REV7 is involved in outcomes of platinum-based chemotherapy in pancreatic cancer by controlling the DNA damage response.

REV7 is a multifunctional protein implicated in various biological processes, including DNA damage response. REV7 expression in human cancer cells affects their sensitivity to DNA-damaging agents. In the present study, we investigated the significance of REV7 in pancreatic ductal adenocarcinoma (PDAC). REV7 expression was immunohistochemically examined in 92 resected PDAC specimens and 60 endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) specimens of unresectable PDAC treated with platinum-based chemotherapy, and its association with clinicopathologic features was analyzed. Although REV7 expression was not significantly associated with the progression of primary tumors (T-factor and Stage) in either resected or unresectable PDAC, decreased levels of REV7 expression in EUS-FNAB specimens of unresectable PDAC were significantly associated with better outcomes of platinum-based chemotherapy and a favorable prognosis. REV7-deficient PDAC cell lines showed suppressed cell growth and enhanced sensitivity to cisplatin in vitro. Tumor-bearing mice generated using REV7-deficient PDAC cell lines also showed enhanced sensitivity to cisplatin in vivo. RNA sequencing analysis using WT and REV7-deficient PDAC cell lines revealed that REV7 inactivation promoted the downregulation of genes involved in the DNA repair and the upregulation of genes involved in apoptosis. Our results indicate that decreased expression of REV7 is associated with better outcomes of platinum-based chemotherapy in PDAC by suppressing the DNA damage response. It is also suggested that REV7 is a useful biomarker for predicting the outcome of platinum-based chemotherapy and the prognosis of unresectable PDAC and is a potential target for PDAC treatment.

Tumor thickness as a novel risk factor for lymph node metastasis by superficial squamous cell carcinoma of head and neck.

Narrow-band imaging combined with magnified endoscopy has enabled the detection of superficial squamous cell carcinoma of the head and neck (SSCCHN) that has been resected with minimally invasive treatment, preserving vocalization and swallowing functions. However, risk factors of lymph node metastasis (LNM) must be identified, as some patients with LNM have a poor prognosis. From an initial 599 patients with 700 lesions who underwent trans-oral surgery in 27 Japanese hospitals (a nationwide registration survey), we enrolled 541 patients with 633 SSCCHNs, as indicated by central pathological diagnoses. All pathological specimens for each patient were examined using 20 pathological factors that are thought to affect the LNM of SSCCHN. In all, 24 (4.4%) of the 568 SSCCHNs exhibited LNM, and all 24 had at least one solitary nest of epithelial neoplastic cells present in the stroma, clearly separated from the intraepithelial carcinoma. Multivariate analysis also showed that tumor thickness (p = 0.0132, RR: 7.85, 95% confidence interval [CI]: 1.54-40.02), and an INFc pattern classified as infiltrating growth (INF) with unclear boundaries between tumor and non-tumor tissues (p = 0.0003, RR: 14.47, 3.46-60.46), and tumor budding (p = 0.0019, RR: 4.35, CI: 1.72-11.01) were significantly associated with LNM. Solitary nests may be indicative of LNM. In addition, tumor thickness was revealed to be a risk factor for LNM in SSCCHNs using pT factors that do not include an invasion depth element because of the anatomical absence of the muscularis mucosae.

Identification of the promoter region regulating the transcription of the REV7 gene.

REV7 is involved in various biological processes including DNA repair and mutagenesis, cell cycle regulation, gene transcription, and carcinogenesis. REV7 is highly expressed in adult testicular germ cells as well as several malignant tumors. REV7 expression levels are associated with prognosis in several human cancers, however, the mechanism of REV7 transcriptional regulation has not been elucidated. In this study, we characterized the promoter region of the REV7 gene. A luciferase reporter assay using the human germ cell tumor cell line NEC8 was utilized to examine the upstream genomic region of REV7 for transcriptional activity, and two transcriptional activation regions were identified. We determined a small genomic region important for transcriptional activation using site-directed mutagenesis; this region is shared by several putative binding motifs for transcription factors, including the cAMP-responsive element modulator (CREM), cAMP-response element binding protein (CREB), and B-lymphocyte-induced maturation protein-1 (BLIMP-1). Exogenous CREM and CREB expression had no effect on the transcriptional activity in NEC8 cells or the human embryonic kidney cell line HEK293T. In contrast, exogenous BLIMP-1 expression increased luciferase reporter activity in HEK293T cells but unexpectedly decreased activity in NEC8 cells. Chromatin immunoprecipitation analysis demonstrated that BLIMP-1 binds to the genomic region near the binding motif in the REV7 promoter. Additionally, BLIMP-1 overexpression promoted endogenous REV7 expression in HEK293T cells. These findings suggest that BLIMP-1 may be a putative transcriptional regulator of REV7 in mammalian cells.

