Publications by authors named "Jun Akiba"

187 Publications

Diversity and shared T-cell receptor repertoire analysis in esophageal squamous cell carcinoma.

Oncol Lett 2021 Aug 24;22(2):618. Epub 2021 Jun 24.

Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.

The tumor immune response is dependent on the interaction between tumor cells and the T-cell subset expressing the T-cell receptor (TCR) repertoire that infiltrates into the tumor microenvironment. The present study explored the diversity and shared TCR repertoires expressed on the surface of locoregional T cells and identified the T lymphocyte subsets infiltrating into esophageal squamous cell carcinoma (ESCC), in order to provide insight into the efficiency of immunotherapy and the development of a novel immune-oriented therapeutic strategy. A total of 53 patients with ESCC were enrolled in the present study, and immunohistochemical analysis of CD3, CD8, CD45RO, FOXP3, CD274, HLA class I and AE1/AE3 was performed. Digital pathological assessment was performed to evaluate the expression level of each marker. The clinicopathological significance of the immuno relation high (IR-Hi) group was assessed. Adaptor ligation PCR and next-generation sequencing were performed to explore the diversity of the TCR repertoire and to investigate the shared TCR repertoire in the IR-Hi group. Repertoire dissimilarity index (RDI) analysis was performed to assess the diversity of TCR, and the existence of shared TCRα and TCRβ was also investigated. Further stratification was performed according to the expression of markers of different T-cell subsets. Patients were stratified into IR-Hi and immuno relation low (IR-Lo) groups. Cancer-specific survival and recurrence-free survival rates were significantly improved in the IR-Hi group compared with in the IT-Lo group. The diversity of the TCR repertoire was significantly higher in the IR-Hi group. TCR repertoire analysis revealed 27 combinations of TCRα and 23 combinations of TCRβ VJ regions that were shared among the IR-Hi group. The IR-Hi group was divided into three clusters. Overall, the current findings revealed that the IR-Hi group maintained the diversity of TCR, and a portion of the IR-Hi cases held the T cells with shared TCR repertoires, implying recognition of shared antigens. The prognosis of patients with ESCC was affected by the existence of immune response cells and may possibly be stratified by the T-cell subsets.
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http://dx.doi.org/10.3892/ol.2021.12879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243081PMC
August 2021

A deep learning model to detect pancreatic ductal adenocarcinoma on endoscopic ultrasound-guided fine-needle biopsy.

Sci Rep 2021 Apr 19;11(1):8454. Epub 2021 Apr 19.

Department of Pathology, Kurume University School of Medicine, Kurume, 830-0011, Japan.

Histopathological diagnosis of pancreatic ductal adenocarcinoma (PDAC) on endoscopic ultrasonography-guided fine-needle biopsy (EUS-FNB) specimens has become the mainstay of preoperative pathological diagnosis. However, on EUS-FNB specimens, accurate histopathological evaluation is difficult due to low specimen volume with isolated cancer cells and high contamination of blood, inflammatory and digestive tract cells. In this study, we performed annotations for training sets by expert pancreatic pathologists and trained a deep learning model to assess PDAC on EUS-FNB of the pancreas in histopathological whole-slide images. We obtained a high receiver operator curve area under the curve of 0.984, accuracy of 0.9417, sensitivity of 0.9302 and specificity of 0.9706. Our model was able to accurately detect difficult cases of isolated and low volume cancer cells. If adopted as a supportive system in routine diagnosis of pancreatic EUS-FNB specimens, our model has the potential to aid pathologists diagnose difficult cases.
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http://dx.doi.org/10.1038/s41598-021-87748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055968PMC
April 2021

Neoadjuvant Hyperthermia and Chemoradiotherapy for Borderline Resectable Pancreatic Cancer.

Gan To Kagaku Ryoho 2021 Mar;48(3):388-390

Dept. of Surgery, Munakata Suikokai General Hospital.

Pancreatic cancer(PC)is associated with poor prognosis and low resectability rates. Currently, only 15-20% of all patients are candidates for upfront surgery at the time of diagnosis, which offers the chance of long-term survival. In recent years, patients with borderline resectable PC(BR-PC)have been treated with surgery following neoadjuvant chemoradiotherapy or intensive multi-agent chemotherapy. In PC, which is therapy resistant due to its hypoxic microenvironment, hyperthermia may enhance the effect of chemo(radio)therapy. An 84-year-old man with fatty stool was diagnosed with pancreatic head cancer according to the result of contrast computed tomography(CT), which showed a 37 mm irregular low-density area at the pancreatic head infiltrating nearly half of the superior mesenteric artery(SMA)plexus. There were no findings of lymph node metastasis or distant metastasis. The pretreatment diagnosis was BR-PC, cT3, N0, M0, cStage Ⅱ A. The patient was treated with hyperthermia plus S-1 and radiotherapy. The size of the tumor had reduced from 37 mm to 15 mm after the neoadjuvant therapy, and the infiltration into the SMA plexus had also reduced. Therefore, the patient underwent subtotal stomach-preserving pancreaticoduodenectomy(SSPPD)concomitant resection of the PV, SMV, SV confluence. The histopathological findings were invasive ductal carcinoma with R0 radical resection. There has been no recurrence 18 months after the surgery. Based on the above-mentioned findings, hyperthermia and chemoradiotherapy can be an effective option of neoadjuvant treatment for BR-PC.
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March 2021

The Expression of PEDF and its Putative Receptors in Hepatocellular Carcinoma and Background Liver Tissue.

Anticancer Res 2021 Mar;41(3):1203-1212

Department of Pathology, Kurume University School of Medicine, Kurume, Japan.

Background/aim: Hepatocellular carcinoma (HCC) remains one of the biggest medical issues. Pigment epithelial-derived factor (PEDF) is a glycoprotein that belongs to the superfamily of serine protease inhibitors. PEDF interacts with its two receptors, adipose triglyceride lipase (ATGL) and laminin receptor (LR).

