Publications by authors named "Keiichiro Uehara"

24 Publications

  • Page 1 of 1

Correction to: Retinoic acid receptor γ activation promotes differentiation of human induced pluripotent stem cells into esophageal epithelium.

J Gastroenterol 2020 Oct;55(10):1010-1011

Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.

In the original publication of the article, the following errors were noted and corrected in this correction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00535-020-01718-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645549PMC
October 2020

Retinoic acid receptor γ activation promotes differentiation of human induced pluripotent stem cells into esophageal epithelium.

J Gastroenterol 2020 Aug 16;55(8):763-774. Epub 2020 Jun 16.

Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.

Background: The esophagus is known to be derived from the foregut. However, the mechanisms regulating this process remain unclear. In particular, the details of the human esophagus itself have been poorly researched. In this decade, studies using human induced pluripotent stem cells (hiPSCs) have proven powerful tools for clarifying the developmental biology of various human organs. Several studies using hiPSCs have demonstrated that retinoic acid (RA) signaling promotes the differentiation of foregut into tissues such as lung and pancreas. However, the effect of RA signaling on the differentiation of foregut into esophagus remains unclear.

Methods: We established a novel stepwise protocol with transwell culture and an air-liquid interface system for esophageal epithelial cell (EEC) differentiation from hiPSCs. We then evaluated the effect of all-trans retinoic acid (ATRA), which is a retinoic acid receptor (RAR)α, RARβ and RARγ agonist, on the differentiation from the hiPSC-derived foregut. Finally, to identify which RAR subtype was involved in the differentiation, we used synthetic agonists and antagonists of RARα and RARγ, which are known to be expressed in esophagus.

Results: We successfully generated stratified layers of cells expressing EEC marker genes that were positive for lugol staining. The enhancing effect of ATRA on EEC differentiation was clearly demonstrated with quantitative reverse transcription polymerase chain reaction, immunohistology, lugol-staining and RNA sequencing analyses. RARγ agonist and antagonist enhanced and suppressed EEC differentiation, respectively. RARα agonist had no effect on the differentiation.

Conclusion: We revealed that RARγ activation promotes the differentiation of hiPSCs-derived foregut into EECs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00535-020-01695-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376085PMC
August 2020

Directed differentiation of human induced pluripotent stem cells into mature stratified bladder urothelium.

Sci Rep 2019 07 19;9(1):10506. Epub 2019 Jul 19.

Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan.

For augmentation or reconstruction of urinary bladder after cystectomy, bladder urothelium derived from human induced pluripotent stem cells (hiPSCs) has recently received focus. However, previous studies have only shown the emergence of cells expressing some urothelial markers among derivatives of hiPSCs, and no report has demonstrated the stratified structure, which is a particularly important attribute of the barrier function of mature bladder urothelium. In present study, we developed a method for the directed differentiation of hiPSCs into mature stratified bladder urothelium. The caudal hindgut, from which the bladder urothelium develops, was predominantly induced via the high-dose administration of CHIR99021 during definitive endoderm induction, and this treatment subsequently increased the expressions of uroplakins. Terminal differentiation, characterized by the increased expression of uroplakins, CK13, and CK20, was induced with the combination of Troglitazone + PD153035. FGF10 enhanced the expression of uroplakins and the stratification of the epithelium, and the transwell culture system further enhanced such stratification. Furthermore, the barrier function of our urothelium was demonstrated by a permeability assay using FITC-dextran. According to an immunohistological analysis, the stratified uroplakin II-positive epithelium was observed in the transwells. This method might be useful in the field of regenerative medicine of the bladder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-46848-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642190PMC
July 2019

[A Case of Systemic Polyarteritis Nodosa Presenting with Scrotal Pain].

Hinyokika Kiyo 2019 Apr;65(4):127-131

The Department of Urology, Kobe City Medical Center General Hospital.