Upregulation of REV7 correlates with progression of malignant melanoma.

REV7 is a multifunctional protein implicated in DNA damage tolerance, cell cycle control, and gene expression, and is involved in the carcinogenesis of various human tumors. It has been reported that REV7 expression is associated with ultraviolet-induced mutagenesis; however, the role of REV7 expression in skin cancers, including malignant melanomas, remains unclear. In the present study, we investigated the clinical and biological significance of REV7 in malignant melanoma. Levels of REV7 expression in human skin cancers were evaluated immunohistochemically. Positive expression of REV7 was frequently observed in malignant melanomas, as well as in squamous cell carcinomas and basal cell carcinomas. Enhanced immunoreactivity to REV7 was closely linked with cell proliferation assessed by Ki-67 labeling indexes in the three skin cancers, and was related with tumor thickness in malignant melanomas. REV7 depletion in malignant melanoma cells MEWO and G361 suppressed cell proliferation, migration, and invasion abilities. REV7 depletion also affected the expression of intracellular signaling molecules AKT and ERK in MEWO cells, resulting in downregulation of ERK signal activation. In addition, REV7 depletion facilitated sensitivity to cisplatin, but not to dacarbazine, in MEWO cells. Our results suggest that REV7 expression correlates with disease progression of malignant melanoma.

Increased expression of REV7 in small cell lung carcinomas and its association with tumor cell survival and proliferation.

REV7 is involved in multiple biological processes including DNA damage tolerance, cell cycle regulation and gene expression, and is an accessory subunit of the mutation-prone DNA polymerase ζ. It has been reported that REV7 expression is associated with poor prognosis in several human cancers. The aim of this study is to investigate the significance of REV7 in lung carcinogenesis. Immunohistochemical analyses of surgically resected lung cancer specimens revealed that REV7 shows an increased expression in small cell lung carcinomas (SCLCs) when compared with other histological types of lung carcinoma. Association between REV7 expression levels and clinicopathological factors was investigated using SCLC cases with or without surgical resection. Our analyses revealed that high REV7 expression significantly correlated with tumor cell proliferation, assessed by Ki-67 labeling indices, and was negatively associated with distant metastasis and extensive-stage disease. No significant association was detected between REV7 expression and other factors, including prognosis or response to chemoradiotherapy in SCLC. Increase in REV7 expression in SCLC was confirmed using SCLC cell lines. In addition, siRNA-mediated depletion of REV7 activated the apoptotic pathway and suppressed cell growth in SCLC cells. These results suggest that REV7 plays an important role in tumor cell survival and proliferation in SCLC.

An autopsy case of GM1 gangliosidosis type II in a patient who survived a long duration with artificial respiratory support.

GM1 gangliosidosis is a storage disorder with autosomal recessive inheritance caused by deficiency of ß-galactosidase (GLB1), which is a lysosomal hydrolase, due to mutations in GLB1. We describe here an autopsy case of GM1 gangliosidosis in a female patient who survived for 38 years with a long period of artificial respiratory support (ARS). She was born after a normal pregnancy and delivery. Although development was normal until one year old, she was unable to walk at two years old and started having seizures by nine years old. At 21 years old, she became unable to communicate and was bed-ridden. At 36 years old, she suffered from pneumonia and required ARS. She died of pneumonia at 40 years old. Neuropathological examination revealed severe atrophy, predominantly found in the frontal lobes. Microscopically, severe gliosis and neuronal loss were observed in the cerebral cortex, putamen, cerebellum, the latter including Purkinje cell and granule cell layers. The hippocampus was relatively preserved. Severe neuronal swelling was observed in the limbic regions and stored a material in these neurons negative for periodic acid-Schiff (PAS). A PAS-positive granular storage material in neurons and macrophages was mainly observed in the brainstem and limbic regions. Exome analysis showed a known c.152T>C (p.I51T) variant that has been described in type III patients and a novel c.1348-2A>G variant in GLB1. Detailed analysis of reverse transcription-polymerase chain reaction products of GLB1 mRNA revealed that these variants were present in a compound heterozygous state. In our case, clinical features and neuropathological findings were most consistent with type II, although the entire course was longer than any previously reported cases. This may be explained by the residual enzyme activity in this patient whose severity lay between types II and III. Our finding of relative preservation of the limbic regions suggests that neuronal loss in GM1 gangliosidosis has regional selectivity.