Materials And Methods: We conducted immunohistochemical staining for PEDF, LR and ATGL in 151 resected HCCs and their background liver tissues.

Results: High expression of LR in HCC was associated with high histological grade and portal vein invasion, while high expression of PEDF in HCC was associated with absence of portal vein invasion. High LR expression in background liver was statistically associated with low serum albumin levels and was an independent prognostic factor of worse outcomes. No cases with more than 5% fatty degeneration in the background liver tissue showed high PEDF expression.

Conclusion: PEDF/LR/ATGL could be potential biomarkers in HCC and various chronic hepatic disorders.
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http://dx.doi.org/10.21873/anticanres.14877DOI Listing
March 2021

Investigation of clinicopathological characters and gene expression features in colorectal signet-ring cell carcinoma utilizing CMS classification.

Mol Clin Oncol 2021 May 12;14(5):98. Epub 2021 Mar 12.

Department of Surgery, Kurume University Hospital, Kurume, Fukuoka 830-0011, Japan.

Signet ring cell carcinoma (SRCC) is a rare pathological type of colorectal cancer, of which the clinicopathological features and genetic background have not yet been fully investigated. Previous research has focused on the optimization of colorectal cancer treatment utilizing consensus molecular subtyping (CMS). However, it is not known what type of CMS would be designated to SRCC treatment. In the current study, of 1,350 patients diagnosed with colorectal cancer who underwent surgery, 14 were diagnosed with SRCC. The case-control cohort that fit the clinical background of the SRCC case was constructed. Statistical comparison between the SRCC group and the case-control cohort was performed among clinicopathological variables. SRCC and well to moderately adenocarcinoma case mRNA were submitted to microarray analysis and CMS analysis. Compared with the case-control cohort, the SRCC group was located more in the right-sided colon, the lymphatic invasion was more severe and the peritoneal dissemination was more frequent. The cancer-specific survival and the progression-free survival were significantly worse in the SRCC group compared with the case-control cohort. Microarray and CMS analysis identified that one SRCC case was significantly well assigned in the CMS 4 group and the other case was assigned in the CMS 1 group. Gene set analysis revealed the upregulation of EMT related genes and the downregulation of fatty acid, glycolysis, differentiation, MYC, HNF4A, DNA repair genes. In conclusion, the clinical characteristics of SRCC are severe but there is a possibility of the presence of different phenotypes according to CMS analysis.
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http://dx.doi.org/10.3892/mco.2021.2260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976453PMC
May 2021

The herbal medicines Inchinkoto and Saireito improved hepatic fibrosis via aquaporin 9 in the liver of a rat bile duct ligation model.

Pediatr Surg Int 2021 Aug 12;37(8):1079-1088. Epub 2021 Mar 12.

Department of Pediatric Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan.

Objective: To determine if the administration of the Japanese herbal medicines Inchinkoto (ICKT) and Saireito (SRT) ameliorate hepatic fibrosis and derangement of hepatocyte aquaporins (AQPs) following bile duct ligation (BDL) in a rat model of obstructive cholestasis.

Materials And Methods: Five groups of Wistar rats were used, and the groups included sham surgery (Sham group), BDL with no treatment (NT group), BDL plus ICKT (ICKT group), BDL plus SRT (SRT group), and BDL plus ICKT and SRT (SRT/ICKT group). Each herbal medicine was administered at 1 g/kg/day on the first postoperative day. The serum levels and various clinical markers were measured with real-time polymerase chain reaction. Staining was used to evaluate the degree of fibrosis and the inflammatory responses.

Results: Serum aspartate aminotransferase and alanine aminotransferase in the ICKT and SRT/ICKT groups were significantly lower than those in the NT group. NF-κB mRNA expression was significantly decreased in the ICKT group and the SRT/ICKT group compared with the NT group. AQP9 mRNA expression was significantly increased in the ICKT group and the SRT/ICKT group compared with the NT group. The degree of Masson's trichrome staining in the SRT/ICKT group was significantly lower than that in the NT group. The degree of NF-κB staining in the SRT/ICKT group was significantly lower than that in the NT, ICKT, or SRT group.

Conclusions: The postoperative administration of ICKT and SRT induced synergistic beneficial effects, resulting in the reduction of hepatic fibrosis via mechanisms involving the inhibition of NF-κB expression and the improvement of AQP9 downregulation.
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http://dx.doi.org/10.1007/s00383-021-04882-6DOI Listing
August 2021

Laparoscopic left hepatectomy for a patient with intrahepatic cholangiocarcinoma metastasis in the falciform ligament: a case report.

BMC Surg 2021 Mar 8;21(1):122. Epub 2021 Mar 8.

Department of Surgery, Kurume University Hospital, Kurume, Japan.

Background: Intrahepatic cholangiocarcinoma (ICC) is primary cancer of the liver with poor prognosis because of its high potential for recurrence and metastasis. We experienced a rare case of ICC with hematogenous metastasis to the falciform ligament. We aimed to clarify the route of metastasis to the mesentery by increasing the accuracy of preoperative imaging and establish a hepatectomy to control cancer.

Case Presentation: An 85-year-old woman was referred to our hospital for a detailed study of progressively increasing liver tumors. She had no subjective symptoms. Her medical history showed hypertension, aneurysm clipping for cerebral hemorrhage, and gallstones. A detailed physical examination and laboratory data evaluation included tumor markers but did not demonstrate any abnormalities. On computed tomography scan, contrast-enhanced ultrasound, and magnetic resonance imaging with gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid, the tumor appeared to be located in liver segment IV, protruding outside the liver. It appeared to contain two distinct components; we suspected ICC in the intrahepatic tumor component. Laparoscopic observation revealed that the extrahepatic lesion was an intra-falciform ligament mass; laparoscopic left hepatectomy was performed. Microscopically, the main tumor in segment IV was 15 mm in diameter and was diagnosed as moderately and poorly differentiated ICC. The tumor of the intra-falciform ligament was not continuous with the main intrahepatic nodule and was also diagnosed as ICC with extensive necrosis. There were no infiltrates in the round ligament of the liver, and several tumor thrombi were found in the small veins of the falciform ligament.