A 76-year-old man with a history of hypertension was admitted with high fever and left scrotal pain. Laboratory findings revealed high serum C-reactive protein levels. The left epididymis appeared to be swollen on computed tomography. The patient was diagnosed with bacterial epididymitis and treatment with antibiotics was initiated. Despite treatment, his left scrotal pain and fever did not improve. Additionally, he developed right scrotal and posterior neck pain. For histopathological diagnosis, a left high orchiectomy was performed and the findings revealed thickened arteriolar walls with infiltration of inflammatory cells around the testis, leading to a final diagnosis of systemic polyarteritis nodosa. Treatment with steroids led to complete resolution of the patient's systemic pain and inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14989/ActaUrolJap_65_4_127DOI Listing
April 2019

Clinicopathological analysis of clinically occult extrapulmonary lymphangioleiomyomatosis in intra-pelvic and para-aortic lymph nodes associated with pelvic malignant tumors: A study of nine patients.

Pathol Int 2019 Jan;69(1):29-36

Department of Pathology, Kobe City Medical Center General Hospital, Kobe, Japan.

The clinicopathological and immunohistochemical characteristics of clinically occult extrapulmonary lymphangioleiomyomatosis in lymph nodes (LN-LAM) being dissected during surgical staging of pelvic malignancy have not been well investigated. We assessed samples from nine female patients (median age, 61). None had past or familial history of tuberous sclerosis and had LAM lesions other than LN such as lung. The primary malignancies included four endometrial endometrioid carcinomas, one endometrial carcinosarcoma, three ovarian serous carcinomas and one urothelial carcinoma. Median follow-up was 43 months. The number of affected LNs ranged from 1 to 15 (median, 2) with sizes ranging from 1 to 13 mm (median, 3.0). Six cases had clinically occult LN-LAM only within the pelvic LNs, two only within para-aortic LNs, and one within both pelvic and para-aortic lymph nodes. Immunohistochemically, LAM cells exhibited a strong diffuse positivity for β-catenin and E-cadherin in all nine cases. Clinically occult LN-LAM mainly affects peri- or post-menopausal women. On rare occasions, occult LN-LAM may manifest as systemic LAM, including in the lung. β-catenin and E-cadherin carry potential utility as additional diagnostic markers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pin.12749DOI Listing
January 2019

ROS1-rearranged high-PD-L1-expressing lung adenocarcinoma manifesting as mediastinal tumor: A case report.

Oncol Lett 2019 Jan 25;17(1):488-491. Epub 2018 Oct 25.

Division of Thoracic Surgery, Graduate School of Medicine, Kobe University, Kobe, Hyogo 650-0017, Japan.

ROS proto-oncogene 1 receptor tyrosine kinase (ROS1)-rearranged lung cancer is rare and comprises only 1% of lung adenocarcinoma cases. It has recently been reported to have good response to crizotinib, a tyrosine kinase inhibitor of anaplastic lymphoma kinase. Driver oncogene mutations with approved therapies seldom coexist with a high expression of Programmed death-ligand 1 (PD-L1). The present case report describes a rare case of ROS1 rearrangement with high-PD-L1-expressing occult lung adenocarcinoma. A 32-year-old woman presented with chest pain and a prolonged cough. Chest computed tomography (CT) revealed a 57×36-mm tumor in the mediastinum, with no tumors detected in other regions. Positron emission tomography (PET)-CT showed a strong fluorodeoxyglucose accumulation in the tumor (SUVmax 13.2). Mediastinal tumor resection was completely resected using a video-assisted thoracic surgery approach. Pathological examination showed the tumor cells were positive for thyroid transcription factor 1, Napsin-A, ROS1, and PD-L1 (tumor proportion score >99%). ROS1 rearrangement was confirmed by fluorescence hybridization. The mediastinal tumor was diagnosed as mediastinal lymph node metastasis of ROS1-rearranged PD-L1 high-expression undifferentiated lung adenocarcinoma (pathological stage 3, TxN2M0). Two months after the operation, the CT scan showed multiple mediastinum lymph nodes metastases with rapid tumor growth. The patient achieved a complete response after three cycles of S-1 plus cisplatin with concurrent radiotherapy 60 Gy/30 Fr.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/ol.2018.9622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313173PMC
January 2019

Successful Bridging Chemotherapy with Gemcitabine, Carboplatin, and Dexamethasone before Unrelated Stem Cell Transplantation for Hepatosplenic T-cell Lymphoma.

Intern Med 2019 Mar 19;58(5):707-712. Epub 2018 Nov 19.

The Division of Medical Oncology and Hematology, Department of Medicine, Kobe University Hospital, Japan.