Cytoskeleton-Associated Protein 4 Is a Novel Serodiagnostic Marker for Lung Cancer.

Our aim was to develop a serodiagnostic marker for lung cancer. Monoclonal antibodies were generated, and one antibody designated as KU-Lu-1, recognizing cytoskeleton-associated protein 4 (CKAP4), was studied further. To evaluate the utility of KU-Lu-1 antibody as a serodiagnostic marker for lung cancer, reverse-phase protein array analysis was performed with sera of 271 lung cancer patients and 100 healthy controls. CKAP4 was detected in lung cancer cells and tissues, and its secretion into the culture supernatant was also confirmed. The serum CKAP4 levels of lung cancer patients were significantly higher than those of healthy controls (P < 0.0001), and the area under the curve of receiver-operating characteristic curve analysis was 0.890, with 81.1% sensitivity and 86.0% specificity. Furthermore, the serum CKAP4 levels were also higher in patients with stage I adenocarcinoma or squamous cell carcinoma than in healthy controls (P < 0.0001). Serum CKAP4 levels may differentiate lung cancer patients from healthy controls, and they may be detected early even in stage I non-small cell lung cancer. Serum CKAP4 levels were also significantly higher in lung cancer patients than in healthy controls in the validation set (P < 0.0001). The present results provide evidence that CKAP4 may be a novel early serodiagnostic marker for lung cancer.

Basigin expression as a prognostic indicator in stage I pulmonary adenocarcinoma.

We established the KU-Lu-8 monoclonal antibody (MoAb) using a lung cancer cell line as an antigen and a random immunization method. The KU-Lu-8 MoAb recognizes basigin (BSG), which is a transmembrane-type glycoprotein that is strongly expressed on the cell membranes of lung cancer cells. This study aimed to clarify the relationships between BSG expression and clinicopathological parameters and determine the prognostic significance of BSG expression in pulmonary adenocarcinoma (AC) patients. To evaluate the significance of BSG expression in lung cancer, we immunohistochemically analyzed 113 surgically resected pulmonary adenocarcinomas, and the associations between BSG expression and various clinicopathological parameters were evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to investigate the effects of BSG expression on survival. Clinicopathologically, BSG expression was significantly associated with tumor differentiation, vascular invasion, lymphatic invasion, and a poor prognosis. In particular, BSG expression was significantly correlated with poorer survival in patients with stage I AC. The high BSG expression group (compared with the low BSG expression group) exhibited adjusted hazard ratios for mortality of 4.694. BSG expression is indicative of a poor prognosis in AC patients, particularly in those with stage I disease.

Pathological and immunoblot analysis of phosphorylated TDP-43 in sporadic amyotrophic lateral sclerosis with pallido-nigro-luysian degeneration.