Conclusions: To date, there have been a few reports of metastases of primary liver cancer to the falciform ligament. At the time of preoperative imaging and pathological diagnosis, this case was suggestive of considering that the malignant liver tumor might be suspected of metastasizing to the falciform ligament. Our case improves awareness of this pathology, which can be useful in the future when encountered by hepatic specialists and surgeons.
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http://dx.doi.org/10.1186/s12893-021-01115-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941886PMC
March 2021

Therapeutic Potential of a Self-Assembling Peptide Hydrogel to Treat Colonic Injuries Associated with Inflammatory Bowel Disease.

J Crohns Colitis 2021 Feb 17. Epub 2021 Feb 17.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

Background And Aims: The Self-assembling Peptide Hydrogel (SAPH, PuraMatrix TM), a fully synthetic peptide solution designed to replace collagen, has recently been used to promote mucosal regeneration in iatrogenic ulcers following endoscopic submucosal dissection. Herein, we evaluated its utility in ulcer repair using a rat model of topical trinitrobenzene sulfonic acid (TNBS)-induced colonic injuries.

Methods: Colonic injuries were generated in 7-week-old rats by injecting an ethanol solution (35%, 0.2 mL) containing 0.15 M TNBS into the colonic lumen. At 2- and 4-days post-injury, the rats were subjected to endoscopy, and SAPH (or vehicle) was topically applied to the ulcerative lesion. Time-of-flight secondary ion mass spectrometry (TOF-SIMS) was used to detect SAPH. Colonic expression of cytokines and wound healing-related factors were assessed using real-time polymerase chain reaction or immunohistochemistry.

Results: SAPH treatment significantly reduced ulcer length (P = 0.0014) and area (P = 0.045), while decreasing colonic weight (P = 0.0375) and histological score (P = 0.0005) 7 days after injury. SAPH treatment also decreased colonic expression of interleukin (IL)-1α (P = 0.0233) and IL-6 (P = 0.0343) and increased that of claudin-1 (P = 0.0486), villin (P = 0.0183), and β-catenin staining (P = 0.0237). TOF-SIMS revealed lesional retention of SAPH on day 7 post-injury. Furthermore, SAPH significantly promoted healing in in vivo mechanical intestinal wound models.

Conclusions: SAPH application effectively suppressed colonic injury, downregulated inflammatory cytokine expression, and upregulated wound healing-related factor expression in the rat model; thus, it may represent a promising therapeutic strategy for IBD-related colonic ulcers.
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http://dx.doi.org/10.1093/ecco-jcc/jjab033DOI Listing
February 2021

Dentigerous cyst exhibiting prominent mucous cell metaplasia: report of a unique case mimicking central mucoepidermoid carcinoma.

Med Mol Morphol 2021 Jan 12. Epub 2021 Jan 12.

Department of Anatomic Pathology, Hirosaki University Graduate School of Medicine, 5 Zaifu, Hirosaki, 036-8562, Japan.

A Japanese male aged 61 presented with persistent pain in the left posterior area of the mandible for several weeks. A panoramic X-ray revealed a unilocular lesion showing characteristics of a dentigerous cyst associated with an impacted third molar. A cystectomy was performed and histopathological examination revealed a cystic lesion with a fibrous wall. The lumen was covered with non-keratinizing squamous cells with obvious intercellular bridges, which were intermingled with partially ciliated goblet-cell-type mucous and columnar cells. Such cystic lesions should be carefully examined to distinguish them from the glandular odontogenic cyst and central mucoepidermoid carcinoma of the jawbone.
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http://dx.doi.org/10.1007/s00795-020-00278-yDOI Listing
January 2021

ER staining levels affect HER2 staining and heterogeneity.

Breast Cancer 2021 May 9;28(3):720-726. Epub 2021 Jan 9.

Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan.

Purpose: This study explored the relationship of ER expression levels with HER2 staining properties and heterogeneity and discussed the differences in HER2 assessment caused by the 2018 ASCO/CAP guideline updates from that of the 2013 version.

Methods: HER2-positive breast cancer was divided into three groups of the high hormone receptor expression (LH-high) group, low expression (LH-low) group, or negative (NLH) group to (1) compare differences in the percentage of the HER2 IHC test score of 2 + based on the 2013 ASCO/CAP guideline and in the intratumor heterogeneity of HER2 expression for breast cancer with an IHC score of 3 + among these groups, (2) compare the HER2/CEP17 ratio and the average HER2 copy number, and classified ISH groupings according to the 2018 ASCO/CAP guideline algorithm.

Results: (1) Of 244 HER2-positive breast cancers, the cases with a HER2 IHC score of 2 + (n = 54, 22.1%) were significantly more common in the LH-high group (n = 45, P < 0.001). The frequency of heterogeneity was low (n = 25, 10.2%) for the HER2 score of 3 + (n = 190, 77.9%), and significantly higher in the LH-high group (n = 19, 76%, P = 0.002). (2) In a HER2 IHC score of 2 + , Group 2 which is deemed HER2 negative according to the revised 2018 ASCO/CAP guideline was observed in 17 (39.5%) out of 43 cases, of which 16 cases (94.1%) were in the LH-high group.

Conclusions: The LH-high group is a heterogeneous group largely consisting of heterogeneous cases with HER2 IHC scores of 2 + or 3 + . NLH, in contrast, is a homogenous group.
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http://dx.doi.org/10.1007/s12282-020-01208-7DOI Listing
May 2021

Programmed Death-Ligand 1 and Programmed Death-Ligand 2 Expression Can Affect Prognosis in Extramammary Paget's Disease.

