman spectra could be explained in terms of two components: the amount of the active pharmaceutical ingredient and the kinds of excipients. Principal component analysis score plot indicated one substandard, and the falsified tablets have similar principal components in Raman spectra, in contrast to authentic products. The locations of samples within the PCA score plot varied according to the source country, suggesting that manufacturers in different countries use different excipients. Our results indicate that the handheld Raman device will be useful for detection of SFs in the field. Principal component analysis of that Raman data clarify the difference in chemical properties between good quality products and SFs that circulate in the Asian market.

Classification and Visualization of Physical and Chemical Properties of Falsified Medicines with Handheld Raman Spectroscopy and X-Ray Computed Tomography.

Analytical methods for the detection of substandard and falsified medical products (SFs) are important for public health and patient safety. Research to understand how the physical and chemical properties of SFs can be most effectively applied to distinguish the SFs from authentic products has not yet been investigated enough. Here, we investigated the usefulness of two analytical methods, handheld Raman spectroscopy (handheld Raman) and X-ray computed tomography (X-ray CT), for detecting SFs among oral solid antihypertensive pharmaceutical products containing candesartan cilexetil as an active pharmaceutical ingredient (API). X-ray CT visualized at least two different types of falsified tablets, one containing many cracks and voids and the other containing aggregates with high electron density, such as from the presence of the heavy elements. Generic products that purported to contain equivalent amounts of API to the authentic products were discriminated from the authentic products by the handheld Raman and the different physical structure on X-ray CT. Approach to investigate both the chemical and physical properties with handheld Raman and X-ray CT, respectively, promise the accurate discrimination of the SFs, even if their visual appearance is similar with authentic products. We present a decision tree for investigating the authenticity of samples purporting to be authentic commercial tablets. Our results indicate that the combination approach of visual observation, handheld Raman and X-ray CT is a powerful strategy for nondestructive discrimination of suspect samples.

Combination of SDS-PAGE and intact mass analysis for rapid determination of heterogeneities in monoclonal antibody therapeutics.

mAbs are currently mainstream in biopharmaceuticals, and their market has been growing due to their high target specificity. Characterization of heterogeneities in mAbs is performed to secure their quality and safety by physicochemical analyses. However, they require time-consuming task, which often strain the resources of drug development in pharmaceuticals. Rapid and direct method to determine the heterogeneities should be a powerful tool for pharmaceutical analysis. Considering the advantages of electrophoresis and MS, this study addresses the combination of SDS-PAGE and intact mass analysis, which provides direct, rapid, and orthogonal determination of heterogeneities in mAb therapeutics. mAb therapeutics that migrated in SDS-PAGE were recovered from gel by treatment with SDC-containing buffer. Usage of SDC-containing buffer as extraction solvent and ethanol-based staining solution enhanced the recovery of intact IgG from SDS-PAGE gels. Recovery of mAbs reached more than 86% with 0.2% SD. The heterogeneities, especially N-glycan variants in the recovered mAb therapeutics, were clearly determined by intact mass analysis. We believe that the study is important in pharmaceuticals‧ perspective since orthogonal combination of gel electrophoresis and intact mass analysis should be pivotal role for rapid and precise characterization of mAbs.