Transactivation response DNA-binding protein 43 kDa (TDP-43) is a key protein of sporadic amyotrophic lateral sclerosis (ALS), and phosphorylated form of TDP-43 (p-TDP-43) is a major pathological protein that accumulates in sporadic ALS. p-TDP-43 is found not only in primary motor neurons, but often propagates to non-motor systems as well. However, pallido-nigro-luysian (PNL) degeneration (PNLD) is rarely associated with ALS. We describe here a 68-year-old ALS patient presenting severe PNLD. He had difficulty walking due to poor movement of his right leg, and was diagnosed as having Parkinson's disease because of akinesia. About 2 years after onset, weakness of his left hand and leg led to a diagnosis of ALS. Tube feeding and non-invasive positive-pressure ventilation were initiated. He died of respiratory failure at the age of 71. There was no family history of either neurological disorders or dementia. Neuropathological examination revealed severe loss of neurons and gliosis in the PNL system in addition to the upper and lower motor neuron system. p-TDP-43 pathology was widespread in the PNL and motor neuron systems and also in the amygdala and hippocampus where no significant gliosis or neuronal loss was detected. Synuclein pathology was not observed in the investigated areas. Immunoblot analysis of p-TDP-43 C-terminal fragments showed a type B band pattern consistent with sporadic ALS. This is the first case of ALS with PNLD, in which p-TDP-43 distribution was widespread in the hippocampal formation (Nishihira type 2 and Brettschneider stage 4), and the type B immunoblot pattern was confirmed. Our case indicated that the PNL system can be involved in the disease process in sporadic ALS cases, although rarely. We also reviewed previous autopsy cases of ALS with PNLD to clarify the clinicopathological features.

Impact of PD-L1 Expression in Patients with Surgically Resected Non-Small-Cell Lung Cancer.

BACKGROUND: Immunotherapy can become a crucial therapeutic option to improve the prognosis of patients with non-small-cell lung cancer (NSCLC). Here, we evaluated the impact of programmed cell death ligand-1 (PD-L1) expression in surgically resected NSCLCs. METHODS: We estimated PD-L1 expression in 229 consecutive NSCLC specimens using rabbit polyclonal antibodies to human PD-L1 in a SP263 immunohistochemical assay and evaluated PD-L1 expression for potential associations with clinicopathological parameters and survival time. RESULTS: PD-L1 expression was significantly higher in tumors from men or current smokers. Squamous cell carcinoma histology was independently associated with high PD-L1 expression according to multivariate analysis (p = 0.015). The 5-year survival rate of patients was 70%, and the difference in the 5-year survival rate according to PD-L1 expression was not statistically significant (high expression group [67%] vs. low expression group [68%]); however, the squamous cell carcinoma group exhibited significantly lower 5-year survival rates as compared to the non-squamous cell carcinoma group (53 and 71%, respectively; p = 0.026). CONCLUSION: Here, we revealed high PD-L1 expression and poor prognosis observed in patients with surgically resected squamous NSCLC as compared with non-squamous NSCLC. Our results support the identification of patient subsets that most likely respond to anti-PD-1 therapy as the first step in precision medicine.

[Conversion Surgery for Initially Unresectable Locally Advanced Pancreatic Cancer Following Gemcitabine plus Nab-Paclitaxel - A Case Report].

We report a case of unresectable locally advanced pancreatic cancer successfully resected after gemcitabine(GEM)plus nab-paclitaxel(PTX)treatment. A 68-year-old man was referred to our institution with jaundice. We diagnosed pancreatic head cancer using computed tomography(CT)and endoscopic retrograde cholangiopancreatography. We initially diagnosed it as locally advanced unresectable pancreatic cancer because of extensive invasion to the portal vein. GEM plus nab- PTX was administered to the patient as systemic chemotherapy. After 9 courses of chemotherapy, a CT scan revealed that the tumor had significantly reduced in size and range of portal vein invasion. Therefore, we performed pancreaticoduodenectomy with resection of the portal vein and achieved R0 resection. Currently, the patient is alive without recurrence. Therefore, conversion surgery after treatment with GEM plus nab-PTX chemotherapy for unresectable pancreatic cancer should be considered.

Micropapillary and solid components as high-grade patterns in IASLC grading system of lung adenocarcinoma: Clinical implications and management.