Anticancer Res 2021 Jan;41(1):219-226

Department of Pathology, Kurume University School of Medicine, Kurume, Japan.

Background: Extramammary Paget's disease (EMPD) is a type of carcinoma that usually progresses slowly but may cause metastasis and subsequent death of patients. We investigated the relationship between the expression of programmed death-ligand 1 (PD-L1)/programmed death-ligand 2 (PD-L2) and stromal CD8 tumor-infiltrating lymphocytes (TILs) in EMPD and clinicopathological findings, including prognosis.

Materials And Methods: We examined 47 cases of EMPD and performed immunohistochemical staining of formalin-fixed paraffin-embedded full-face sections.

Results: PD-L1 expression in tumor cells was observed in 13 cases (27.7%) while PD-L2 expression was observed in 21 cases (44.7%). The cumulative postoperative recurrence-free rate in the group with positivity for PD-L1 and/or PD-L2 with a low CD8 TIL count was significantly lower than that of the corresponding group with a high CD8 TIL count and of the PD-L1- and PD-L2-negative group (p=0.026).

Conclusion: The expression of PD-L1/PD-L2 in tumor cells was shown to be a factor for poor prognosis.
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http://dx.doi.org/10.21873/anticanres.14768DOI Listing
January 2021

Sulfite Oxidase Is a Novel Prognostic Biomarker of Advanced Gastric Cancer.

In Vivo 2021 Jan-Feb;35(1):229-237

Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan.

Background/aim: Sulfite oxidase (SUOX) is an enzyme present in the mitochondria, which has been demonstrated to be correlated with various malignant tumours.

Materials And Methods: We evaluated SUOX expression in tissues of 98 cases of advanced gastric cancer and performed a clinicopathological assessment for metrics.

Results: Among 98 cases, 55 cases were classified into the SUOX low expression group, and 43 cases into the SUOX high expression group. There were more pStage IV cases in the low expression group. The median overall survival of the low expression group was shorter than that of the high expression group (p=0.020). In univariate and multivariate analysis, SUOX low expression level (p=0.039) and pStage (p<0.001) were independent prognostic factors.

Conclusion: SUOX is an independent prognostic factor. Therefore, SUOX expression could also serve as a useful marker for elucidating the mechanism of gastric cancer proliferation and progression.
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http://dx.doi.org/10.21873/invivo.12251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880800PMC
June 2021

Primary Pituitary Adenoid Cystic Carcinoma: A Rare Salivary Gland-Like Tumor in the Sella.

Head Neck Pathol 2021 Jan 4. Epub 2021 Jan 4.

Department of Neurosurgery, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka, 830-0011, Japan.

Adenoid cystic carcinoma (ACC) is a tumor of the exocrine glands that originates primarily from the minor and major salivary glands, nasopharynx, and lacrimal glands. ACC grows slowly but is locally aggressive and prone to recurrence. It is uncommon for ACCs to develop in the pituitary gland as a primary tumor. We present a case of primary pituitary ACC extending to the sphenoid sinus resembling an invasive adenoma in a 71-year-old woman with a history of nasal epistaxis. We reviewed other reported cases of pituitary ACCs with retrospective validation of whether the tumor was primary or not. The intrasellar tumor exhibited MYB rearrangement with enlargement and destruction of the sella turcica and dural tears toward the sphenoid sinus, which would be consistent for a tumor originating from the pituitary gland. Including our case, only four intrasellar and one suprasellar ACC have been confirmed as primary tumors. All intrasellar ACCs had the characteristic of some form of invasion of neighboring structures with evidence of hyperprolactinemia. ACC could develop in the pituitary gland as a form of salivary gland-like tumor derived from the ectopic salivary gland rests. ACCs rarely arise from the pituitary gland; however, the accurate determination of primary occurrence is difficult because of the invasive nature of these tumors, and the anatomical relationship with the sphenoid sinus and the cavernous sinus. Excessive bleeding from the tumor or unexpected internal carotid artery injury should be avoided during surgery for primary and secondary pituitary ACC.
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http://dx.doi.org/10.1007/s12105-020-01256-7DOI Listing
January 2021

A rare case of intrahepatic cholangiocarcinoma with tumor thrombus in the bile duct.

Clin J Gastroenterol 2021 Feb 30;14(1):275-282. Epub 2020 Oct 30.

Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Fukuoka, Japan.

Intrahepatic cholangiocarcinoma (ICC) is a refractory liver malignancy; however, as its histological characteristics have been clarified, a good operative strategy for the subtypes of ICC can be expected. A 72-year-old woman was diagnosed with a large primary liver cancer with biliary tumor thrombus (BTT) and obstructive jaundice. An enhanced imaging modality showed hypervascular ICC or combined hepatocellular carcinoma (HCC). As her liver functional parameters permitted major hepatectomy, preoperative biliary drainage was performed, followed by a radical left hepatectomy accompanied by tumor thrombectomy with D2 lymphadenectomy. During the operation, the BTT was found to have widely spread into the right hepatic duct and the common bile duct and was histologically diagnosed as an adenocarcinoma. As ductal cancer invasion was not macroscopically observed, the planned operation was completed. The postoperative histological diagnosis was determined by discussion to be a rare mass-forming ICC with BTT. Her postoperative course was uneventful, and a 1-year survival without tumor relapse was observed with adjuvant chemotherapy. In the field of biliary surgery, although advanced ICC still has a poor prognosis, curable surgical intervention is possible for specific findings, such as BTT and HCC with BTT.
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http://dx.doi.org/10.1007/s12328-020-01275-5DOI Listing
February 2021

Prognostic Value of Tumor Proportion Score in Salivary Gland Carcinoma.

Laryngoscope 2021 05 6;131(5):E1481-E1488. Epub 2020 Oct 6.