A 45-year-old woman was diagnosed with hepatosplenic T-cell lymphoma (HSTCL), a rare subtype of peripheral T-cell lymphoma. She received different types of chemotherapy, but disease progression was observed. To reduce the tumor burden before an unrelated bone marrow transplantation, combination chemotherapy consisting of the gemcitabine, carboplatin, and dexamethasone (GCD) was administered as bridging therapy, resulting in a reduction in the number of lymphoma cells. We were then able to perform bone marrow transplantation. Although she experienced some adverse events, she successfully achieved long-term remission. We herein report a successful case of HSTCL treated with unrelated stem cell transplantation following the GCD regimen as bridging chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.1266-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443557PMC
March 2019

Programmed Cell Death Ligand 1 Expression in Non-Small-cell Lung Cancer Patients With Interstitial Lung Disease: A Matched Case-control Study.

Clin Lung Cancer 2018 09 5;19(5):e667-e673. Epub 2018 May 5.

Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Hyogo, Japan.

Background: Programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) checkpoint inhibitors have demonstrated antitumor activity, and immunohistochemical analysis of PD-L1 expression has been used to identify the response in patients with non-small-cell lung cancer (NSCLC). Recently, considerable interest has ensued toward extending the benefit of these inhibitors to high-risk patients, such as those with NSCLC and interstitial lung disease (ILD). However, no studies have compared PD-L1 expression in NSCLC patients with and without ILD. Therefore, we conducted a case-control study to evaluate PD-L1 expression and stromal CD8 lymphocyte density in these patients.

Materials And Methods: The data from patients with pathologic stage I or II NSCLC who had undergone surgery from January 2007 to January 2016 were analyzed.

Results: We identified 62 patients with pathologic stage I or II NSCLC and ILD. We compared these patients with 1:1-matched cohort. In both groups with and without ILD, approximately 60% were PD-L1. Tumor cell PD-L1 expression was similar between the groups (median, 1%; interquartile range, 0%-5%; vs. median, 1%; interquartile range, 0%-5%; P = .49). The proportion of patients with positive (≥ 1%) and strongly positive (≥ 50%) PD-L1 expression was also similar between the 2 groups (P = .46 and P = 1.00, respectively). Additionally, the CD8 lymphocyte density did not differ between patients with and without ILD.

Conclusion: PD-L1 expression and stromal CD8 lymphocyte density were comparable between the NSCLC patients with and without ILD. PD-1 axis inhibitors might be effective for NSCLC patients with ILD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cllc.2018.04.012DOI Listing
September 2018

[A Case of Chromophobe Renal Cell Carcinoma Associated with Birt-Hogg-Dubé Syndrome].

Hinyokika Kiyo 2018 Mar;64(3):107-110

The Department of Urology, Kobe City Medical Center General Hospital.

A 61-year-old man with a left renal mass, which was detected by ultrasound during a routine health examination, was referred to our department. The patient had a surgical history of two pneumothorax operations, and the patient's brother also had a history of pneumothorax surgery. A case of Birt-Hogg-Dubé (BHD) syndrome was suspected based on patient history. The pathological diagnosis of the resected tumor, which used robot-assisted laparoscopic partial nephrectomy, was determined to be chromophobe renal cell carcinoma (grade 2, pT1a). BHD syndrome was confirmed by genetic testing, where a nonsense mutation of exon 9 in the FOLLICULIN (FLCN) gene was detected. The patient is currently alive 10 months after surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14989/ActaUrolJap_64_3_107DOI Listing
March 2018

Reduced Tumour Proportion Scores for Programmed Cell Death Ligand 1 in Stored Paraffin Tissue Sections.

Anticancer Res 2018 03;38(3):1401-1405

Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.

Background/aim: We evaluated the effects of storage of formalin-fixed, paraffin-embedded (FFPE) sections on the tumour proportion score (TPS) for programmed cell death ligand 1 (PD-L1), as indicator in non-small cell lung cancer (NSCLC) tissues of treatment efficacy.

Materials And Methods: NSCLC postoperative specimens with PD-L1 TPS ≥50% were obtained and cut into five serial sections. One section was stained immediately, and four were stored at 4°C for 2, 4, 6, or 8 weeks. Slides were subjected to PD-L1 immunohistochemistry using the anti-PD-L1 clone 28-8. PD-L1 TPS were blindly evaluated by two independent pathologists.

