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Background Programmed cell death-1 (PD-1) immune checkpoint inhibitor antibody has proven to be effective in advanced non-small cell lung cancer (NSCLC) patients positive for programmed cell death-1 ligand-1 (PD-L1). However, there are currently no prospective studies evaluating PD-L1 expression for small biopsy samples. Methods To prospectively investigate the reliability of small samples for NSCLC, we included patients who underwent diagnostic biopsy by flexible bronchoscopy, computed tomography (CT) and ultra-sonography (US) guided core-needle to determine the PD-L1 expression status. In pathologically confirmed NSCLC, PD-L1 expression was evaluated using companion diagnostic PD-L1 immunohistochemistry. We evaluated: 1) tumor cell count and sample size, 2) tumor proportion score (TPS): <1, 1–49%, 50%≦, and 3) the concordance rate of TPS by biopsy and surgical samples. Results Of the 153 cases of PD-L1 expression, 110 were assessed using endobronchial ultrasonography guided transbronchial biopsy (EBUS-TBB) (thin bronchoscopy 84 cases; normal bronchoscopy 26 cases), 23 were endobronchial ultrasonography guided transbronchial needle aspiration (EBUS-TBNA), and 20 cases of CT or US-guided core-needle biopsy. Tumor cell count and sample size were significantly larger for normal bronchoscopy than thin bronchoscopy or EBUS-TBNA samples. Moreover, tumor cell counts for each subsequent biopsy decreased. In all cases, TPS distribution (undiagnosed, <1%, 1–49, 50%≦) was 2.6, 34.6, 31.4, 31.4%, respectively. TPS positive cases using thin bronchoscope was 55.9%, normal bronchoscope was 73.1% and EBUS-TBNA was 78.3%. In early stage adenocarcinoma, TPS was lower compared with advanced stages. Conversely, in squamous cell carcinoma, the rates of TPS were similar regardless of stage. The concordance rate of TPS by biopsy and surgical materials was 86.7%. Conclusion Utilizing smaller samples for evaluation, the frequency of TPS was comparable to past clinical trials using larger samples. The differences in TPS were influenced by diagnostic tools, cancer histologic types and staging. The concordance of TPS between EBUS-TBB samples and surgical materials was high. Trial registration This study was performed at the Department of Respiratory Medicine at St. Marianna University School of Medicine Hospital, with ethics approval (#3590) and registered as a clinical trial ( UMIN000027030 ).

No therapeutic targets have been identified for lung squamous cell cancer (SqCC) which is the second most prevalent lung cancer because its molecular profiles remain unclear. This study aimed to unveil disease-related protein networks by proteomic and bioinformatic assessment of laser-microdissected cancerous cells from seven SqCCs compared with eight representative lung adenocarcinomas. We identified three network modules significant to lung SqCC using weighted gene co-expression network analysis. One module was intrinsically annotated to keratinization and cell proliferation of SqCC, accompanied by hypoxia-induced aerobic glycolysis, in which key regulators were activated ( HIF1A , ROCK2 , EFNA1-5 ) and highly suppressed ( KMT2D ). The other two modules were significant for translational initiation, nonsense-mediated mRNA decay, inhibited cell death, and interestingly, eIF2 signaling, in which key regulators, MYC and MLXIPL , were highly activated. Another key regulator LARP1 , the master regulator in cap-dependent translation, was highly suppressed although upregulations were observed for hub proteins including EIF3F and LARP1 targeted ribosomal proteins, among which PS25 is the key ribosomal protein in IRES-dependent translation. Our results suggest an underlying progression mechanism largely caused by switching to the cap-independent, IRES-dependent translation of mRNA subsets encoding oncogenic proteins. Our findings may help to develop therapeutic strategies to improve patient outcomes.