Department of Pathology, Kurume University School of Medicine, Kurume, Japan.

Objective: Limited information is available regarding the role of programmed death ligand 1 (PD-L1) expression and CD8 tumor-infiltrating lymphocyte (TIL) density in the tumor immune microenvironment (TIM) of patients with salivary gland carcinoma (SGC). This study aimed to assess the association between the prognosis of SGC patients and the probability of PD-L1 expression in tumor and/or immune cells using the tumor proportion score (TPS), mononuclear immune cell density score (MIDS), combined positive score (CPS), and CD8 TIL density in the TIM.

Study Design: Retrospective cohort study.

Methods: We retrospectively reviewed 73 SGC patients treated with definitive surgery between 2000 and 2015. Immunohistochemical analysis was used to assess TPS, MIDS, CPS, and CD8 TIL density, followed by prognostic evaluation of these immune-related parameters.

Results: Histological grade was associated with TPS, MIDS, and CPS based on PD-L1 expression, and these scores exhibited a significant association with CD8 TIL density. Patients with positive TPS had an unfavorable disease-free survival and overall survival. Multivariate analyses indicated that the TPS was a significant and independent prognostic factor.

Conclusion: Our results suggest that TPS might be a useful prognostic biomarker in SGC patients receiving definitive surgery. Laryngoscope, 131:E1481-E1488, 2021.
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http://dx.doi.org/10.1002/lary.29120DOI Listing
May 2021

CD8+ T Cell Infiltration Predicts Chemoradiosensitivity in Nasopharyngeal or Oropharyngeal Cancer.

Laryngoscope 2021 04 15;131(4):E1179-E1189. Epub 2020 Sep 15.

Department of Otolaryngology-Head and Neck Surgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan.

Objectives: Limited information exists regarding the associations between pre-existing immune parameters in the tumor immune microenvironment (TIM) and either chemoradiosensitivity or prognosis for patients with squamous cell carcinoma of the nasopharynx or oropharynx involving virus-related or nonvirus-related tumors.

Study Design: Retrospective cohort study.

Methods: We retrospectively reviewed 141 patients with EBV+, p16+, or EBV- and p16- statuses who are receiving chemoradiotherapy. We performed immunohistochemistry using pretreatment biopsy specimens to analyze the programed death ligand 1 (PD-L1) levels in tumor and immune cells and CD8+ tumor-infiltrating lymphocyte (TIL) density. We evaluated chemoradiosensitivity and prognosis with respect to these immune-related parameters.

Results: Virus-related tumors showed associations with both PD-L1 expression and high CD8+ TIL density. Patients with higher CD8+ TIL density or greater numbers of PD-L1+ tumor and immune cells showed significant rates of favorable local recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS). Multivariate analyses demonstrated that higher CD8+ TIL density is an independent, significant, and favorable predictive factor for LRFS (P = .005) and OS (P = .003), although it is not a significant predictor of PFS (P = .077).

Conclusions: Higher CD8+ TIL density represents a useful and favorable biomarker of chemoradiosensitivity in patients receiving chemoradiotherapy for nasopharyngeal or oropharyngeal cancer.

Level Of Evidence: 3 Laryngoscope, 131:E1179-E1189, 2021.
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http://dx.doi.org/10.1002/lary.29097DOI Listing
April 2021

Paraganglioma of the urinary bladder: Case report and literature review.

IJU Case Rep 2020 Sep 4;3(5):192-195. Epub 2020 Jul 4.

Department of Urology Kurume University School of Medicine Kurume Japan.

Introduction: Paraganglioma of the urinary bladder is a very rare disease accounting for 0.06% of all bladder tumors. Owing to their rarity and symptomatic variability, preoperative diagnosis is often difficult.

Case Presentation: A 70-year-old male was referred to our department for hematuria. Cystoscopy showed a non-papillary broad-based tumor. Computed tomography and magnetic resonance imaging revealed a 32-mm bladder tumor at the top of the bladder, which suggested muscle-invasive bladder tumor. We diagnosed muscle-invasive bladder cancer or urachal carcinoma, and transurethral resection of the bladder tumor was performed. At the initiation of transurethral resection of the bladder tumor, the systolic blood pressure was elevated to over 200 mmHg. The pathological findings revealed paraganglioma of the urinary bladder, and afterward, a partial cystectomy was performed.

Conclusion: We herein reported the case of paraganglioma in the bladder whose blood pressure became extremely elevated during transurethral resection of the bladder tumor. In addition, we analyzed important factors for preoperative diagnosis using 162 cases reported in Japan.
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http://dx.doi.org/10.1002/iju5.12185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469756PMC
September 2020

Predictive value of CD8/FOXP3 ratio combined with PD-L1 expression for radiosensitivity in patients with squamous cell carcinoma of the larynx receiving definitive radiation therapy.

Head Neck 2020 12 18;42(12):3518-3530. Epub 2020 Aug 18.

Department of Otolaryngology-Head and Neck Surgery, Kurume University School of Medicine, Kurume, Japan.

Background: Little is known about immune-related radiosensitivity in patients with squamous cell carcinoma of the larynx (SCC-L) treated with radiation therapy (RT).

Methods: We retrospectively reviewed 91 patients with SCC-L treated with RT or chemoradiation therapy and performed immunohistochemical examination to analyze PD-L1 level on tumor cells, CD4 tumor-infiltrating lymphocytes (TILs), CD8 TIL, and FOXP3 TIL using pretreated biopsy specimens. The association between these immune-related parameters and radiosensitivity was evaluated.

Results: Multivariate analyses showed that high CD8/FOXP3 ratio combined with negative PD-L1 expression was an independent and significant favorable predictive factor for local control, compared with the other groups.

