Oncology Letters

Our medical research library holds 41 studies published in Oncology Letters (2010–2026). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 41 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: Spandidos Publications]
• Published: 2010 to the present, Greece
• Language: English
• ISSN: 1792-1074 (print), 1792-1082 (electronic)
• Its record in the NLM Catalog

2020s

• Diffuse peritoneal mesothelioma presenting with the appearance of mesenteric panniculitis: A case report. Y. Chen, Q. Fu, J. Xu, et al. 2026;32(2):340. Case report PubMed · Publisher · Free full text

  Abstract

  Diffuse peritoneal mesothelioma (DPM) is a rare and aggressive malignancy of the peritoneum. Early symptoms are non-specific and the condition is liable to misdiagnosis. In the present case, a 54-year-old man was misdiagnosed between April 2020 and October 2021 with mesenteric panniculitis. The patient later presented with a 2-month history of persistent upper-middle abdominal pain and weight loss in April 2022. A laparoscopic biopsy was performed and the sample was positive for Wilms tumor protein, Hector Battifora mesothelial-1 and podoplanin. Therefore, a diagnosis of DPM was made. A total of six cycles of pemetrexed-cisplatin chemotherapy were given and elicited a partial response. The disease progressed and intraperitoneal bevacizumab-cisplatin therapy was administered, which was ineffective. The patient died 13 months post-diagnosis. DPM often has a similar presentation to benign conditions, such as mesenteric panniculitis. Correct diagnosis is facilitated by an awareness of occupational exposure risk, such as that of asphalt exposure for the present case, and early histopathological evaluation. The prognosis for DPM remains poor despite multimodal therapy, and novel therapeutic strategies are needed.

  Copyright: © 2026 Chen et al.

• Malignant mesothelioma of the tunica vaginalis testis: A case report. Z. Liu, A. Han, S. Li, et al. 2026;32(5):517. Case report PubMed · Publisher · Free full text

  Abstract

  The aim of the present study was to report a case of malignant mesothelioma of the tunica vaginalis testis (MMTVT) and to discuss clinicopathological features and therapeutic dilemmas to provide references for individualized management of similar cases. The case of a 57-year-old male patient with MMTVT, admitted in February 2025, was retrospectively analyzed. The patient presented with left scrotal pain and had a 30-year history of vasectomy. Scrotal ultrasound, testicular MRI and serum tumor marker analyses were performed, followed by local resection of the left tunica vaginalis tumor under spinal anesthesia. Diagnosis was confirmed using postoperative pathology and immunohistochemistry. After comprehensive counseling on recurrence and metastasis risks, the patient and their family declined radical orchiectomy and adjuvant chemotherapy, and close surveillance was instituted. Postoperative pathology confirmed biphasic MMTVT. Immunohistochemistry demonstrated positive mesothelial biomarkers: D2-40(+), calretinin (focal+) and cytokeratin 5/6 (focal weak+). Ki-67 was ~10%, with wild-type p53 expression. The tumor was completely excised with negative margins. No recurrence or metastasis was observed at the 12-month follow-up. This case, presenting with scrotal pain as initial presentation, further highlights the clinical heterogeneity of MMTVT. The remote vasectomy history, which is rarely documented, raises an etiological question for investigation. The biphasic subtype with low Ki-67 suggests that prognostic evaluation requires integrating histological subtype and molecular biomarkers. The 12-month recurrence-free survival time following isolated local excision provides preliminary evidence for organ-sparing management, although long-term outcomes require continued surveillance.

  Copyright: © 2026 Liu et al.

• Pan-cancer prognostic value of TGFBR1: Bioinformatics and experimental validation with a focus on gastric cancer. X. Zhao, L. Shen, Z. Gong, et al. 2026;32(5):523. PubMed · Publisher · Free full text

  Abstract

  TGF-β receptor 1 (TGFBR1) is a key component of TGF-β signaling and has been implicated in tumor progression. However, its expression patterns, prognostic relevance and associated molecular contexts vary among malignancies and remain incompletely characterized within a consistent pan-cancer framework. In the present study, TGFBR1 expression, clinicopathological associations, survival outcomes, immune and stromal infiltration, genomic features, co-expression profiles and transcriptional programs were systematically evaluated using The Cancer Genome Atlas (TCGA), TCGA-Genotype-Tissue Expression and complementary public datasets. Multivariable Cox regression was performed with adjustment for age, sex and pathological stage and the independent GSE15459 gastric cancer (GC) cohort was used for external prognostic validation and gene-set enrichment analysis. TGFBR1 exhibited cancer type-dependent expression alterations rather than uniform upregulation across malignancies. Higher TGFBR1 expression remained associated with poorer overall survival (OS) in mesothelioma (MESO), adrenocortical carcinoma (ACC) and kidney renal papillary cell carcinoma and with poorer disease-specific survival in ACC, esophageal carcinoma, MESO, lung squamous cell carcinoma, stomach adenocarcinoma and bladder urothelial carcinoma after multivariable adjustment. In GSE15459, elevated TGFBR1 expression was associated with shorter OS and remained significant after adjustment for age, sex, pathological stage and Lauren classification. TGFBR1 expression was also associated with distinct immune, stromal, genomic and transcriptional contexts across cancer types. In GC, enrichment analyses revealed an association between higher TGFBR1 expression and apoptosis- and stress-response-associated programs, epithelial cell proliferation, focal-adhesion assembly and actin-cytoskeleton organization. In vitro, TGFBR1 knockdown reduced the proliferation and migration of GC cells, altered epithelial-mesenchymal transition-associated protein expression and promoted apoptosis. Collectively, these findings define the cancer-type-specific clinical and biological relevance of TGFBR1 and support its prognostic importance in selected malignancies, particularly GC, while further mechanistic and prospective validation remains necessary.

  Copyright: © 2026 Zhao et al.

• Primary thymic papillary adenocarcinoma with a rare CD5/CD117-negative and PAX8/WT1-positive immunophenotype: A case report. D. Zhu, C. Wan, J. Guo, et al. 2026;32(3):402. Case report PubMed · Publisher · Free full text

  Abstract

  Primary thymic papillary adenocarcinoma (PAT) is an exceptionally rare epithelial malignancy that poses substantial diagnostic challenges due to its non-specific radiological presentation and highly heterogeneous immunophenotype. The present study reports a case of early-stage PAT in a 48-year-old man with a long-standing history of rheumatoid arthritis. Chest computed tomography (CT) revealed a 3.3-cm, well-circumscribed, lobulated anterior mediastinal nodule demonstrating homogeneous contrast enhancement, radiologically mimicking a benign thymic cyst or thymoma. Following complete resection via video-assisted thoracoscopic surgery (VATS), histopathological examination demonstrated a cystic and solid tumor with conspicuous papillary architecture. Diagnostic interpretation was confounded by an atypical immunoprofile: The tumor was negative for the traditional thymic carcinoma markers CD5 and CD117, yet exhibited diffuse expression of paired box gene 8 and WT1, thereby closely resembling metastatic renal cell carcinoma or mesothelioma. A diagnosis was strongly supported through a rigorous process of exclusion, integrating an extended negative immunohistochemical panel (including Spalt-like transcription factor 4, thyroid transcription factor-1 and D2-40) with the morphological identification of residual atrophic thymic tissue at the tumor periphery. The tumor was classified as Masaoka-Koga stage I PAT, and the patient remained free of recurrence at the 6-month postoperative follow-up. The present case highlights the diagnostic pitfalls of PAT, particularly its deceptively benign imaging appearance and unusual immunophenotype. It emphasizes that CD5/CD117 negativity does not preclude a thymic origin, underscoring the necessity of a comprehensive, exclusion-based approach for accurate diagnosis.

  Copyright: © 2026 Zhu et al.