Results: Twelve specimens (60 slides) were evaluated. After slide storage for 2, 4, 6, and 8 weeks, a TPS of <50% was obtained in five (41%), four (33%), seven (58%), and eight (67%) patients, respectively.

Conclusion: TPS values for PD-L1 were reduced by long-term slide storage of FFPE specimens. Sectioned slides should be stained for PD-L1 without delay.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.12363DOI Listing
March 2018

Predictive Performance of Four Programmed Cell Death Ligand 1 Assay Systems on Nivolumab Response in Previously Treated Patients with Non-Small Cell Lung Cancer.

J Thorac Oncol 2018 03 9;13(3):377-386. Epub 2017 Dec 9.

Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.

Introduction: Nivolumab has demonstrated efficacy against metastatic NSCLC. Four programmed cell death ligand 1 (PD-L1) immunohistochemistry (IHC) assay systems are available for identification of responders among patients with NSCLC, and these assays show some differing characteristics. Accordingly, in this study, we evaluated the ability of these assays to identify responders to nivolumab therapy.

Methods: We retrospectively analyzed patients with previously treated advanced NSCLC, who received nivolumab between January 2016 and September 2016. Specimens were stained using four PD-L1 IHC assays (28-8, 22C3, SP142, and SP263). We classified patients as having test results that were strongly positive (tumor proportion score [TPS] ≥50%), weakly positive (TPS 1%-49%), or negative (TPS <1%).

Results: A total of 40 patients with NSCLC and their specimens were analyzed. Analytical comparisons demonstrated good concordance of PD-L1-stained tumor cells among the 28-8, 22C3, and SP263 assays (weighted κ coefficient 0.64-0.71), whereas the SP142 assay showed lower concordance with other assays (weighted κ coefficient 0.39-0.55). Progression-free survival in patients showing strongly positive PD-L1 staining classified by 28-8, 22C3, and SP263 assays was significantly longer than that in patients with a negative result for PD-L1 staining. Predictive performance of response to nivolumab, as assessed by receiver operating characteristic analysis, was also equivalent among the 28-8, 22C3, and SP263 assays (area under the curve 0.75-0.82), whereas the SP142 assay exhibited lower predictive performance (area under the curve 0.68).

Conclusions: The 28-8, 22C3, and SP263 PD-L1 IHC assays showed equivalent predictive performance, whereas the SP142 assay showed lower predictive performance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2017.11.123DOI Listing
March 2018

Early Immune-Related Adverse Events and Association with Outcome in Advanced Non-Small Cell Lung Cancer Patients Treated with Nivolumab: A Prospective Cohort Study.

J Thorac Oncol 2017 12 20;12(12):1798-1805. Epub 2017 Sep 20.

Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Hyogo, Japan.

Introduction: Retrospective studies have shown immune-related adverse events (irAEs) to be associated with better prognosis. However, no prospective clinical trials have been conducted, and little is known regarding the association between irAEs and the outcome of patients with NSCLC after treatment with immunotherapy.

Methods: We conducted a prospective cohort study of patients with advanced NSCLC who were treated with nivolumab between January and December 2016. The association between clinical outcome and irAEs 2 to 6 weeks after commencement of nivolumab treatment was investigated. IrAEs were assessed by at least three independent medical professionals.

Results: A total of 43 patients were enrolled, including 19 patients with irAEs 2 weeks after commencement of nivolumab treatment. Common irAEs included rash, pyrexia, and diarrhea. Programmed cell death ligand 1-positive tumor cell expression was not significantly different between patients with and without irAEs. The objective response and disease control rates were higher in patients with irAEs than in those without irAEs (37% versus 17% and 74% versus 29% [p = 0.17 and p < 0.01], respectively]). Patients with irAEs were associated with a significantly longer median progression-free survival than those without (6.4 months [95% confidence interval: 2.5-not reached] versus 1.5 months [95% confidence interval: 1.2-2.3] [p = 0.01]). These findings were comparable to those for patients with and without irAEs 6 weeks after commencement of nivolumab treatment.

Conclusions: Early irAEs are associated with a better outcome after treatment with immunotherapy. We predicted responses to nivolumab by using early irAEs. Further research is needed to elucidate the mechanisms of these associations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2017.08.022DOI Listing
December 2017

Alteration of PD-L1 expression and its prognostic impact after concurrent chemoradiation therapy in non-small cell lung cancer patients.