Conclusions: We showed that high CD8/FOXP3 ratio combined with negative PD-L1 expression might be a useful biomarker of radiosensitivity in patients with SCC-L receiving definitive RT. We propose that coassessment of CD8/FOXP3 ratio and PD-L1 expression level in tumor cells can help predict potential radiosensitivity in patients with SCC-L.
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http://dx.doi.org/10.1002/hed.26416DOI Listing
December 2020

Androgen receptor expression is useful to predict the therapeutic effect in HER2-positive breast carcinoma.

Breast Cancer Res Treat 2020 Nov 8;184(2):277-285. Epub 2020 Aug 8.

Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan.

Purpose: Although HER2-positive (HER2+) invasive breast carcinomas (BC) have a different clinical therapeutic responsiveness according to estrogen and progesterone receptor expression, the relationship with androgen receptors (AR), which are the same family of steroid hormones, is poorly understood. We investigated the relationship between AR expression in HER2 BCs and therapeutic responsiveness and prognosis in this study.

Methods: We evaluated patients with HER2 (H) + invasive BC undergoing surgery after neoadjuvant chemotherapy (± HER2-targeted therapies) from 2007-2017, classified as hormone receptor-positive (Allred score: 2-8) (luminal B: LH) and receptor-negative groups (Allred: score 0) (non-luminal: NLH). AR expression was assessed by immunostaining pre-neoadjuvant chemotherapy biopsy specimens, positive with Allred score ≥ 4. The pathological complete response, disease-free survival, and overall survival rates were compared between AR-positive and AR-negative groups.

Results: We classified 82 patients with HER2 + invasive BC into LH (n = 45, 54.9%) and NLH groups (n = 37, 45.1%), and AR + was observed in 43 patients (52.4%) (LH: 23, 51.1%; NLH: 20, 54.1%; p = 0.79). Quasi-pathological complete response was observed in 40 patients (48.8%) (LH: 18, 40%; NLH: 22, 59.5%; p = 0.08) overall, and in 31 AR + patients (72.1%) (LH: 15, 34.9%; NLH: 16, 37.2%), significantly higher than in the AR - group for both subgroups (p < 0.001). Regarding prognosis, disease-free survival was relatively better in the AR + group in all HER2 + BCs (p = 0.085), and overall survival was significantly better in the AR + group for NLH (p = 0.029).

Conclusions: High AR expression may be a useful predictor of therapeutic effects and prognosis in both subgroups of HER2 + BCs.
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http://dx.doi.org/10.1007/s10549-020-05855-4DOI Listing
November 2020

Prognostic Impact of Desmoplastic Reaction Evaluation for Intrahepatic Cholangiocarcinoma.

Anticancer Res 2020 Aug;40(8):4749-4754

Department of Surgery, Faculty of Medicine, Kurume University, Kurume, Japan.

Background/aim: The purpose of this study was to clarify the relationship between the desmoplastic reaction (DR) and clinicopathological features, and the prognosis using cases of resected intrahepatic cholangiocarcinoma (ICC).

Patients And Methods: Out of 54 cases that were preoperatively diagnosed with ICC and underwent resection at our department, 47 patients were included in this study. All sections were prepared from resected specimens and were microscopically observed following H&E staining. Stroma were evaluated at the advancing edge of the cancer and stratified into three DR types: mature (DR1), intermediate (DR2), and immature (DR3).

Results: DR was correlated to the serum levels of CA19-9, but not to the other tumor factors. In multivariate analysis, only DR and tumor size were determined as independent prognostic factors.

Conclusion: Evaluation of DR for ICC may be useful for prognostic assessments.
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http://dx.doi.org/10.21873/anticanres.14476DOI Listing
August 2020

Quercetin Suppresses Proliferation of Liver Cancer Cell Lines .

Anticancer Res 2020 Aug;40(8):4695-4700

Department of Pathology, Faculty of Medicine, Kurume University, Kurume, Japan.

Background/aim: We investigated the anti-proliferative effect of quercetin on liver cancer cell lines.

Materials And Methods: Thirteen liver cancer cell lines were cultured followed by treatment with varying concentrations of quercetin (0-100 μM) or quercetin and 5-FU, and the cell viability was analysed by the MTT assay. Flow cytometry was also used to examine cell cycle progression after treatment with quercetin.

Results: The addition of quercetin resulted in a dose- and time-dependent suppression of cell proliferation. In some cell lines, treatment with quercetin and 5-FU caused an additional or synergistic effect. Most cell lines displayed cell cycle arrest at different phases of the cell cycle.

Conclusion: Quercetin inhibits the proliferation of liver cancer cells via induction of apoptosis and cell cycle arrest.
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http://dx.doi.org/10.21873/anticanres.14469DOI Listing
August 2020

Changes in immune parameters between pre-treatment and recurrence after (chemo) radiation therapy in patients with head and neck cancer.

Sci Rep 2020 07 20;10(1):11973. Epub 2020 Jul 20.

Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Kurume University, Asahimachi 67, Kurume, Fukuoka, 830-0011, Japan.

Squamous cell carcinoma of the head and neck (SCCHN) has a high recurrence rate after (chemo) radiation therapy [(C)RT]. The relationship between the changing levels of immune checkpoint molecules and immune cells in pre-(C)RT tissues and locally recurrent tissues in the irradiated field, after (C)RT completion, is not known. This study aimed to assess the changes in these immune parameters between pre-(C)RT tissue and the same area after local recurrence post-(C)RT. We retrospectively reviewed 30 (C)RT-treated patients with SCCHN. We performed immunohistochemical analyses on these immune parameters using paired tissue samples obtained pre-(C)RT and at local recurrence sites post-(C)RT. No significant changes in immune parameters were found between the pre-(C)RT and locally recurrent tissues. An increased density of CD8+ tumor-infiltrating lymphocytes (TILs) showed a significantly positive correlation with PD-L expression on tumor cells (TC-PD-L1). Patients with increased TC-PD-L1 expression and CD8+TIL density showed favourable prognosis, and one of them showed a favourable response to nivolumab therapy. Our study shows a positive association between TC-PD-L1 upregulation and increased CD8+TIL density, and demonstrates that patients with these changes have a favourable survival outcome.
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http://dx.doi.org/10.1038/s41598-020-68938-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371733PMC
July 2020

Usefulness of Tumor Tissue Biopsy for Predicting the Biological Behavior of Hepatocellular Carcinoma.