• Pembrolizumab as an effective treatment for diffuse malignant peritoneal mesothelioma with long‑term survival: A case report and literature review. C. Xue, Z. Dong, K. Tan, et al. 2025;29(4):187. Case report PubMed · Publisher · Free full text

  Abstract

  Primary diffuse malignant peritoneal mesothelioma (MPEM) is a malignant disease without standard treatments recommended. Recently, immunotherapy has revolutionized the field of tumor therapy. According to current clinical evidence, advanced MPEM may gain potential clinical benefits from immune checkpoint inhibitors. The present study reported a 61-year-old female patient with persistent low fever as the initial symptom, who was eventually diagnosed with MPEM. This patient obtained significant clinical benefits from pembrolizumab, with disappearance of symptoms, a lasting stable disease response with a progression-free survival of 10.0 months and a long overall survival of 26.2 months. The application of pembrolizumab was explored as an emerging effective treatment for patients with MPEM. In addition, the clinical characteristics, diagnosis, treatment, pathogenesis and target regulation in MPEM were discussed and previous studies were reviewed. Further evidence is needed from future extensive clinical trials.

  Copyright: © 2025 Xue et al.

• A rare malignant mesothelioma of the tunica vaginalis testis: A case report. Y. Jiang, Y. Cai, X. Xu, et al. 2024;27(4):172. Case report PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma of the tunica vaginalis testis is a rare, highly invasive urogenital malignant tumor with no specific clinical manifestations. Reported cases of this disease are limited. Therefore, an early preoperative diagnosis is difficult. The current study presents a case of malignant mesothelioma of the tunica vaginalis testis and a literature review. A 52-year-old man was admitted to Xiaoshan Affiliated Hospital of Wenzhou Medical University (Hangzhou, China) in December 2022 and underwent radical resection of the right testicle and epididymis but did not undergo radiotherapy or chemotherapy. The patient was followed up for 5 months, and no recurrence or metastasis was found. The rarity of testicular mesothelioma poses a challenge to its etiology and diagnosis, which is rarely achieved preoperatively. Malignant mesothelioma of the testicular tunica vaginalis has a poor prognosis and is not sensitive to radiotherapy or chemotherapy, requiring close postoperative follow-up. This condition is rare in clinical practice; therefore, it needs to be reported to aid clinicians' decision-making regarding diagnosis and treatment.

  Copyright: © 2024 Jiang et al.

• Biomarkers to predict the benefits of immune‑checkpoint blockade‑based therapy in patients with malignant peritoneal mesothelioma (Review). C. Wang, Y. Zhao, W. Liang. 2024;28(6):600. Review PubMed · Publisher · Free full text

  Abstract

  Malignant peritoneal mesothelioma (MPeM) is a type of rare and highly lethal tumor. Immune checkpoint blockade (ICB)-based therapy has shown encouraging clinical activity for MPeM. However, no definitive biomarkers have been identified for predicting which patients with MPeM will benefit from ICB-based therapy. At present, there are several novel potential biomarkers proposed for predicting the response to ICB-based therapy, and biomarkers available in MPeM cells and in the tumor microenvironment have been identified with the potential to predict the efficacy of ICB-based therapy in MPeM. According to the molecular characteristics of MPeM itself, the feasibility of biomarkers in practice, and the body of available evidence, we hypothesize that the following five types of biomarkers can be used to predict the response of ICB-based therapy in patients with MPeM: Tertiary lymphoid structures, immune checkpoints and their ligands, fusion gene neoantigen burden, BRCA1-associated protein-1 haploinsufficiency and transcriptome-based biomarkers. The present review discusses the value and limitations of each type of biomarker, and potential solutions to address the limitations are proposed. The aim of the present review is to provide a background for future studies on ICB-based therapy for MPeM.

  Copyright: © 2024 Wang et al.

• Successful treatment of simultaneous malignant pleural mesothelioma and pulmonary adenocarcinoma: A case report. Y. Amakusa, T. Suzuki, Y. Hikosaka, et al. 2024;27(4):155. Case report PubMed · Publisher · Free full text

  Abstract

  The present report described the case of a 74-year-old male patient with asbestos exposure whose chest computed tomography revealed a right lower lobe nodule and right pleural effusion. Pleural biopsy led to the diagnosis of epithelial malignant pleural mesothelioma (cT2N0M0, stage IB). Combination therapy with cisplatin + pemetrexed led to the complete remission of malignant pleural mesothelioma; however, the right lower lobe nodule grew in size over time. The patient was subsequently diagnosed with lung adenocarcinoma (cT1aN0M0, stage IA1) by computed tomography-guided biopsy performed 18 months after chemotherapy initiation and achieved remission of lung adenocarcinoma with stereotactic radiotherapy. The patient was alive without recurrence at the 12-month follow-up. The present case illustrated that multiple active regimens are currently available for malignant pleural mesothelioma and lung cancer that can aid in the treatment of complex cases.

  Copyright: © Amakusa et al.

• SHP2 is involved in the occurrence, development and prognosis of cancer. S. Li, J. Qu, X. Wang, et al. 2023;26(3):393. PubMed · Publisher · Free full text

  Abstract

  Src homology-2 domain-containing protein tyrosine phosphatase (SHP2), encoded by protein tyrosine phosphatase non-receptor type 11 (PTPN11), is widely expressed in several human tissue types, and plays an important role in a variety of diseases. The present study assessed the impact of SHP2 on the occurrence, development and prognosis of solid tumors. The transcriptome sequencing data of 33 cancer types were downloaded from The Cancer Genome Atlas database. Clinical information of the corresponding patients, tumor mutational burden and information pertinent to microsatellite instability were also downloaded. The log-rank test and univariate Cox's regression test were used to evaluate patient survival. The 'ESTIMATE' method was used to assess the tumor microenvironment, and the 'CIBERSORT' algorithm was used to evaluate tumor immune cell infiltration. Spearman's correlation analysis was used to evaluate the correlation between SHP2 expression and the targets identified. ELISA was used to assess the SHP2 expression levels in peripheral blood samples of patients with breast, ovarian, endometrial and cervical cancer. The data indicated that the expression levels of SHP2 were increased in a variety of tumor tissues, and were associated with tumor progression and prognosis. In peripheral blood, the positive rates of SHP2 expression in breast cancer (71.43%) and ovarian cancer (58.82%) were significantly higher than those in the corresponding control groups. However, the positive rates of SHP2 expression in patients with endometrial cancer (31.03%) and cervical cancer (41.30%) were significantly lower than those in the corresponding control groups. Increased SHP2 expression improved overall survival (OS) and disease free survival (DFS) time in patients with kidney renal clear cell carcinoma. However, increased SHP2 expression reduced OS and DFS in patients with urothelial carcinoma, and cervical and endocervical cancer types. Moreover, the elevated expression of SHP2 could also reduce the OS of patients with breast invasive carcinoma, mesothelioma and liver hepatocellular carcinoma. PTPN11 expression was associated with the tumor microenvironment of various tumor types. The tumor mutational burden of various tumor types was associated with microsatellite instability. PTPN11 inhibited T-cell activation and promoted M2 macrophage activation in several tumors. Therefore, SHP2 may be used in the evaluation of tumor progression and prognosis, and it may be an optimal potential biological target for cancer therapy.

  Copyright: © Li et al.

• SLC17A9 expression levels in a pan‑cancer panel and validation of the role of SLC17A9 as a novel prognostic biomarker for osteosarcoma. J. Li, F. Wu, L. Su, et al. 2023;26(3):383. PubMed · Publisher · Free full text

  Abstract

  Previous studies have demonstrated the involvement of the solute carrier family 17 member 9 (SLC17A9) in certain types of cancer; however, the precise role of SLC17A9 is not well defined. In the present study, a comprehensive analysis was performed to determine the involvement of SLC17A9 in a pan-cancer panel. First, data on SLC17A9 expression levels from publicly available databases were obtained to determine SLC17A9 expression profiles in various types of cancer. Next, the involvement of SLC17A9 in the prognosis of patients, stemness indices and the immune microenvironment was examined in 34 types of cancer. Furthermore, CCK-8 and colony-formation assays were performed to determine the effect of SLC17A9 on osteosarcoma (OSS) cells. In a pan-cancer panel, a difference in SLC17A9 expression levels was observed in the tumor tissues as compared with healthy tissues. Furthermore, survival analysis revealed a significant association between SLC17A9 expression levels and the prognosis of patients with various cancer types, including adrenocortical carcinoma, kidney renal clear cell carcinoma, glioblastoma, kidney renal papillary cell carcinoma, low grade glioma, liver hepatocellular carcinoma, mesothelioma, lung adenocarcinoma, skin cutaneous melanoma, uveal melanoma, stomach adenocarcinoma and OSS. The results of the present study revealed correlations between stemness indices, tumor immunity and SLC17A9 expression levels. Furthermore, univariate and multivariate Cox regression analyses indicated that SLC17A9 may be utilized as an independent risk factor for overall survival of patients with OSS. In vitro experiments demonstrated that SLC17A9 promotes the proliferation and viability of OSS cells. Taken together, the results of the present study suggest an association between SLC17A9 and the prognosis of patients as well as tumor immunity in various cancer types. SLC17A9 may serve as a novel prognostic biomarker and target for improving the prognosis of patients with OSS.