We previously reported on two women with breast lesions in whom radiological examination could not exclude malignancy. In both cases, mastectomy was performed, and histological analyses revealed papillary lesions lined by fibrovascular stroma and nuclear inverse polarity. Hematoxylin–eosin, p63, and calponin staining indicated an absence of myoepithelial cells. However, it was concluded that the lesions had been non-malignant. These women have now been under long-term surveillance (74 months for one case and 62 months for the other) and have had no disease recurrence. Mucin (MUC)1, MUC2, MUC4, MUC5AC, MUC5B, and MUC6 immunostaining has also been performed in these women to investigate further whether their tumors were malignant or benign. In both cases, the tumors were only positive for MUC1 in apical luminal apical cells, as in normal breast tissue. MUC5B immunostaining, even when weak, can detect early breast cancer but was completely negative in our two cases. Therefore, both tumors were considered benign. Our findings in these cases suggest that nuclear inverse polarity papillary lesions lacking myoepithelial cells are benign. This knowledge should decrease the number of unnecessary operations performed for this tumor and their negative impact on patients’ quality of life.

It is unclear how epidermal growth factor receptor EGFR major driver mutations (L858R or Ex19del) affect downstream molecular networks and pathways. This study aimed to provide information on the influences of these mutations. The study assessed 36 protein expression profiles of lung adenocarcinoma (Ex19del, nine; L858R, nine; no Ex19del/L858R, 18). Weighted gene co-expression network analysis together with analysis of variance-based screening identified 13 co-expressed modules and their eigen proteins. Pathway enrichment analysis for the Ex19del mutation demonstrated involvement of SUMOylation, epithelial and mesenchymal transition, ERK/mitogen-activated protein kinase signalling via phosphorylation and Hippo signalling. Additionally, analysis for the L858R mutation identified various pathways related to cancer cell survival and death. With regard to the Ex19del mutation, ROCK, RPS6KA1, ARF1, IL2RA and several ErbB pathways were upregulated, whereas AURK and GSKIP were downregulated. With regard to the L858R mutation, RB1, TSC22D3 and DOCK1 were downregulated, whereas various networks, including VEGFA, were moderately upregulated. In all mutation types, CD80/CD86 (B7), MHC, CIITA and IFGN were activated, whereas CD37 and SAFB were inhibited. Costimulatory immune-checkpoint pathways by B7/CD28 were mainly activated, whereas those by PD-1/PD-L1 were inhibited. Our findings may help identify potential therapeutic targets and develop therapeutic strategies to improve patient outcomes.

We report a rare case of a dumbbell-shaped mesenchymal chondrosarcoma (MCS) in the lumbar canal. A 29-year-old man presented with lower back pain and pain in the left leg. Magnetic resonance imaging (MRI) showed a homogeneously enhanced dumbbell-shaped mass at the left L2-3 level. The mass was intradurally located and extended extradurally into the extraforaminal space through the left L2-3 intervertebral foramen. Computed tomography (CT) showed a calcified portion in the intradural mass. We exposed and excised the tumor via a posterior approach through a hemi-laminectomy of the left L2-3. The tumor had penetrated the dura mater and required repair. Following surgery, his symptoms resolved completely. The most likely histopathological diagnosis was MCS. Histologic examination of our surgical samples revealed the typical biphasic pattern, but there was also cartilage matrix resembling osteoid. Finally, molecular assays confirmed the presence of the HEY1::NCOA2 fusion gene. Although spinal intradural extramedullary MCS is rare, only a few reports in the literature mention spinal dumbbell-shaped MCS. Following the removal of dumbbell-shaped MCS, the dura mater may require repair. While histopathological evaluation remains the gold standard for confirming a diagnosis of MCS, the HEY1::NCOA2 fusion gene is a specific molecular marker for MCS, and the presence of this gene has become a powerful tool for diagnosis.