Sci Rep 2017 09 12;7(1):11373. Epub 2017 Sep 12.

Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.

Concurrent chemoradiation therapy (CCRT) is the treatment of choice for locally advanced non-small cell lung cancer (LA-NSCLC). Several clinical trials that combine programmed cell death 1 (PD-1) axis inhibitors with radiotherapy are in development for patients with LA-NSCLC. However, the effect of CCRT on programmed cell death ligand-1 (PD-L1) expression on tumor cells is unknown. In this study, we analysed paired NSCLC specimens that had been obtained pre- and post-CCRT. PD-L1 expression on tumor cells was studied by immunohistochemistry. A total of 45 patients with LA-NSCLC were included, among which there were sufficient pre- and post-CCRT specimens in 35 patients. Overall, the percentage of tumor cells with PD-L1 expression significantly decreased between pre- and post-CCRT specimens (P = 0.024). Sixteen, 15, and 4 patients had decreased, unchanged, or increased PD-L1 expression after CCRT, respectively. Median OS of patients with decreased, unchanged, or increased PD-L1 expression was 85.1, 92.8, and 14.6 months, respectively (P < 0.001). In conclusion, the percentage of PD-L1-positive tumor cells significantly decreased after CCRT. Alteration of PD-L1 expression after neoadjuvant CCRT was associated with prognosis in patients with LA-NSCLC. These data should be considered when developing the optimal approach of integrating PD-1 axis inhibitors with CCRT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-11949-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595796PMC
September 2017

Natural history and clinical characteristics of multiple pulmonary nodules with ground glass opacity.

Respirology 2017 11 13;22(8):1615-1621. Epub 2017 Jun 13.

Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.

Background And Objective: Ground glass nodules (GGNs) are frequently encountered in the lungs. We report the natural history and characteristics of multiple GGNs, and propose a management plan for patients with multiple GGNs.

Methods: We retrospectively analysed patients with GGNs that met the following criteria: (i) GGN diameter of 3 cm or less, (ii) ground glass opacity proportion of 50% or more and (iii) observation without treatment for ≥6 months. We evaluated size changes in computed tomography images. Two end points, 'incidence of growth at 36 months' and 'time to growth' were analysed using logistic regression models and Cox proportional hazards model.

Results: Between April 2008 and December 2014, 187 patients fulfilled the inclusion criteria (78 (42%) had multiple lesions). Among the multiple-GGN patients, the median observation period was 45.5 months, 25 patients (32%) experienced GGN progression at 36 months and 4 patients (5.1%) after 36 months. Between the multiple and single GGNs, there were no significant differences in growth incidence at 36 months (P = 0.1), after 36 months (P = 0.6) or in time to growth (P = 0.3). Among patients with multiple GGNs who experienced one GGN growth, 41% of patients experienced residual GGN growth afterwards.

Conclusion: Patients with multiple GGNs showed a tendency to growth within the first 36 months, and a significant proportion of patients experienced multiple GGN progression. We suggest that the optimal observation period for patients with multiple GGNs is 36 months, but careful observation is needed after a lesion begins to grow.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/resp.13089DOI Listing
November 2017

Aprepitant for refractory nivolumab-induced pruritus.

Lung Cancer 2017 07 27;109:58-61. Epub 2017 Apr 27.

Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan.

Although substantial progress has been made in the treatment of non-small-cell lung cancer (NSCLC) patients with immune checkpoint inhibitors (ICIs), severe immune-related adverse events (irAEs) sometimes occur. Here, we report a case of severe refractory pruritus after Stevens-Johnson syndrome (SJS) in a patient with NSCLC treated with nivolumab. The patient was a 76-year-old Japanese woman with advanced NSCLC treated with nivolumab. After the second dose, she experienced severe rash with mucous involvement. We diagnosed SJS and started 50mg of oral prednisolone (1mg/kg). The rash completely resolved after prednisolone was started, but we could not manage the severe pruritus with emollients, antihistamines, and steroids. Finally, we administered aprepitant, an oral neurokinin-1 receptor antagonist, for her refractory pruritus. Her symptoms improved within 5days. Severe refractory pruritus can arise from ICIs, and aprepitant may be a useful treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2017.04.020DOI Listing
July 2017

The prognostic value of serum CA 19-9 for patients with advanced lung adenocarcinoma.