  Copyright: © Li et al.

• Downregulation of FTL decreases proliferation of malignant mesothelioma cells by inducing G1 cell cycle arrest. T. Kambara, V.J. Amatya, K. Kushitani, et al. 2022;23(6):174. PubMed · Publisher · Free full text

  Abstract

  Pleural malignant mesothelioma is a malignant tumor with a poor prognosis that is strongly associated with asbestos exposure during its development. Because there is no adequate treatment for malignant mesothelioma, investigation of its molecular mechanism is important. The ferritin light chain (FTL) is a subunit of ferritin, and its high expression in malignant tumors, including malignant mesothelioma, has recently been reported; however, its role in malignant mesothelioma is unclear. The purpose of the present study was to clarify the function of FTL in malignant mesothelioma. The expression levels of FTL in malignant mesothelioma were examined using the Cancer Cell Line Encyclopedia database and our previous data. The short interfering (si)RNA against FTL was transfected into two mesothelioma cell lines, ACC-MESO-1 and CRL-5915, and functional analysis was performed. Expression of p21, p27, cyclin-dependent kinase 2 (CDK2) and phosphorylated retinoblastoma protein (pRb) associated with the cell cycle were examined as candidate genes associated with FTL. The expression levels of the FTL mRNA were higher in malignant mesothelioma compared with other tumors in the Cancer Cell Line Encyclopedia database, and among other genes in our previous study. Reverse transcription-quantitative PCR and western blotting demonstrated suppression of FTL expression in two cell lines transfected with FTL siRNA compared with cells transfected with negative control (NC) siRNA. In the two cell lines transfected with FTL siRNA, proliferation was significantly suppressed, and cell cycle arrest was observed in the G1 phase. The levels of p21 and p27 were increased, while those of CDK2 and pRb were decreased compared with NC. However, no significant differences in invasion and migration ability were revealed between FTL siRNA-transfected cells and NC. In conclusion, FTL may increase the proliferative capacity of malignant mesothelioma cells by affecting p21, p27, CDK2 and pRb, and promoting the cell cycle at the G1 phase.

  Copyright: © Kambara et al.

• Establishment and characterization of NCC-DMM1-C1, a novel patient-derived cell line of desmoplastic malignant pleural mesothelioma. R. Noguchi, Y. Yoshimatsu, T. Ono, et al. 2022;23(2):64. PubMed · Publisher · Free full text

  Abstract

  Desmoplastic malignant pleural mesothelioma (DMM) is a rare histological variant of malignant pleural mesothelioma, which is a highly aggressive neoplasm of the mesothelium. DMM is associated with distant metastases and short survival. Effective treatments for DMM are not established and the development of histotype-tailored treatments is difficult due to the rarity of the disease. Although patient-derived cancer models are crucial tools for the development of novel therapeutics, they are difficult to obtain for DMM; no DMM cell lines or xenografts are available from public biobanks and only two cell lines have been reported. Thus, the present study aimed to establish a novel cell line of DMM as a resource for drug screening. A cell line of DMM was established, designated as NCC-DMM1-C1, using surgically resected tumor tissues from a 73-year-old male patient with DMM. Characteristics of NCC-DMM1-C1 cells were examined, such as growth, spheroid formation and invasion capability. Drug targets and anti-cancer drugs with anti-proliferative efficacy were examined using a comprehensive kinase activity assay and drug screening of 213 anti-cancer agents, respectively. NCC-DMM1-C1 exhibited fast growth, spheroid formation and invasion capability, suggesting that the NCC-DMM1-C1 cells retained the aggressive features of DMM. NCC-DMM1-C1 cells and the tumor tissue shared common activity profiles of kinases, which included FES, Wee1, platelet-derived growth factor receptor-β and Src. The drug screening revealed that bortezomib, fostamatinib, gemcitabine, homoharringtonine and vinorelbine had anti-proliferative effects, which have not been previously reported for DMM. It was concluded that NCC-DMM1-C1 cells may be a useful tool for the study of DMM.

  Copyright: © Noguchi et al.

• Organic extract of Geodia cydonium induces cell cycle block in human mesothelioma cells. F. Di Meo, R. Esposito, R. Cuciniello, et al. 2022;24(2):286. PubMed · Publisher · Free full text

  Abstract

  The serious side effects caused by chemotherapeutics and the development of cancer chemoresistance represent the most significant limitations in the treatment of cancer. Some alternative approaches have been developed in recent years, which are based on natural compounds, and have allowed important advances in cancer therapeutics. During the last 50 years, sponges have been considered a promising source of natural products from the marine environment, representing ~30% of all marine natural products. Among sponges, the Mediterranean species Geodia cydonium represents a potential source of these type of products with considerable biotechnological interest as pharmaceutical agents. The present study demonstrated the antiproliferative effect of an organic G. cydonium extract (GEOCYDO) against three human mesothelioma cell lines, MSTO-211H (MSTO), NCI-H2452 (NCI) and Ist-Mes2 (Mes2), which differ in their sensitivity (MSTO and NCI) and resistance (Mes2) to standard combined treatment with cisplatin and piroxicam. To this aim, the activity of the extract was evaluated by analyzing its effects on cell viability, cancer properties and cell cycle progression by means of colony formation assay, cell cycle analysis and protein expression analysis. The results revealed, in mesothelioma, this extract was able to reduce self-renewal, cell migration and it could induce cell cycle arrest in G0/G1 stage, thus blocking cell proliferation. In conclusion, to the best of our knowledge, the present results indicated for the first time that GEOCYDO can contain active compounds able to affect cell proliferation in mesothelioma, suggesting that it could be considered as a potential novel drug source for cancer treatment.

  Copyright: © Di Meo et al.

• Sarcomatoid malignant pleural mesothelioma treated with nivolumab: A case series. K. Hashimoto, H. Ozasa, A. Yoshizawa, et al. 2022;24(5):402. PubMed · Publisher · Free full text

  Abstract

  Immune checkpoint therapy (ICT) with nivolumab has been widely used to treat malignant pleural mesothelioma (MPM) since clinical trials confirmed its efficacy. However, only a few clinical trials have been conducted for the treatment of sarcomatoid MPM, which is a rare histological type of MPM. Additionally, clinical reports of sarcomatoid MPM are scarce. Therefore, the benefits and risks of nivolumab treatment for sarcomatoid MPM remain unclear. The present report describes the treatment of 3 cases of sarcomatoid MPM (all 3 were men) with nivolumab monotherapy. In all three cases, nivolumab was effective despite variations in the duration of treatment, although side effects were observed in 2 patients. Programmed death ligand 1 (PD-L1) expression was positive in all 3 cases. In particular, the patient with the highest PD-L1 expression had the most rapid response of the 3 patients, and the effect lasted as long as those of the other 2, despite receiving the smallest number of doses of nivolumab. It has been reported that sarcomatoid MPM tends to respond poorly to chemotherapy and express higher levels of PD-L1 than epithelial MPM; thus, ICT may be necessary in these cases. This case series suggests that ICT with nivolumab is a promising treatment option for sarcomatoid MPM.

  Copyright: © Hashimoto et al.