OBJECTIVES: The grading system proposed by the International Association for the Study of Lung Cancer is based on a combination of predominant histologic subtypes and the proportion of high-grade components with a cutoff of 20%. We aimed to examine the clinical implications of the grading system beyond the discrimination of patient prognosis, while assessing the biological differences among high-grade subtypes. METHODS: We retrospectively reviewed 648 consecutive patients with resected lung adenocarcinomas and examined their clinicopathologic, genotypic, and immunophenotypic features and treatment outcomes. Besides the differences among grades, the clinical impact of different high-grade components: micropapillary (MIP) and solid (SOL) patterns, was individually evaluated. RESULTS: Survival outcomes were well-stratified according to the grading system. Grade 3 tumors exhibited aggressive clinicopathologic features, while being an independent prognostic factor in multivariable analysis. A small proportion (<20 %) of high-grade components in grade 2 had a negative prognostic impact. The prognostic difference bordering on the 20 % cutoff of the MIP proportion was validated; however, the proportion of SOL component did not affect prognosis. A survival benefit from adjuvant chemotherapy was observed in grade 3 tumors regardless of histologic subtype, but not in grade 1-2 tumors. The molecular and immunophenotypic features were different among grades, but still heterogeneous in grade 3, with MIP harboring frequent EGFR mutation and SOL exhibiting high PD-L1 expression. The treatment outcome after recurrence was worse in grade 3, but tumors with MIP pattern had an equivalent prognosis to that of grade 1-2 tumors, reflecting the high frequency of molecular targeted therapy. CONCLUSIONS: In addition to stratifying patient prognosis, the current grading system could discriminate clinical course, therapeutic effects of adjuvant chemotherapy, and molecular and immunophenotypic features. Further stratification based on biological heterogeneity in grade 3 remains necessary to enhance the role of the grading system in guiding patient management.

Insight into the significance of CD8+ tumor-infiltrating lymphocytes in squamous cell lung cancer.

BACKGROUND: Although there are great expectations regarding the use of tumor-infiltrating lymphocytes (TILs) to predict effects of immunotherapies and prognosis, knowledge about TILs remains insufficient for clinical application. METHODS: We objectively investigated the prognostic significance of tumor-infiltrating CD8 + lymphocytes (CD8 + TILs) in squamous cell lung cancer (SQ-LC). Among patients who underwent surgical resection of SQ-LC in 2011-2017, 100 patients with pathological stage IA3-III were immunohistochemically studied to evaluate CD8 + TILs in the tumor stroma and parenchyma. The impact of CD8 + TILs on relapse-free survival was analyzed using a Kaplan-Meier survival analysis and multivariate analyses using Fine-Gray and Cox proportional hazards models. RESULTS: The multivariate analysis showed that large and small numbers, but not intermediate numbers, of CD8 + TILs in the tumor stroma may be related to a more favorable prognosis (small vs. intermediate: HR, 0.64; 95% CI: 0.29-1.41, p = 0.27; large vs. intermediate: HR, 0.48; 95% CI: 0.21-1.09, p = 0.08). In contrast, a large number of CD8 + TILs in the tumor parenchyma was associated with a poor prognosis (HR, 2.60; 95% CI: 0.91-7.42, p = 0.075). An exploratory analysis showed a potentially strong association between an extremely large number of CD8 + TILs in the tumor parenchyma and a poor prognosis, even with a large number of CD8 + TILs in the tumor stroma. CONCLUSION: Our study provided partial but important information on the significance of CD8 + TILs in SQ-LC. To use CD8 + TILs as biomarkers, a better understanding of CD8 + TILs as well as other important components in the tumor microenvironment and the inflammatory phenotypes they form may be needed.

Insight into the significance of Foxp3 + tumor-infiltrating lymphocytes in squamous cell lung cancer.