BMC Cancer 2016 11 14;16(1):890. Epub 2016 Nov 14.

Department of Respiratory Medicine, Kobe City Medical Center, General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan.

Background: This study aimed to assess the prognostic accuracy of serum CA 19-9 in patients with advanced lung adenocarcinoma.

Methods: We retrospectively reviewed data of 246 patients who were diagnosed at our institute with advanced (stage IIIB or IV) lung adenocarcinoma between March 2006 and December 2012. We excluded patients who received no chemotherapy, or for whom we had no data on pre-treatment tumor markers. We also evaluated 116 consecutive resected specimens from patients with clinical stage I lung adenocarcinoma pathologically.

Results: The 76 (31 %) patients who were CA 19-9 had shorter overall survival (OS) than CA 19-9 group (12.5 vs 26.2 months, P = 0.005). Cox's multivariate regression analysis identified Eastern Cooperative Oncology Group Performance Status 0 or 1 (P < 0.001), mutated epidermal growth factor receptor (EGFR) status (P < 0.001), stage IIIB (P < 0.001), CYFRA 21-1 (P < 0.001), CA 19-9 (P = 0.005) and use of platinum doublet therapy (P = 0.034) as independent predictors of longer OS. We stratified patients by CA 19-9 and CYFRA 21-1 as double positive (CA 19-9/CYFRA 21-1, n = 59), single positive (either CA19-9 or CYFRA 21-1, n = 113), or double negative (CA 19-9/CYFRA 21-1, n = 74). Their respective OS were 10.0, 23.3 and 31.8 months (P < 0.001). Pathological analysis also correlated CA 19-9 expression with malignant features such as vessel invasion, pleural invasion, cancer invasive factors and mucin production.

Conclusions: CA 19-9 and CYFRA 21-1 are independent prognostic markers in patients with advanced lung adenocarcinoma. Combined use of CA 19-9 and CYFRA 21-1 provides further prognostic information in patients with advanced lung adenocarcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-016-2897-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5109711PMC
November 2016

The prospect of endoscopic submucosal dissection for early anal canal squamous cell carcinoma.

Clin J Gastroenterol 2016 Dec 13;9(6):384-388. Epub 2016 Oct 13.

Department of Gastroenterology, Kobe City Medical Center General Hospital, Minatojimaminami-machi 2-1-1, Chuo-ku, Kobe-Shi, Hyogo, 650-0047, Japan.

Squamous cell carcinoma (SCC) of the anal canal is seldom diagnosed at an early stage. Chemoradiation therapy is a standard in Europe and the United States, though in squamous cell carcinoma there is no evidence-based therapy. In Japan, endoscopic submucosal dissection (ESD) is the standard minimally invasive treatment for early stage cancer of the digestive tract, including the colorectum. Therefore, if the lesion is diagnosed at an early stage, ESD may be selected for anal canal lesions. We experienced two cases of early stage anal canal cancer in which the diagnosis and the extent of the lesions were confirmed using magnifying endoscopy with narrow-band imaging (NBI), as well as performing ESD. Pathological examination showed the resected specimen to be SCC in situ; the horizontal and vertical margins were free of tumor; and in one case there was no lymphovascular invasion. In the other case it showed the tumor was contained within the epithelium; horizontal and vertical margins were free of tumor; The follow-up period is not long enough to assert that ESD for anal canal squamous cell carcinoma may be an option of minimally invasive therapy. However, if there is a possibility of lymphatic invasion as in one of our cases, we need to give serious consideration to ESD for these lesions, and careful follow-up is necessary even if the lesion is in situ.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12328-016-0690-3DOI Listing
December 2016

Transformation to large cell neuroendocrine carcinoma as acquired resistance mechanism of EGFR tyrosine kinase inhibitor.

Lung Cancer 2015 Nov 8;90(2):364-8. Epub 2015 Sep 8.

Departments of Respiratory Medicine, Kobe City Medical Centre General Hospital, Kobe, Japan.