• Usefulness of malignant pleural effusion for early cytological diagnosis of mesothelioma in situ: A case report. Y. Yabuuchi, K. Hiroshima, H. Oshima, et al. 2022;24(6):440. PubMed · Publisher · Free full text

  Abstract

  Mesothelioma in situ (MIS) is defined as a preinvasive mesothelioma that forms a single layer of mild atypical mesothelial cells lining on the serosa surface of pleura. The atypical mesothelial cells present loss of BRCA-1 associated protein-1 (BAP-1) and/or methylthioadenosine phosphorylase as examined by immunohistochemistry (IHC) and/or homozygous deletion of cyclin-dependent kinase inhibitor 2A/p16 as examined by fluorescence in situ hybridization. It is difficult to diagnose because of the unremarkable clinical findings except for pleural effusion. The present report describes a case in which MIS was diagnosed at the time of sampling due to the presence of clearly malignant mesothelial cells in the pleural fluid. In 2016, a 74-year-old man with a history of past exposure to asbestos was admitted to Ibaraki Higashi National Hospital (Tokai-mura, Japan) with dyspnea. Chest CT indicated only right pleural effusion. Malignant mesothelial cells were suspected in a cell block made using pleural effusion; therefore, right pleural biopsy was performed. Pathologically, there was proliferation of mesothelial cells with mild atypia that formed a single-flat layer on the pleural surface; however, there was no invasion. Furthermore, IHC revealed loss of BAP-1 in cells from the biopsied pleura and pleural effusion. MIS was suspected at the time; however, the patient arbitrarily quit his medical check-ups. After 44 months, the patient was readmitted to our hospital complaining of dyspnea. CT indicated a large right pleural mass. A specimen of the mass obtained via CT-guided needle biopsy revealed malignant mesothelioma. The patient continued to deteriorate and eventually died. This case indicated that pleural effusion could be used to demonstrate overtly malignant mesothelial cells and diagnose MIS at the time of sampling. To the best of our knowledge, this is first report of MIS with overtly malignant mesothelial cells in pleural effusion. Pleural effusion may serve an important role in MIS diagnosis.

  Copyright: © Yabuuchi et al.

• Novel circulating tumor cell-detection chip combining conventional podoplanin and EGFR antibodies for all histological malignant pleural mesothelioma. M. Kanayama, R. Oyama, M. Mori, et al. 2021;22(1):522. PubMed · Publisher · Free full text

  Abstract

  In our previous study, a microfluidic system was developed based on podoplanin detection for capturing circulating tumor cells (CTCs), derived from malignant pleural mesothelioma (MPM). However, non-epithelioid MPM shows low podoplanin protein expression compared with that in epithelioid MPM; thus, some CTC populations may be missed. To overcome this limitation, a new CTC-detection chip was developed by combining the conventional podoplanin antibody (clone: NZ-1.2) with an epidermal growth factor receptor (EGFR)-targeted antibody (cetuximab). The cell-capture efficiency of the Cocktail-chip reached 100% in all the histological MPM cell lines. The median CTC-counts from 19 patients with MPM (epithelioid/non-epithelioid: 10/9) with the NZ-1.2- and Cocktail-chips were 1 and 3 (P=0.311) in 1 ml peripheral blood, 1.5 and 2 (P=0.332) in epithelioid MPM, and 1 and 3 (P=0.106) in non-epithelioid MPM, respectively. Overall, the Cocktail-chip showed an improved ability to detect more CTCs in patients with non-epithelioid MPM compared with that in the conventional NZ-1.2-chip, showing non-significant, but higher CTC detection. Furthermore, CTC-counts, determined using the Cocktail-chip were significantly correlated with the clinical stage of non-epithelioid MPM. In epithelioid MPM, the Cocktail-chip achieved a CTC-detection efficiency equivalent to that in the conventional NZ-1.2-chip. The Cocktail-chip enabled sensitive CTC detection of all histological MPM, including the non-epithelioid subtype, which may provide a foundation for the diagnosis, treatment, and prognosis of MPM progression.

  Copyright: © Kanayama et al.

• Bex1 significantly contributes to the proliferation and invasiveness of malignant tumor cells. T. Doi, H. Ogawa, Y. Tanaka, et al. 2020;20(6):362. PubMed · Publisher · Free full text

  Abstract

  Invasion has a significant role in cancer progression, including expansion to surrounding tissue and metastasis. Previously, we assessed the invasive ability of cancer cells using an easy-to-prepare double-layered collagen gel hemisphere (DL-CGH) method by which cancer cell invasion can be easily visualized. The present study examined multiple lung adenocarcinoma and malignant pleural mesothelioma (MPM) cell lines using the DL-CGH method and identified inherently invasive cell lines. Next, by comparing gene expression between invasive and non-invasive cells by cDNA microarray, the potential candidate gene brain-expressed x-linked protein 1 (Bex1) was identified to be involved in cancer invasion, as it was highly expressed in the invasive cell lines. Downregulation of Bex1 suppressed the invasion and proliferation of the invasive tumor cell lines. The findings of the present study suggested that Bex1 may promote metastasis in vivo and could be a potential oncogene and molecular therapeutic target in lung adenocarcinoma and MPM.

  Copyright: © Doi et al.

• Diffuse mesothelin expression leads to worse prognosis through enhanced cellular proliferation in colorectal cancer. S. Inoue, T. Tsunoda, M. Riku, et al. 2020;19(3):1741-1750. PubMed · Publisher · Free full text

  Abstract

  Mesothelin (MSLN) is a glycophosphatidylinositol (GPI)-linked cell surface protein that is highly expressed in several types of malignant tumor, including malignant pleural mesothelioma, ovarian cancer and pancreatic adenocarcinoma. Recently, a comprehensive immunohistochemical study using MN-1 monoclonal antibody identified a significant number of colorectal tumors in which MSLN was expressed. However, the clinicopathological profiles and survival of patients with MSLN-positive colorectal cancer have not been fully analyzed. In the current study, the expression of MSLN in 270 primary and 44 metastatic colorectal tumors was immunohistochemically analyzed to determine the clinical usefulness of MSLN immunohistochemistry and to identify potential candidates for future anti-MSLN therapy. In vitro experiments using colon cancer cell lines were performed to investigate the biological significance of MSLN expression in tumors. The results of univariate analyses identified a significant correlation between MSLN expression and females (P=0.0042). Furthermore, an inverse correlation between MSLN expression and solid/sheet-like proliferation (P=0.014) was also revealed. Additionally, overall survival was significantly shorter in patients with diffuse luminal/membranous expression of MSLN (P=0.018). Multivariable Cox hazards regression analysis revealed diffuse MSLN expression (hazard ratio, 2.26; 95% confidence interval, 1.04-4.91; P=0.039) as a potential risk factor. When comparing primary CRCs and the metastasis of each, a weakly positive correlation was identified for MSLN positivity (% positive cells; R=0.484; P<0.0001). The in vitro experiments revealed a positive role for MSLN in colon cancer cell proliferation. Thus, MSLN immunohistochemistry may be useful in the prognostication of patients with CRC. The results demonstrated that significant numbers of patients with MSLN-positive CRC exhibiting metastasis could be targeted by anti-MSLN therapies.

  Copyright: © Inoue et al.

• Survivin expression as an independent predictor of overall survival in malignant peritoneal mesothelioma. G. Zhang, D.L. Yang, G. Zheng, et al. 2020;19(6):3871-3880. PubMed · Publisher · Free full text

  Abstract

  Malignant peritoneal mesothelioma (MPeM) is an incurable cancer strongly associated with asbestos exposure and characterised by poor prognosis. The aim of the present study was to elucidate the prognostic and predictive value of CD146 and survivin expression in MPeM. Diagnostic biopsies from 60 patients with MPeM were collected and analysed for CD146, survivin and Ki-67 expression using immunohistochemistry. Complete clinical and follow-up information was obtained from patients' records. CD146 was expressed in 31/60 MPeM specimens and survivin in 34/60 specimens, with both expression levels being significantly associated with the Ki-67 labelling index (Ki-67LI). Kaplan-Meier and univariate Cox regression analyses revealed that a lower peritoneal cancer index (PCI), tumour-directed treatment, stage I, lower Ki-67LI and lower CD146 and survivin expression had a statistically positive effect on overall survival (OS). Cox regression analysis revealed that PCI [hazard ratio (HR)=1.99; 95% CI, 1.04-3.83; P=0.038], survivin (HR=1.47; 95% CI, 1.03-2.10; P=0.034) and treatment protocol including intraperitoneal chemotherapy (HR=0.28; 95% CI, 0.14-0.57; P=0.013) and systemic chemotherapy (HR=0.13; 95% CI, 0.04-0.42; P=0.013) retained independent prognostic significance for OS. All of these were included in the nomogram. Calibration curves showed good agreement between nomogram-predicted and observed survival. The C-index of the nomogram for predicting OS was 0.77. A lower PCI, intraperitoneal chemotherapy, systemic chemotherapy and a lower level of survivin were powerful prognostic markers in patients with MPeM. The proposed nomogram provides individual survival prediction for patients with MPeM.