PURPOSE: Although developing a better understanding of tumor-infiltrating Foxp3 + lymphocytes (Foxp3 + TILs) might provide essential knowledge to predict response to immunotherapy and prognosis, our current knowledge about Foxp3 + TILs is inadequate. This study investigated the prognostic significance of tumor-infiltrating Foxp3 + lymphocytes (Foxp3 + TILs) in squamous cell lung cancer (SQ-LC) objectively. METHODS: Among patients with SQ-LC surgically resected in our institution between 2011 and 2017, those with pathological stage IA3-IIIA were immunohistochemically studied to evaluate Foxp3 + TILs in their tumor stroma. The impact of Foxp3 + TILs on relapse-free survival (RFS) was analyzed with Kaplan-Meier survival analysis and multivariate analysis using a Cox proportional hazards model/Fine-Gray model. RESULTS: This study analyzed 100 patients. Multivariate analysis showed that a large number of Foxp3 + TILs in the stroma does not associate with a poor prognosis, rather that a large number of Foxp3 + TILs (≥ 64 cells) tend to be associated with a more favorable prognosis than a small number of Foxp3 + TILs (< 64 cells) (large vs small number: HR, 0.56; 95% CI, 0.17-1.83; P = 0.34). Exploratory analysis also showed that in the two populations divided by a difference in Foxp3 expression levels, similar trends to the main analysis were observed. CONCLUSION: Our results showed that a large number of Foxp3 + TILs in the stroma may not associate with a poor prognosis in SQ-LC. To use the seemingly complicated information of Foxp3 + TILs as biomarkers, better understanding the diversity and heterogeneity of Foxp3 + TILs and analyzing their subpopulations that increase in the TME may be needed.

Lewy body pathology in a patient with a homozygous parkin deletion.

BACKGROUND: We report neuropathologic findings in a patient with homozygous deletions of exons 2 to 4 of parkin. RESULTS: Although the absence of Lewy bodies has been considered a neuropathologic characteristic of parkin mutation, here we report a pathologic finding with the presence of Lewy bodies. METHODS: The patient was a 72-year-old woman with onset of the disease at age 61. Her autopsy revealed marked decrease in melanized neurons in the substantia nigra and the locus coeruleus. Lewy bodies were found in the substantia nigra, the locus coeruleus, the dorsal motor nucleus of the vagus, the basal nucleus of Meynert, the amygdaloid nucleus, and the sympathetic nerve bundles in the myocardium. CONCLUSIONS: Only 3 previous case reports described Lewy body formation in patients carrying parkin mutations. The distribution of Lewy bodies in our patient appeared to be reminiscent of sporadic Parkinson's disease.

REV7 in Cancer Biology and Management.

DNA repair and cell cycle regulation are potential biological fields to develop molecular targeting therapies for cancer. Human REV7 was originally discovered as a homologous molecule to yeast Rev7, which is involved in DNA damage response and mutagenesis, and as the second homolog of yeast Mad2, involved in the spindle assembly checkpoint. Although REV7 principally functions in the fields of DNA repair and cell cycle regulation, many binding partners of REV7 have been identified using comprehensive analyses in the past decade, and the significance of REV7 is expanding in various other biological fields, such as gene transcription, epigenetics, primordial germ cell survival, neurogenesis, intracellular signaling, and microbial infection. In addition, the clinical significance of REV7 has been demonstrated in studies using human cancer tissues, and investigations in cancer cell lines and animal models have revealed the greater impacts of REV7 in cancer biology, which makes it an attractive target molecule for cancer management. This review focuses on the functions of REV7 in human cancer and discusses the utility of REV7 for cancer management with a summary of the recent development of inhibitors targeting REV7.

The Significance of CD109 Expression in Oropharyngeal Squamous Cell Carcinoma.

BACKGROUND/AIM: Up-regulation of CD109 occurs in malignant tumours, although its role is unknown. Here we aimed to evaluate the significance of CD109 expression in oropharyngeal squamous cell carcinoma (OPSCC). PATIENTS AND METHODS: Immunohistochemical analysis was performed to assess CD109 expression in 169 patients with OPSCC. We assessed the effects of small interfering RNA (siRNA)-mediated inhibition of CD109 expression on the proliferation and invasiveness of the human papillomavirus 16-positive (HPV16+) head and neck SCC cell line UM-SCC-47. RESULTS: Expression of CD109 was associated with higher tumour differentiation in p16+ OPSCC (p=0.0036), and the CD109+ subgroup experienced significantly shorter progression-free survival (p=0.03). UM-SCC-47 cells with siRNA-mediated inhibition of CD109 expression showed reduced invasiveness (p=0.07). CONCLUSION: CD109 expression is associated with poor prognosis of HPV16+ OPSCCs.

Clinicopathological Significance of BRCAness in Resectable Pancreatic Ductal Adenocarcinoma and Its Association With Anticancer Drug Sensitivity in Pancreatic Cancer Cells.