Objectives: Several different acquired resistance mechanisms to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy have been described. Although rare, the transformation from adenocarcinoma to small cell carcinoma (SCLC) is one of these important mechanisms. We report a rare case that indicates transformation into large-cell neuroendocrine carcinoma (LCNEC) as an acquired resistance mechanism to EGFR-TKI therapy.

Materials And Methods: The patient was a 68-year-old male with a diagnosis of cT2N2M0 pulmonary adenocarcinoma with L858R mutation on exon 21. He received lobectomy and underwent several courses of chemotherapies, including EGFR-TKIs, each time he relapsed. He finally relapsed with a mass that protruded into his left main bronchus. Resection of the metastatic site identified LCNEC that retained the original EGFR mutation. Immunohistochemistry revealed the loss of expression of EGFR and retinoblastoma (Rb) in the LCNEC.

Conclusions: This case highlights acquisition of EGFR-TKI resistance by transformation to LCNEC, not SCLC. Loss of EGFR and Rb expression in the LCNEC suggests the same mechanism as transformation to SCLC. Further study is needed to elucidate this mechanism, especially regarding the similarities and differences to SCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2015.09.002DOI Listing
November 2015

Melanotic oncocytic metaplasia of the nasopharynx.

Pathol Int 2015 Mar 9;65(3):144-7. Epub 2015 Jan 9.

Department of Pathology, Saitama Medical University, Saitama International Medical Center, Saitama, Japan; Department of Clinical Pathology, Kobe City Medical Center General Hospital, Hyogo, Japan.

We present three cases of melanotic oncocytic metaplasia of the nasopharynx. Case 1 and Case 2 were a 70- and a 61-year-old woman, and Case 3 was a 74-year-old man. Although Case 1 was asymptomatic, Cases 2 and 3 had hoarseness. All cases were Japanese and their nasopharyngeal examination revealed single or multiple black nodules measuring a few millimeters in diameter. In each case, biopsies were performed to rule out malignancy. Histological examination showed respiratory mucosa with oncocytic metaplasia and melanin pigments. Immunohistochemically, S-100 protein and melan-A positive dendritic melanocytes were observed in the basal layer of the oncocytes. Melanotic oncocytic metaplasia is extremely rare, and so far only 21 cases have been reported in the English literature to our knowledge. It has been reported in only older Asians, predominantly in males; there have been only three female patients including our two cases. All of our cases were long-time smokers, which supports the previously described hypothesis that smoking may be a predisposing factor for melanin pigmentation. Since melanotic oncocytic metaplasia may clinically mimic a malignant tumor, it is important to be aware of this lesion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pin.12247DOI Listing
March 2015

The first report of adolescent TAFRO syndrome, a unique clinicopathologic variant of multicentric Castleman's disease.

BMC Pediatr 2014 Jun 2;14:139. Epub 2014 Jun 2.

Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-Cho, Chuo-ku, Kobe 650-0017, Japan.

Background: TAFRO syndrome is a unique clinicopathologic variant of multicentric Castleman's disease that has recently been identified in Japan. It is characterized by a constellation of symptoms: Thrombocytopenia, Anasarca, reticulin Fibrosis of the bone marrow, Renal dysfunction and Organomegaly (TAFRO). Previous reports have shown that affected patients usually respond to immunosuppressive therapy, but the disease sometimes has a fatal course. TAFRO syndrome occurs in the middle-aged and elderly and there are no prior reports of the disease in adolescents. Here we report the first adolescent case, successfully treated with anti-IL-6 receptor antibody (tocilizumab, TCZ) and monitored with serial cytokine profiles.

Case Presentation: A 15-year-old Japanese boy was referred to us with fever of unknown origin. Whole body computed tomography demonstrated systemic lymphadenopathy, organomegaly and anasarca. Laboratory tests showed elevated C-reactive protein and hypoproteinemia. Bone marrow biopsy revealed a hyperplastic marrow with megakaryocytic hyperplasia and mild reticulin fibrosis. Despite methylprednisolone pulse therapy, the disease progressed markedly to respiratory distress, acute renal failure, anemia and thrombocytopenia. Serum and plasma levels of cytokines, including IL-6, vascular endothelial growth factor, neopterin and soluble tumor necrosis factor receptors I and II, were markedly elevated. Repeated weekly TCZ administration dramatically improved the patient's symptoms and laboratory tests showed decreasing cytokine levels.