  Copyright: © Zhang et al.

2010s

• Diagnosis of mesothelioma with deep learning. X. Hu, Z. Yu. 2019;17(2):1483-1490. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma (MM) is a rare but aggressive cancer. The definitive diagnosis of MM is critical for effective treatment and has important medicolegal significance. However, the definitive diagnosis of MM is challenging due to its composite epithelial/mesenchymal pattern. The aim of the current study was to develop a deep learning method to automatically diagnose MM. A retrospective analysis of 324 participants with or without MM was performed. Significant features were selected using a genetic algorithm (GA) or a ReliefF algorithm performed in MATLAB software. Subsequently, the current study constructed and trained several models based on a backpropagation (BP) algorithm, extreme learning machine algorithm and stacked sparse autoencoder (SSAE) to diagnose MM. A confusion matrix, F-measure and a receiver operating characteristic (ROC) curve were used to evaluate the performance of each model. A total of 34 potential variables were analyzed, while the GA and ReliefF algorithms selected 19 and 5 effective features, respectively. The selected features were used as the inputs of the three models. SSAE and GA+SSAE demonstrated the highest performance in terms of classification accuracy, specificity, F-measure and the area under the ROC curve. Overall, the GA+SSAE model was the preferred model since it required a shorter CPU time and fewer variables. Therefore, the SSAE with GA feature selection was selected as the most accurate model for the diagnosis of MM. The deep learning methods developed based on the GA+SSAE model may assist physicians with the diagnosis of MM.

• Capture of mesothelioma cells with 'universal' CTC-chip. K. Yoneda, Y. Chikaishi, T. Kuwata, et al. 2018;15(2):2635-2640. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma (MM) is a highly aggressive malignant tumor, predominantly associated with job-related exposure to asbestos. Development of effective and non-invasive modalities for diagnosis is an important issue in occupational medicine. Circulating tumor cells (CTCs), which are tumor cells that are shed from primary tumors and circulate in the peripheral blood, may be detected at an earlier stage than malignant tumors, and detection of CTCs may provide a novel insight into the diagnosis of MM. In a previous study evaluating clinical utility of CTCs, detected with a widely used system 'CellSearch', the authors indicated a significant however insufficient capability in the diagnosis of MM, suggesting need for a more sensitive system. Accordingly, the authors developed a novel microfluidic system to capture CTCs (CTC-chip), and demonstrated that the CTC-chip effectively captured MM cells (ACC-MESO-4) spiked in the blood by conjugating an anti-podoplanin antibody. The results of the present study demonstrated that the CTC-chip coated with the anti-podoplanin antibody captured another MM cell (ACC-MESO-1). However, the capture efficiencies were lower than those for ACC-MESO-4. In addition, an anti-mesothelin antibody was used to capture CTCs, however the CTC-chip coated with the anti-mesothelin antibody failed to effectively capture MM cells, possibly due to low mesothelin expression. Overall, the CTC-chip may capture specific types of CTCs by conjugating any antibody against an antigen expressed on CTCs, and may be a useful system for the diagnosis of malignant tumors, including MM.

• Synergistic effect of targeting dishevelled-3 and the epidermal growth factor receptor-tyrosine kinase inhibitor on mesothelioma cells in vitro. G. Moriyama, M. Tanigawa, K. Sakai, et al. 2018;15(1):833-838. PubMed · Publisher · Free full text

  Abstract

  It was previously revealed that Wnt signaling is activated in mesothelioma cells. Although epidermal growth factor receptor (EGFR) is expressed in mesothelioma cells, EGFR-tyrosine kinase inhibitors (TKIs) are not effective for mesothelioma treatment. However, in non-small cell lung cancer, the blocking of Wnt signaling has been identified to enhance the anticancer effect of EGFR-TKIs. To confirm the anticancer effect of blocking Wnt signaling in combination with EGFR-TKI treatment in mesothelioma, the present study evaluated the effect of simultaneous suppression of human dishevelled-3 (Dvl-3) expression with Dvl-3 small interfering RNA (siRNA) and of EGFR inhibition with gefitinib on mesothelioma cell viability. Mesothelioma cell lines with and without β-catenin gene expression were transfected with Dvl-3 siRNA and were cultured with gefitinib, and cell viability, colony formation and cell cycle analyses were performed. Dvl-3 siRNA downregulated the expression of Dvl-3 in mesothelioma cells. The combination of Dvl-3 siRNA with gefitinib acted synergistically to induce concomitant suppression of cell viability and colony formation, suggesting that inhibition of Wnt signaling by downregulating Dvl-3 with siRNA and inhibiting EGFR with gefitinib leads to significant antitumor effects.

• Utility of Survivin, BAP1, and Ki-67 immunohistochemistry in distinguishing epithelioid mesothelioma from reactive mesothelial hyperplasia. K. Kushitani, V.J. Amatya, A.S. Mawas, et al. 2018;15(3):3540-3547. PubMed · Publisher · Free full text

  Abstract

  Histological distinction between epithelioid mesothelioma (EM) and reactive mesothelial hyperplasia (RMH) can be challenging. The aim of this study was to assess the diagnostic utility of Survivin, Ki-67, and loss of BRCA1-associated protein 1 (BAP1) expressions in distinguishing EM from RMH using immunohistochemistry. Formalin-fixed, paraffin-embedded specimens from 78 cases of EM and 80 cases of RMH were immunohistochemically examined for Survivin, BAP1, and Ki-67. In addition, receiver operating characteristic curve analyses were performed to establish the cut-off values for Survivin and Ki-67 labelling indices. Survivin (cut-off value: 5%) had 67.7% sensitivity and 100% specificity, while Ki-67 (cut-off value: 10%) had 85.1% sensitivity and 87.5% specificity, and BAP1 had 66.2% sensitivity and 100% specificity for the differentiation of EM from RMH. Among the combinations of two markers, the combination of Survivin and BAP1 (Survivin-positive and/or BAP1-loss finding) had the highest diagnostic accuracy (sensitivity: 89.8%; specificity: 100%; accuracy: 95.3%). We recommend using the combination of Survivin and BAP1 to distinguish EM from RMH.

• Identification of tumor antigens in malignant mesothelioma. Y.R. Kim, M.H. Song, J.W. Lee, et al. 2017;14(4):4557-4562. PubMed · Publisher · Free full text

  Abstract

  Serological analysis of recombinant tumor cDNA expression library (SEREX) is a powerful and widely used method to explore the cancer immune environment. In the present study, immunoscreening of normal testicular tissues and malignant mesothelioma (MM) cancer MSTO-211H cell line cDNA libraries with sera from 5 MM patients led to the isolation of 16 independent antigens, which were designated 'Korea Pusan-Malignant Mesothelioma' (KP-MM)-1 to -16. In total, 3/16 antigens were identified using the results of previous SEREX analyses, and 13 were newly identified. Of these, KP-MM-8, which was subsequently identified as amyotrophic lateral sclerosis 2 chromosome region candidate 11, was shown to be tissue-restricted. Reverse transcription-polymerase chain reaction demonstrated KP-MM-8 to be expressed strongly only in the normal testis, and weakly in the spleen, prostate, ovary, heart and skeletal muscle. In addition, KP-MM-8 mRNA was identified in MM cell lines, and in various other cancer cell lines, including MM (3/4), lung cancer (5/7), melanoma (5/7) and liver cancer (5/5) cell lines. Additionally, 2/16 antigens (KP-MM-2 and KP-MM-6) exclusively reacted with sera from cancer patients. However, KP-MM-8 reacted with 1 of 8 MM sera. Notably, 8/8 patients with MM and 8/8 normal individuals exhibited antibodies reactive to KP-MM-5, which was identified as cell division cycle 25B, a known oncogene. Overall, this data suggests that KP-MM-8 may be considered as a cancer/testis-like antigen and KP-MM-5 as an immunogenic tumor antigen in MM patients.