Small-cell lung carcinoma (SCLC) and large-cell neuroendocrine lung carcinoma (LCNEC) are high-grade lung neuroendocrine tumors (NET). However, comparative protein expression within SCLC and LCNEC remains unclear. Here, protein expression profiles were obtained via mass spectrometry-based proteomic analysis. Weighted gene co-expression network analysis (WGCNA) identified co-expressed modules and hub genes. Of 34 identified modules, six were significant and selected for protein-protein interaction (PPI) network analysis and pathway enrichment. Within the six modules, the activation of cellular processes and complexes, such as alternative mRNA splicing, translation initiation, nucleosome remodeling and deacetylase (NuRD) complex, SWItch/Sucrose Non-Fermentable (SWI/SNF) superfamily-type complex, chromatin remodeling pathway, and mRNA metabolic processes, were significant to SCLC. Modules enriched in processes, including signal recognition particle (SRP)-dependent co-translational protein targeting to membrane, nuclear-transcribed mRNA catabolic process of nonsense-mediated decay (NMD), and cellular macromolecule catabolic process, were characteristically activated in LCNEC. Novel high-degree hub genes were identified for each module. Master and upstream regulators were predicted via causal network analysis. This study provides an understanding of the molecular differences in tumorigenesis and malignancy between SCLC and LCNEC and may help identify potential therapeutic targets.

The goal-setting diary is designed to enhance goal-related performance through self-monitoring. It is essential to ensure that the contents of the diary are related to the degree of goal attainment and simplify its format prior to clinical application. This foundational study aimed to investigate the relationship between the contents of a goal-setting diary and goal attainment. The participants were 252 healthy occupational therapy students (OTS) aged 18 years or older from three training institutions (a university, a junior college, and a vocational school). Students with diseases that are being treated were excluded. Multiple regression analysis (stepwise method) was performed, with goal attainment as the dependent variable. Quantitative data from the goal-setting diary, including the number of strategies, importance, satisfaction, confidence to continue, difficulty, persistence, self-efficacy, and effort, along with the participant's basic attributes, were used as explanatory variables. A total of 167 healthy participants completed a goal-setting diary for seven days (response rate: 66.3%). Multiple regression analysis revealed effort (B = 0.58, p < 0.001, 95% confidence interval, 0.46-0.71) and satisfaction (B = 0.05, p < 0.001, 95% confidence interval, 0.03-0.06) as significant explanatory variables for goal attainment (adjusted R = 0.57). Our results emphasize the importance of daily monitoring of effort and satisfaction levels in relation to goal attainment. Furthermore, the goal-setting diary can be simplified because it has many sections. As the participants in this study were healthy OTS, future studies are needed to apply the revised goal-setting diary, which is composed of effort and satisfaction, to clients in clinical settings and examine its effectiveness.

The tumourigenesis of early lung adenocarcinomas, including adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic predominant invasive adenocarcinoma (LPA), remains unclear. This study aimed to capture disease-related molecular networks characterising each subtype and tumorigenesis by assessing 14 lung adenocarcinomas (AIS, five; MIA, five; LPA, four). Protein–protein interaction networks significant to the three subtypes were elucidated by weighted gene co-expression network analysis and pairwise G-statistics based analysis. Pathway enrichment analysis for AIS involved extracellular matrix proteoglycans and neutrophil degranulation pathway relating to tumour growth and angiogenesis. Whereas no direct networks were found for MIA, proteins significant to MIA were involved in oncogenic transformation, epithelial-mesenchymal transition, and detoxification in the lung. LPA was associated with pathways of HSF1-mediated heat shock response regulation, DNA damage repair, cell cycle regulation, and mitosis. Genomic alteration analysis suggested that LPA had both somatic mutations with loss of function and copy number gains more frequent than MIA. Oncogenic drivers were detected in both MIA and LPA, and also LPA had a higher degree of copy number loss than MIA. Our findings may help identifying potential therapeutic targets and developing therapeutic strategies to improve patient outcomes.