OBJECTIVE: The concept of BRCAness has been proposed as a homologous recombination repair dysfunction triggered by a genetic defect in the BRCA pathway including the BRCA1/2 mutations. A certain number of pancreatic ductal adenocarcinoma (PDAC) patients have BRCAness. However, a large-scale analysis of BRCAness in PDAC has not been performed. In addition, no basic studies have examined the significance of BRCAness in PDAC cell lines. METHODS: Ninety-two patients who underwent surgery for PDAC were enrolled. Formalin-fixed and paraffin-embedded specimens of resected PDACs were used to analyze BRCAness by multiplex ligation-dependent probe amplification. We also analyzed BRCAness in pancreatic cancer cell lines and the sensitivity to cisplatin and olaparib using a colony formation assay. RESULTS: Of the 92 patients with PDAC, 6 were detected to have BRCAness-positive PDAC (6.5%). No significant differences in overall survival and progression-free survival were observed between the BRCAness-positive and BRCAness-negative groups. One PDAC cell line, KP-2, was positive for BRCAness and was more sensitive to cisplatin and olaparib than the BRCAness-negative cell lines. CONCLUSIONS: Our results revealed that a considerable number of PDACs are positive for BRCAness, suggesting that BRCAness status could be a useful biomarker for selecting anticancer treatments for advanced or relapsed PDAC.

CD109 expression in tumor cells and stroma correlates with progression and prognosis in pancreatic cancer.

CD109 is a glycosylphosphatidylinositol-anchored glycoprotein, whose expression is upregulated in some types of malignant tumors. High levels of CD109 in tumor cells have been reported to correlate with poor prognosis; however, significance of CD109 stromal expression in human malignancy has not been elucidated. In this study, we investigated the tumorigenic properties of CD109 in pancreatic ductal adenocarcinoma (PDAC). Immunohistochemical analysis of 92 PDAC surgical specimens revealed that positive CD109 expression in tumor cells was significantly associated with poor prognosis (disease-free survival, p = 0.003; overall survival, p = 0.002), and was an independent prognostic factor (disease-free survival, p = 0.0173; overall survival, p = 0.0104) in PDAC. Furthermore, CD109 expression was detected in the stroma surrounding tumor cells, similar to that of α-smooth muscle actin, a histological marker of cancer-associated fibroblasts. The stromal CD109 expression significantly correlated with tumor progression in PDAC (TNM stage, p = 0.033; N factor, p = 0.024; lymphatic invasion, p = 0.028). In addition, combined assessment of CD109 in tumor cells and stroma could identify the better prognosis group of patients from the entire patient population. In MIA PaCa-2 PDAC cell line, we demonstrated the involvement of CD109 in tumor cell motility, but not in PANC-1. Taken together, CD109 not only in the tumor cells but also in the stroma is involved in the progression and prognosis of PDAC, and may serve as a useful prognostic marker in PDAC.

High expression of L-type amino-acid transporter 1 (LAT1) in gastric carcinomas: comparison with non-cancerous lesions.

Amino acid transporters are essential for maintenance and proliferation of both normal and transformed cells. In the present study, L-type amino-acid transporter 1 (LAT1) immunoreactive expression was investigated in gastric carcinomas, in comparison with gastric adenomas and non-neoplastic lesions, using our recently developed novel monoclonal antibody. In a total of 87 cases of advanced gastric cancer, high LAT1 expression was observed in carcinoma cells, predominantly at plasma membranes with greater intensity in non-scirrhous than scirrhous carcinomas. Gastric carcinoma cases with lymph node metastasis showed significantly higher LAT1 expression than cases without lymph node metastasis. A positive correlation with Ki-67 LI was observed and the highly expressing non-scirrhous carcinomas showed a significantly poorer prognosis than the low LAT1 group. Cox hazard test revealed that TNM stage and LAT1 expression were independent prognostic factors in non-scirrhous carcinoma group. Further, a significant poor prognosis was confirmed in high LAT1 expression group, when limited to undifferentiated carcinoma cases excluding scirrhous carcinoma. Lower levels were found in adenomas. In conclusion, LAT 1 expression may be linked with cell proliferation and prognosis of gastric carcinomas, and offers a potential target for future anticancer therapy by inhibitors.