• The diagnostic utility of PAX8 immunostaining of malignant peritoneal mesothelioma presenting as serous ovarian carcinoma: A single-center report of two cases. K. Nakamura, K. Nakayama, R. Nagaoka, et al. 2017;13(1):263-266. PubMed · Publisher · Free full text

  Abstract

  Malignant peritoneal mesotheliomas (MPMs) are rare and progressive tumors, which may present similarly to primary peritoneal carcinoma or ovarian carcinoma (OC). The current study reports two cases of MPM that initially presented with the features of OC, for which paired box 8 (PAX8) immunostaining was found to be useful for diagnosis. The two patients were women, aged 58 and 56 years, respectively. The primary presenting symptoms and clinical findings included prolonged abdominal pain, abdominal swelling and cough. The two cases were initially diagnosed as OC and were treated with primary debulking surgery. The patient in case 1 had no history of asbestos exposure, while the patient in case 2 did. Final diagnoses were determined based on histological and immunohistochemical results, which included negative PAX8 immunostaining, and which were consistent with MPM. The present cases demonstrated that PAX8 negativity may be a useful diagnostic biomarker for differentiating MPM from OC.

• Fluoro-edenite induces fibulin-3 overexpression in non-malignant human mesothelial cells. V. Rapisarda, R. Salemi, A. Marconi, et al. 2016;12(5):3363-3367. PubMed · Publisher · Free full text

  Abstract

  Exposure to asbestos is associated with the development of mesothelioma. In addition to asbestos, other fibers have been identified as risk factors for malignant and non-malignant diseases of the lungs. Among these, fluoro-edenite (FE) was found in patients from Biancavilla (Sicily, Italy) with pleural and lung disease, suggesting its role for tumor expansion. In this context, the identification of early biomarkers useful for the diagnosis of cancer is mandatory. Fibulin-3 represents an important marker for the diagnosis of mesothelioma. However, it remains to be determined whether it is directly associated with exposure to asbestos-like fibers. In the present study, peripheral blood levels of fibulin-3 from 40 asbestos-exposed workers were compared with those detected in 27 street cleaners from Biancavilla. Intriguingly, the results showed that fibulin-3 levels were higher in the group of street cleaners compared with those of the asbestos-exposed workers, suggesting that these workers used the personal protective equipment according to the current regulations. These data suggest that subjects exposed to FE should be monitored for the risk of mesothelioma. FE and volcanic particulates are probably contained within dust inhaled by street cleaners from Biancavilla during their work activities. Based on these criteria, in this study, such fibers were used to treat mesothelial cells (MeT5A) in order to verify whether fibulin-3 levels are affected by these treatments. The results showed that only treatment with FE was associated with fibulin-3 overexpression at both the transcript and protein levels. It was previously demonstrated that mesothelial cells exhibited low levels of p27 following treatment with FE. Notably, p27 downregulation is associated with stathmin upregulation in cancer, conferring an aggressive phenotype of tumor cells. This observation prompted us to perform a computational evaluation demonstrating the activation of stathmin in lung cancer in patients exposed to asbestos. Overall, it can be speculated that both fibulin-3 and stathmin overexpression may be associated with the malignant transformation of mesothelial cells following exposure to asbestos-like fibers.

• Malignant peritoneal mesothelioma in a patient with intestinal fistula, incisional hernia and abdominal infection: A case report. S. Hong, M.M. Bi, P.W. Zhao, et al. 2016;11(3):2047-2050. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma is a rare type of cancer, most commonly associated with exposure to asbestos. Mesothelioma of the peritoneum, the membrane lining the abdominal cavity, is extremely rare. The current study reports the case of a 60-year-old female who presented with intestinal fistula, recurrent incisional hernia and abdominal infection, with no history of asbestos exposure, and was diagnosed with clear cell MPM. Computed tomography scans of the abdomen revealed extensive small bowel adhesions and massive peritoneal effusion. Histological examination of biopsy specimens indicated a diagnosis of malignant peritoneal mesothelioma with clear cell morphology. A laparotomy was performed, with subsequent resection of the bowel with fistula. Follow-up examination performed at 1-year post-surgery revealed that the patient was alive and in generally good health.

• Simian virus 40 may be associated with developing malignant pleural mesothelioma. T.D. Thanh, N.V. Tho, N.S. Lam, et al. 2016;11(3):2051-2056. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is associated with a history of heavy, long-term exposure to asbestos. However, MPM may also be associated with simian virus 40 (SV40), a polyomavirus. The association between SV40 and MPM remains unclear. The present study was conducted in order to investigate the proportion of SV40 presence in the histological specimens of Vietnamese patients with MPM. Histological specimens were obtained from 45 patients (19 men and 26 women) with MPM at the Pham Ngoc Thach Hospital in Ho Chi Minh City, Vietnam. The specimens were processed and examined in order to detect the presence of the SV40 large T antigen (SV40 Tag) expression using immunohistochemistry. Of the 45 patients, 23 (51%) were epithelioid, 7 (16%) were biphasic, 6 (13%) were sarcomatoid, 4 (9%) were desmoplastic, 4 (9%) were well-differentiated papillary and 1 (2%) was the anaplastic subtype. In total, 9/45 patients (20%) demonstrated SV40 Tag expression. The proportion of patients that demonstrated SV40 Tag expression was not significantly different between the epithelioid subtype and the other subtypes (22 vs. 18%; P=1.000) or between the patients with stage IV disease and other stages (20 vs. 20%; P=1.000). The median survival time was not significantly different between the patients with or without SV40 Tag expression (196 vs. 236 days, P=0.8949). In summary, a 5th of the Vietnamese patients with MPM were associated with infection with SV40. SV40 may be a potential cause of MPM in Vietnam and this potential association requires additional studies.

• Small bowel metastasis from pancreatic cancer in a long-term survival patient with synchronous advanced malignant pleural mesothelioma: A case report and literature review. M. Fasano, C.M. Della Corte, G. Vicidomini, et al. 2016;12(6):4505-4509. PubMed · Publisher · Free full text

  Abstract

  Diffuse malignant pleural mesothelioma (MPM) is an aggressive tumor that originates from the surface of the pleura. Approximately 70% of cases are associated with chronic asbestos exposure. MPM is regarded as an incurable disease, with a median survival of ~2 years following intensive multimodality treatment. Pancreatic cancer is a malignancy also associated with a poor prognosis, with only 2% of patients surviving for 5 years. The majority of patients with pancreatic cancer are diagnosed with an advanced stage of disease and experience a poor response to therapy. The development of synchronous MPM and other types of cancer is rare. The present study describes a patient with synchronous, biphasic MPM and pancreatic adenocarcinoma, who was treated with a multimodal therapeutic approach with stereotactic body radiation therapy. Due to a suspected diagnosis of 'acute abdomen', an emergency small intestine resection was performed and a subsequent diagnosis of moderately-differentiated adenocarcinoma was confirmed. During a further immunohistochemical examination, pathologists determined that the small bowel metastasis descended from pancreatic cancer. The onset of bowel metastasis is an event rarely associated with MPM, and has not been previously described in the literature for cases of pancreatic cancer. Therefore, to the best of our knowledge, the present study describes the first case of intestinal metastasis from pancreatic cancer in a long-term survival patient with biphasic MPM.

• The proliferative effects of asbestos-exposed peripheral blood mononuclear cells on mesothelial cells. Y. Maki, Y. Nishimura, S. Toyooka, et al. 2016;11(5):3308-3316. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma (MM) is thought to arise from the direct effect of asbestos on mesothelial cells. However, MM takes a long time to develop following exposure to asbestos, which suggests that the effects of asbestos are complex. The present study examined the effects of asbestos exposure on the cell growth of MeT-5A human mesothelial cells via cytokines produced by immune cells. Peripheral blood mononuclear cells (PBMCs) were stimulated with antibodies against cluster of differentiation (CD)3 and CD28 upon exposure to the asbestos chrysotile A (CA) or crocidolite (CR); the growth of MeT-5A cells in media supplemented with PBMC culture supernatants was subsequently examined. MeT-5A cells exhibited an increase in proliferation when grown in supernatant from the 7-day PBMC culture exposed to CA or CR. Analysis of cytokine production demonstrated increased levels of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1α, IL-1β, IL-3, IL-5, IL-13 and IL-17A in supernatants. Individual administration of these cytokines, excluding G-CSF and GM-CSF, led to an increase in cell growth of MeT-5A, whereas this effect was not observed following the combined administration of these cytokines. The results indicate that cytokines secreted by immune cells upon exposure to asbestos cause an increase in the growth activity of mesothelial cells, suggesting that alterations in the production of cytokines by immune cells may contribute to tumorigenesis in individuals exposed to asbestos.