Peripheral T‐ or natural killer (NK)‐cell lymphomas are rare and difficult‐to‐recognize diseases. It remains arduous to distinguish between NK cell‐ and cytotoxic T‐lymphocyte‐derived lymphomas through routine histological evaluation. To clarify the cells of origin, we focused on NK‐cell receptors and examined the expression using immunohistochemistry in 22 cases with T‐ and NK‐cell neoplasms comprising angioimmunoblastic T‐cell lymphoma, anaplastic lymphoma kinase (ALK)‐positive and ‐negative anaplastic large‐cell lymphomas, extranodal NK/T‐cell lymphoma, nasal type, monomorphic epitheliotropic intestinal T‐cell lymphoma, aggressive NK‐cell leukemia, and other peripheral T‐cell lymphomas. Inhibitory receptor leukocyte immunoglobulin‐like receptor subfamily B member 1 (LILRB1) was detected in 14 (64%) cases, whereas activating receptors DNAM1, NKp46, and NKG2D were expressed in 7 (32%), 9 (41%), and 5 (23%) cases, respectively. Although LILRB1 was detected regardless of the disease entity, the activating NK‐cell receptors were expressed predominantly in TIA‐1‐positive neoplasms (DNAM1, 49%; NKp46, 69%; and NKG2D, 38%). In addition, NKp46 and NKG2D were detected only in NK‐cell neoplasms and cytotoxic T‐lymphocyte‐derived lymphomas including monomorphic epitheliotropic intestinal T‐cell lymphoma. One Epstein‐Barr virus‐harboring cytotoxic T‐lymphocyte‐derived lymphoma mimicking extranodal NK/T‐cell lymphoma, nasal type lacked these NK‐cell receptors, indicating different cell origin from NK and innate‐like T cells. Furthermore, NKG2D expression showed a negative impact on survival among the 22 examined cases, which mainly received the standard chemotherapy regimen (log‐rank test, P = .024). We propose that the presence of activating NK‐cell receptors may provide new insights into understanding peripheral T‐cell lymphomas and characterizing them as innate‐like T‐cell neoplasm. It remains difficult to distinguish between NK‐cell‐ and cytotoxic T‐lymphocyte‐derived lymphomas through routine histological evaluation. Cytotoxic T‐lymphocyte‐derived lymphomas are characterized as innate‐like T‐cell neoplasms by the expression of activating NK‐cell receptors. NKG2D expression might show a negative impact on survival in T‐ and NK‐cell lymphoma cases receiving the standard CHOP‐like regimen.

Purpose Maximum standardized uptake values (SUV max ) at the primary lesions of non-small-cell lung cancer in 18 F-fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT), and the microscopic local extension of tumors were examined to develop reliable criteria to determine candidates for sublobar resection. Methods We retrospectively analyzed 209 patients who underwent lobectomy, bilobectomy, or pneumonectomy with systematic lymph node dissection. Preoperative SUV max at the primary lesion, microscopic lymphatic, venous, and pleural invasion in addition to lymph node metastases in the resected specimens were examined. Receiver operating characteristic analyses were used to predict an optimal cutoff for lymph node metastases. Results With receiver operating characteristic analysis, the areas under the curve for SUV max and tumor size were 0.693 and 0.545, respectively, suggesting SUV max superiority for prediction of lymph node metastases with a cutoff of 2.9. When a tumor was ≤2.0 cm ( n  = 41, 19.6 %), the percentages of microscopic lymphatic invasion, venous invasion, pleural invasion, and lymph node metastases were 12.2, 7.3, 4.9, and 17.1 %, respectively. When SUV max was <3.0 ( n  = 91, 43.5 %), these percentages were 15.4, 3.3, 7.7, and 8.8 %, showing that SUV max could efficiently exclude nodal metastases in more cases than tumor size. The postoperative 5-year survival rate was 86.6 % in patients with SUV max  < 3.0 and 58.1 % in patients with SUV max  ≥ 3.0 ( p  < 0.001). Conclusions 18 F-FDG uptake value was more useful than tumor size for selecting patients with non-small-cell lung cancer suitable for intentional sublobar resection.