Anticancer Res 2020 Jul;40(7):4105-4113

Department of Pathology, Kurume University School of Medicine, Kurume, Japan.

Background/aim: Assessment of the biological behavior of tumors is important for choosing an appropriate cancer therapy. In hepatocellular carcinoma (HCC), the biological behaviour can be assessed by tumor morphology and molecular biology. This study investigated the usefulness of tumor tissue biopsy for predicting the biological behavior of HCC.

Patients And Methods: We studied 43 patients who underwent hepatectomy and preoperative liver tumor biopsy for HCC. We performed clinicopathological and immunohistochemical (IHC) analyses. The expression of the following molecules was examined: regulator of G-protein signaling 5 (RGS5), glypican-3 (GPC3), keratin 19 (K19), epithelial cell adhesion molecule (EpCAM), protein induced by vitamin K absence or antagonist-II (PIVKA-II), β-Catenin, and p53.

Results: There was an overall 83.7% agreement regarding tumor differentiation between the preoperative biopsy specimens and the resected specimens. The accuracy of IHC analysis was more than 70% for all molecules between the preoperative biopsy specimens and the resected specimens. The RGS5-positive biopsy cases had higher serum α-fetoprotein levels (p=0.04), a higher rate of moderately or poorly differentiated tumors (p=0.02) and portal vein invasion (p=0.0003) than the RGS5-negative biopsy cases. The GPC3-positive biopsy cases were younger (p=0.04), had higher serum PIVKA-II levels (p=0.01), and a higher rate of portal vein invasion (p=0.03) than the GPC3-negative biopsy cases. The PIVKA-II-positive biopsy cases had significantly higher serum PIVKA-II levels than the PIVKA-II-negative biopsy cases (p=0.02). The other molecular markers showed no significantly different clinical findings between the positive and negative cases.

Conclusion: In HCC, there was a high agreement rate of both the histopathological and IHC findings between preoperative biopsy specimens and resected specimens. In the biopsy specimens of HCC, RGS5 and GPC3 expression were useful molecular makers for predicting portal vein invasion. Liver tumor biopsy is useful for predicting the biological behavior of HCC through histopathological and immunohistochemical findings.
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http://dx.doi.org/10.21873/anticanres.14409DOI Listing
July 2020

Pathological Role of Receptor for Advanced Glycation End Products in Calcified Aortic Valve Stenosis.

J Am Heart Assoc 2020 07 17;9(13):e015261. Epub 2020 Jun 17.

Department of Surgery Kurume University School of Medicine Kurume Japan.

Background Aortic stenosis (AS) is highly prevalent in patients with atherosclerotic cardiovascular disease. Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) play a pivotal role for vascular calcification in atherosclerosis. We hypothesize that the AGEs-RAGE axis could also be involved in the pathophysiological mechanism of calcified AS. Methods and Results A total of 54 patients with calcified AS who underwent aortic valve replacement were prospectively enrolled from 2014 to 2016 (mean age 75.3±7.7 years). Aortic valve specimens were obtained from 47 patients and 16 deceased control subjects without aortic valve disease (mean age 63.2±14.5 years). The valvular expression of RAGE was evaluated by immunohistochemistry. Serum levels of AGEs and soluble RAGE were measured in 50 patients with calcified AS and 70 age-matched and sex-matched control subjects without heart disease. The valvular RAGE expression in patients with calcified AS was higher than controls (=0.004) and was significantly associated with a decreased ankle-brachial pressure index (=0.007) and an increased intima-media thickness (=0.026). RAGE and α-smooth muscle actin were coexpressed and were partially costained with osteocalcin and alkaline phosphatase. The serum levels of AGEs and soluble RAGE were significantly higher in the patients with calcified AS than in the controls (=0.013 and <0.001, respectively). Soluble RAGE (inversely) and use of aspirin were independently correlated with changes in left ventricular systolic function after aortic valve replacement (=0.012 and =0.002, respectively). Conclusions Our present study suggests that RAGE may play a role in the pathogenesis of calcified AS, which is a prognostic marker in patients with AS after aortic valve replacement.
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http://dx.doi.org/10.1161/JAHA.119.015261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670521PMC
July 2020

Recent Topics Concerning Combined Hepatocellular Cholangiocarcinoma.

Kurume Med J 2020 Jul 1;66(1):29-36. Epub 2020 May 1.

Department of Pathology, Kurume University School of Medicine.

Combined hepatocellular-cholangiocarcinoma (CHC) is a relatively rare tumor with an incidence range of 1.0-4.7%. CHC is defined as a tumor containing unequivocal, intimately mixed components of both hepatocellular carcinoma and intrahepatic cholangiocarcinoma. The recent development of biochemical methodologies and cancer stem cell theory have paved the way for a clearer understanding of the histogenesis of CHC. The latest edited WHO classification published in 2010 adopted the concept of stem cell/hepatic progenitor cells in the pathological classification of CHC. Although this classification includes novel and unique concepts of histogenesis and facilitates the recognition of CHC, there are several problems with it in practice. To reduce confusion, an international group of hepatic pathologists, radiologists, surgeons, and clinicians formulated a nomenclature for CHC and issued a consensus article in 2018. In this review article, we discuss the problems with the latest WHO classification and introduce recent topics concerning CHC from pathologic and genetic points of view.
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http://dx.doi.org/10.2739/kurumemedj.MS661014DOI Listing
July 2020

NDRG1 activates VEGF-A-induced angiogenesis through PLCγ1/ERK signaling in mouse vascular endothelial cells.