• Detection of pleural plaques in workers exposed to inhalation of natural fluoro-edenite fibres. V. Rapisarda, C. Ledda, V. Ricceri, et al. 2015;9(5):2046-2052. PubMed · Publisher · Free full text

  Abstract

  Fluoro-edenite is a natural mineral species initially isolated in Biancavilla, Sicily. The fibres are similar in size and morphology to certain amphibolic asbestos fibres, the inhalation of which may cause chronic inflammation and cancer. Occupational asbestos exposure is known to be associated with pleural and lung diseases, including pleural plaques. The aim of this study was to report the pleural and lung parenchymal lesions detected by high-resolution computed tomography (HRCT) in a group of construction workers exposed to fluoro-edenite. Information regarding life habits and occupational history was collected from 43 workers enrolled into the study. The participants underwent physical examination, blood analysis, search for uncoated fibres and ferruginous bodies in the sputum, pulmonary function tests, including diffusion capacity for carbon monoxide (TLCO), and HRCT chest imaging. A general descriptive outcome analysis was also conducted; a prevalence ratio (PR) with 95% confidence interval and a two-tailed test P-value were calculated for pleural plaques using log-binomial regression, measuring plaque size and thickness, and cumulative exposure index (CEI). The mean values of the functional respiratory tests were within the normal range for all participants. A restrictive ventilatory defect was identified in two (5%) subjects and an obstructive ventilatory defect in three (7%) subjects. TLCO was reduced in two additional participants. Fibres were detected in 19 (44%) of subjects. Pleural involvement was documented in 39 (91%) workers, of whom 31 (72%) had bilateral plaques. Calcifications were detected in 25 (58%) of these participants. PR indicated a progressive increase in the risk of developing pleural lesions with rising CEI, i.e. length of exposure. The present findings demonstrate for the first time the presence of pleural plaques in the lungs of subjects exposed to fluoro-edenite fibres, and not to asbestos, through residing in Biancavilla and through their occupation.

• DNA copy number gains in malignant pleural mesothelioma. M. Furukawa, S. Toyooka, T. Hayashi, et al. 2015;10(5):3274-3278. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with an extremely poor prognosis. The incidence of MPM is increasing as a result of widespread exposure to asbestos. The molecular pathogenesis of MPM remains unclear. The present study analyzed the frequency of various genomic copy number gains (CNGs) in MPM using reverse transcription-quantitative polymerase chain reaction. A total of 83 primary MPMs and 53 primary lung adenocarcinomas were analyzed to compare the CNGs of EGFR, KRAS, MET, FGFR1 and SOX2. In MPM, the CNGs of EGFR, KRAS, MET, FGFR1 and SOX2 were detected in 12 (14.5%), 8 (9.6%), 5 (6.0%), 4 (4.8%) and 1 (1.2%) of the samples, respectively. In lung adenocarcinomas, the CNGs of EGFR, KRAS, MET, FGFR1 and SOX2 were detected in 21 (39.6%), 12 (22.6%), 5 (9.4%), 10 (18.9%) and 0 (0.0%) of the samples, respectively. The CNGs of EGFR, KRAS and FGFR1 were significantly less frequent in the MPMs compared with the lung adenocarcinomas (P=0.0018, 0.048 and 0.018, respectively). Overall, the MPMs exhibited these CNGs less frequently compared with the lung adenocarcinomas (P=0.0002). The differences in CNGs between the two tumor types suggested that they are genetically different.

• Multiple regulatory mechanisms of hepatocyte growth factor expression in malignant cells with a short poly(dA) sequence in the HGF gene promoter. K. Sakai, M. Takeda, I. Okamoto, et al. 2015;9(1):405-410. PubMed · Publisher · Free full text

  Abstract

  Hepatocyte growth factor (HGF) expression is a poor prognostic factor in various types of cancer. Expression levels of HGF have been reported to be regulated by shorter poly(dA) sequences in the promoter region. In the present study, the poly(dA) mononucleotide tract in various types of human cancer cell lines was examined and compared with the HGF expression levels in those cells. Short deoxyadenosine repeat sequences were detected in five of the 55 cell lines used in the present study. The H69, IM95, CCK-81, Sui73 and H28 cells exhibited a truncated poly(dA) sequence in which the number of poly(dA) repeats was reduced by ≥5 bp. Two of the cell lines exhibited high HGF expression, determined by reverse transcription quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The CCK-81, Sui73 and H28 cells with shorter poly(dA) sequences exhibited low HGF expression. The cause of the suppression of HGF expression in the CCK-81, Sui73 and H28 cells was clarified by two approaches, suppression by methylation and single nucleotide polymorphisms in the HGF gene. Exposure to 5-Aza-dC, an inhibitor of DNA methyltransferase 1, induced an increased expression of HGF in the CCK-81 cells, but not in the other cells. Single-nucleotide polymorphism (SNP) rs72525097 in intron 1 was detected in the Sui73 and H28 cells. Taken together, it was found that the defect of poly(dA) in the HGF promoter was present in various types of cancer, including lung, stomach, colorectal, pancreas and mesothelioma. The present study proposes the negative regulation mechanisms by methylation and SNP in intron 1 of HGF for HGF expression in cancer cells with short poly(dA).

• Adenovirus-mediated REIC/Dkk-3 gene therapy: Development of an autologous cancer vaccination therapy (Review). M. Watanabe, Y. Nasu, H. Kumon. 2014;7(3):595-601. PubMed · Publisher · Free full text

  Abstract

  Reduced expression in immortalized cells (REIC)/Dickkopf (Dkk)-3 is a tumor suppressor and therapeutic gene and has been studied with respect to the application of cancer gene therapy. Our previous studies demonstrated that the intratumoral injection of an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC) suppresses tumor growth in mouse models of prostate, breast and testicular cancer and malignant mesothelioma. The mechanisms underlying these antitumor therapeutic effects have only been clarified recently. It has been demonstrated that Ad-REIC treatment inhibits cancer progression via the upregulation of systemic anticancer immunity. Under experimental conditions, autologous cancer vaccination via cancer-specific apoptosis and anticancer immune activation is a possible therapeutic mechanism. The robust anticancer effects observed in previous preclinical studies support the clinical utility of Ad-REIC. At present, a phase I-IIa study of Ad-REIC gene therapy in prostate cancer patients is ongoing. The current study reviews the observations of previous fundamental studies and summarizes the anticancer mechanisms of intratumoral Ad-REIC treatment in terms of cancer vaccination.

• Clinicopathological characteristics of pulmonary epithelioid hemangioendothelioma: A report of four cases and review of the literature. J. Shao, J. Zhang. 2014;8(6):2517-2522. PubMed · Publisher · Free full text

  Abstract

  This study aimed to investigate the clinicopathological characteristics, differential diagnosis and prognosis of pulmonary epithelioid hemangioendothelioma (PEH). PEH is a rare low-grade malignant vascular tumor. The cause of PEH remains unclear. Patient prognosis is unpredictable, with life expectancy ranging from 1 to 15 years due to the fact that estrogenic receptors behave inconsistently within the tumor and the occurence of the disease in male patients does not support the usual hormonal hypothesis. The clinical manifestations, imaging findings, histopathological characteristics and immunohistochemical phenotypes of four cases of epithelioid hemangioendothelioma occurring in the lung were retrospectively analyzed, and a review of the associated literature was conducted. The age of onset for the four PEH cases was 25-54 years, and the disease manifested as multiple nodules in the lungs or pleura. All of the patients underwent lobectomy or pulmonary wedge resection. The morphology of the tumor cells was epithelioid or spindle-shaped with abundant eosinophilic cytoplasm in which lumina or vacuoles containing erythrocytes were observed. The cells were arranged in nests and cords with degenerated interstitial mucoid. The morphology of the majority of the tumor cells was moderate, including mild atypia and little mitosis or necrosis. Immunohistochemical staining showed positive results for CD31, CD34 and F8. PEH is a rare low- to moderate-level tumor occurring in the lungs with differentiation toward vascular endothelial cells. Clinically, it is difficult to distinguish from a variety of other benign and malignant lung diseases. For diagnosis, a distinction must be made from other diseases such as chronic granulomatous disease, amyloid nodules, hamartoma, primary and metastatic lung cancers, malignant mesothelioma and vascular sarcoma. In the present study, the clinicopathological features of four cases of PEH were investigated and the associated literature was reviewed. The results of this study may improve understanding with regards to the diagnosis and therapeutic options for patients with PEH.