Conclusion: To our knowledge, this is the first report of TAFRO syndrome in a young patient, suggesting that this disease can occur even in adolescence. The patient was successfully treated with TCZ. During our patient's clinical course, monitoring cytokine profiles was useful to assess the disease activity of TAFRO syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2431-14-139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4088371PMC
June 2014

Portal venous tumor growth-type of hepatocellular carcinoma without liver parenchyma tumor nodules: a case report.

Ann Hepatol 2013 Nov-Dec;12(6):969-73

Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

The patient was a 43-year-old man with chronic hepatitis B without history of hepatocellular carcinoma (HCC), who was first diagnosed with thrombosis in right portal vein trunk and portal vein branches and ruptured esophageal varices in October 2011. He underwent endoscopic variceal ligation, but ruptured repeatedly. Despite anti-coagulant therapy, the thrombosis expanded from right portal vein trunk to upper mesenteric vein in March 2012. Computed tomography (CT) scan showed that portal vein thrombosis had low density from early to late phase. No focal liver lesions were identified by CT scan or ultrasound, and alpha-fetoprotein (AFP) was within normal range. He died by intractable esophageal variceal bleeding in April 2012. Pathological examination of autopsy specimen showed that portal vein thrombosis was consistent with poorly-differentiated HCC. The portal vein tumor thrombosis (PVTT) had only a few tumor vessels, which were compressed by fibromatous change originating from HCC formation, so were represented as low-density lesions from arterial to portal phase of CT. In addition, PVTT was negative for AFP, so representing serum value of AFP within normal range. PVTT had positive staining for c-kit, which is a liver stem cell marker. Liver tumors in the whole liver parenchyma were not found pathologically. PVTT might have the characteristics of presumed liver cancer stem cells. We experienced the first case of HCC only in portal vein without liver parenchyma tumor nodules, with difficult differential diagnosis from a non-malignant portal vein thrombosis. We also reported new tumor profiles of the portal venous tumor growth- type of HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
August 2014

Supratentorial pure cortical ependymoma.

J Clin Neurosci 2012 Oct 13;19(10):1453-5. Epub 2012 Aug 13.

Department of Neurosurgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.

Ependymoma usually occurs in the lateral or the fourth ventricle. Supratentorial extraventricular ependymoma is relatively rare. However, extraventricular ependymoma located at the cerebral cortex is extremely rare. We treated a 20-year-old woman who presented with generalized seizures. Cranial CT scan revealed a calcified mass in the left precentral gyrus. MRI confirmed an extraventricular, 12-mm-diameter intracortical mass. After gadolinium injection, tumor enhancement was mild and heterogeneous. The tumor was totally resected without neurological deterioration. Histological features were consistent with ependymoma, forming perivascular pseudorosettes without anaplastic figures. Immunohistochemistry showed positive staining for glial fibrillary acidic protein, S-100, and epithelial membrane antigen. A diagnosis of ependymoma of World Health Organization grade II was made. The patient has not had a seizure since the operation. There has been no clinical or radiologic evidence of recurrence during a 16-month postoperative follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jocn.2011.09.039DOI Listing
October 2012

Peritoneal keratin granuloma associated with endometrioid adenocarcinoma of the uterine corpus.

Diagn Pathol 2011 Oct 28;6:104. Epub 2011 Oct 28.

Department of Pathology, Saitama Medical University, International Medical Center, Japan.

We present a 69-year-old woman with a chief complaint of postmenopausal bleeding. She was diagnosed as having an endometrioid adenocarcinoma by biopsy, and underwent a total abdominal hysterectomy. At the time of surgery, granulation tissue-like nodules were found on the peritoneal serosa of the uterus. In the intraoperative cytology of peritoneal washing, atypical cells were noted. The intraoperative frozen section of the peritoneal nodule revealed granulation tissue with proliferating mesothelial cells. Microscopic examination of the permanent section showed keratin granulomas without viable adenocarcinoma cells on the serosal surface of the ovaries, fallopian tubes and broad ligaments. Postoperative chemotherapy was administered. She has been alive with no evidence of recurrence for 6 months postoperatively. It should be noted that the prognosis of cases in peritoneal keratin granuloma without viable cancer cells is favorable, and that the histological examination is essential for its diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1746-1596-6-104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3216880PMC
October 2011