• Metastasis of mesothelioma to the maxillary gingiva. Y. Ohnishi, M. Sugitatsu, M. Watanabe, et al. 2014;8(3):1214-1216. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma predominantly arises from the serosal surfaces of the pleural or peritoneal cavity. There is currently no effective standard treatment for mesothelioma and the prognosis for patients is poor; the majority of patients with malignant mesothelioma succumb between 12 and 17 months following diagnosis. The association of all forms of malignant mesothelioma with asbestos exposure has been well documented. However, metastasis to the oral gingiva is rare, as only four cases have previously been reported; two cases of metastasis to the tongue and four cases to the jaw bone. In the current report, the case of a 62-year-old male with metastatic mesothelioma is presented. To the best of our knowledge, this is the first report regarding the metastasis of this type of neoplasm to the maxillary gingiva.

• Giant malignant mesothelioma in the upper mediastinum: A case report. S. Zhang, P. Song, B. Zhang. 2013;6(1):181-184. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma in the mediastinum is rare and the majority of known cases have been reported as 'localized mesothelioma'. The present study reports a case of an upper mediastinal tumor, which was diagnosed through thoracoscopic surgery and surgical biopsies of the mass. A computed tomography scan revealed a giant upper mediastinal tumor, adjacent to the aortic arch, trachea, superior vena cava and left pulmonary artery. The vessels in the mediastinum were compressed and were shifted to the lower right. The trachea became stenotic and a small amount of bilateral pleural effusion was observed. The mass was relatively well encapsulated. There was no pleural thickening or clearly swollen lymph nodes in the mediastinum. The histopathological and immunohistochemical examinations of the tumor verified the diagnosis of a malignant mesothelioma. The tumor was demonstrated to be derived from the mediastinal pleural mesothelium cells. The patient received pemetrexed disodium and cisplatin combination chemotherapy for four cycles. At present, the patient is undergoing follow-up.

• Primary intrahepatic malignant mesothelioma with multiple lymphadenopathies due to non-tuberculous mycobacteria: A case report and review of the literature. N. Inagaki, K. Kibata, T. Tamaki, et al. 2013;6(3):676-680. PubMed · Publisher · Free full text

  Abstract

  Primary intrahepatic malignant mesothelioma (PIHMM) is an extremely rare tumor with clinicopathological characteristics that remain to be elucidated. The current study presents the case of a 68-year-old female with PIHMM and multiple lymphadenopathies due to non-tuberculous mycobacteria. The patient presented with an intrahepatic tumor, 70 mm in diameter, in the right lobe of the liver. An ultrasound-guided fine-needle aspiration biopsy of the liver tumor revealed findings that were consistent with an intrahepatic malignant mesothelioma. The systemic lymph node swellings were due to epithelioid granulomas that were caused by non-tuberculous mycobacteria. However, a hepatic rupture occurred due to the rapid growth of the liver tumor and consequently, a surgical resection was not performed. A review of the literature revealed that the clinicopathological characteristics of PIHMM are similar to those of non-occupational mesothelioma. However, PIHMM is usually a solitary tumor and is rarely associated with cavity effusion in contrast with conventional mesothelioma. Therefore, surgical resection with curative intent is often recommended for patients with PIHMM.

• Clinical role of pleural effusion MMP-3 levels in malignant pleural mesothelioma. A. Murakami, C. Tabata, R. Tabata, et al. 2012;3(3):581-585. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin associated with asbestos exposure. MPM exhibits a limited response to conventional chemotherapy and radiotherapy. This, early diagnosis of MPM is essential. Malignant tumor progression requires the destruction of the basement membrane, which is constructed from extracellular matrix (ECM) materials. Various types of human tumor cells are reported to produce ECM-degrading proteases that are important in tumor progression. Among this group of proteolytic enzymes, matrix metalloproteinases (MMPs) are thought to be important due to their wide degrading function. We investigated the pleural effusion MMP-3 levels of patients with MPM and compared them with those of a population with non-malignant pleuritis or lung cancer involving malignant pleural effusion. The pleural effusion MMP-3 concentrations of 52 MPM patients and 67 non-MPM patients were measured. The results showed that the MPM patients had significantly higher pleural effusion MMP-3 levels than the population with non-malignant pleuritis. The overall survival of the MPM patients with lower pleural effusion MMP-3 levels was longer than that of patients with higher pleural effusion MMP-3 levels. Our data therefore suggest a clinical role of pleural effusion MMP-3 levels in malignant pleural mesothelioma.

• The utility of serum N-ERC/mesothelin as a biomarker of ovarian carcinoma. H. Saeki, A. Hashizume, H. Izumi, et al. 2012;4(4):637-641. PubMed · Publisher · Free full text

  Abstract

  Ovarian carcinoma has been difficult to diagnose at an early stage. Recently, it has been recognized that the measurement of blood N-ERC/mesothelin levels aids early detection in and postoperative therapeutic monitoring of patients with mesothelioma, who have been exposed to asbestos. ERC/mesothelin has also been reported to be expressed in ovarian carcinoma. We determined serum N-ERC/mesothelin levels in patients with ovarian carcinoma using an enzyme-linked immunosorbent assay (ELISA). In addition, we immunohistochemically evaluated surgically resected specimens for C-ERC/mesothelin expression. As a result, of the 32 patients with ovarian tumors (18 carcinoma, 2 borderline tumors), one patient with serous adenocarcinoma showed increased N-ERC/ mesothelin levels. Immunohistochemically, of the 20 ovarian tumor (carcinoma and borderline tumor) specimens evaluated for serum N-ERC/mesothelin, 9 (45.0%) were positive for C-ERC/mesothelin. The C-ERC/mesothelin-positive specimens were found to be serous and clear cell adenocarcinomas. If serum N-ERC/mesothelin, which is considered useful for early detection in and therapeutic monitoring of patients with mesothelioma, may also be used for ovarian carcinoma monitoring, it may be a valuable serum tumor marker for the early detection of ovarian carcinoma.

• Potassium octatitanate fibers (TISMO) induce pleural mesothelial cell reactions with iron accumulation in female A/J mice. M. Yokohira, N. Hashimoto, K. Yamakawa, et al. 2010;1(4):589-594. PubMed · Publisher · Free full text

  Abstract

  It is crucial to develop therapeutic approaches for malignant mesothelioma, as well as to obtain information involving the possible mechanism involved in the development of mesothelioma. Subsequently, thoracotomy was performed to infuse test particles directly into the thoracic cavity of A/J mice. Fiber-shaped particles of potassium octatitanate (TISMO) and granular-shaped micro- and nano-size order particles of titanium dioxide (TiO(2)) were employed (1.5 mg in 0.2 ml saline/mouse). The experiment was terminated after 21 weeks to assess responses. Only the fiber-shaped TISMO, morphologically similar to asbestos, induced a severe reaction of the pleura. A number of TISMO fibers were observed in the alveoli, indicating penetration through the pleura. Following Berlin blue staining, positive spots were observed around the TISMO fibers, indicative of iron. These positive spots corresponded with cells that immunostained positively for calretinin, a marker of mesothelial cells. Similar observations were reported for asbestos-induced mesothelioma. The present study showed that only fiber-shaped TISMO induced severe reactions of the mesothelium in the pleura, and these involved iron accumulation derived from endogenous sources. The results indicate that the risk of mesothelial cell reaction does not depend on particle size, but may depend on shape.

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