Commun Biol 2020 03 6;3(1):107. Epub 2020 Mar 6.

Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.

Many diseases, including cancer, have been associated with impaired regulation of angiogenesis, of which vascular endothelial growth factor (VEGF)-A is a key regulator. Here, we test the contribution of N-myc downstream regulated gene 1 (NDRG1) to VEGF-A-induced angiogenesis in vascular endothelial cells (ECs). Ndrg1 mice exhibit impaired VEGF-A-induced angiogenesis in corneas. Tumor angiogenesis induced by cancer cells that express high levels of VEGF-A was also reduced in a mouse dorsal air sac assay. Furthermore, NDRG1 deficiency in ECs prevented angiogenic sprouting from the aorta and the activation of phospholipase Cγ1 (PLCγ1) and ERK1/2 by VEGF-A without affecting the expression and function of VEGFR2. Finally, we show that NDRG1 formed a complex with PLCγ1 through its phosphorylation sites, and the inhibition of PLCγ1 dramatically suppressed VEGF-A-induced angiogenesis in the mouse cornea, suggesting an essential role of NDRG1 in VEGF-A-induced angiogenesis through PLCγ1 signaling.
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http://dx.doi.org/10.1038/s42003-020-0829-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060337PMC
March 2020

Predictive value of CD73 expression for the efficacy of immune checkpoint inhibitors in NSCLC.

Thorac Cancer 2020 04 15;11(4):950-955. Epub 2020 Feb 15.

Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.

Background: CD73 induces the dephosphorylation of adenosine monophosphate converting it to adenosine, enabling malignancies to escape from immune surveillance. Although CD73 overexpression has been reported to be a poor prognostic factor in several malignancies including non-small cell lung cancer (NSCLC), its predictive relevance in NSCLC patients receiving immune checkpoint inhibitors is unknown. The present research was conducted to investigate the prognostic significance of CD73 expression in NSCLC patients receiving immune checkpoint inhibitors (ICIs).

Methods: We screened 91 patients with advanced or recurrent NSCLC who received immune checkpoint inhibitors. CD73 expression was evaluated immunohistochemically using tissue specimens obtained just before treatment with ICIs.

Results: Analysis of progression-free survival (PFS) and overall survival (OS) in relation to several levels of CD73 expression (1%, 10%, 30%, and 50%) showed that both tended to be more favorable as expression of CD73 increased. PFS and OS were longer for patients in whom at least 50% of the tumor cells expressed CD73 than for those in whom <50% of the tumor cells did so. In patients who were positive for EGFR mutation, immune checkpoint inhibitors were significantly more effective in those with high CD73 expression, whereas CD73 expression did not significantly affect the efficacy in patients with EGFR mutation-negative NSCLC. Furthermore, CD73 expression was predictive factor for the PFS independent of PD-L1 expression in patients with EGFR mutation.

Conclusions: High CD73 expression may predict a favorable response to ICIs in NSCLC patients, especially those harboring EGFR mutations.

Key Points: Significant findings of the study: In patients who were positive for EGFR mutation, immune checkpoint inhibitors (ICIs) were significantly more effective in those with high CD73 expression, whereas CD73 expression did not significantly affect the efficacy in patients with EGFR mutation-negative NSCLC.

What This Study Adds: High CD73 expression may predict a favorable response to immune checkpoint inhibitors in NSCLC patients, especially those harboring EGFR mutations.
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http://dx.doi.org/10.1111/1759-7714.13346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113063PMC
April 2020

Targeting Phosphorylation of Y-Box-Binding Protein YBX1 by TAS0612 and Everolimus in Overcoming Antiestrogen Resistance.

Mol Cancer Ther 2020 03 26;19(3):882-894. Epub 2019 Dec 26.

Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

Nuclear expression of Y-box-binding protein (YBX1) is closely correlated with clinical poor outcomes and drug resistance in breast cancer. Nuclear translocation of YBX1 is facilitated by YBX1 phosphorylation at serine 102 by AKT, p70S6K, and p90RSK, and the phosphorylated YBX1 (pYBX1) promotes expression of genes related to drug resistance and cell growth. A forthcoming problem to be addressed is whether targeting the phosphorylation of YBX1 overcomes antiestrogen resistance by progressive breast cancer. Here, we found that increased expression of pYBX1 was accompanied by acquired resistance to antiestrogens, fulvestrant and tamoxifen. Forced expression of YBX1/S102E, a constitutive phosphorylated form, resulted in acquired resistance to fulvestrant. Inversely, YBX1 silencing specifically overcame antiestrogen resistance. Furthermore, treatment with everolimus, an mTORC1 inhibitor, or TAS0612, a novel multikinase inhibitor of AKT, p70S6K, and p90RSK, suppressed YBX1 phosphorylation and overcame antiestrogen resistance and IHC analysis revealed that expression of pYBX1 and YBX1 was augmented in patients who experienced recurrence during treatment with adjuvant endocrine therapies. Furthermore, pYBX1 was highly expressed in patients with triple-negative breast cancer compared with other subtypes. TAS0612 also demonstrated antitumor effect against triple-negative breast cancer Taken together, our findings suggest that pYBX1 represents a potential therapeutic target for treatment of antiestrogen-resistant and progressive breast cancer.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0690DOI Listing
March 2020

Prognostic value of dual-point fluorine-18 fluorodeoxyglucose PET imaging, partial volume correction and glucose transporter-1 expression in resected nonsmall cell lung cancer patients.

Nucl Med Commun 2020 Jan;41(1):48-57

Division of Nuclear Medicine, PET Center, Department of Radiology, Fukuoka Tokushukai Medical Center, Kasuga, Fukuoka, Japan.

Objective: To investigate the relationship between the prognosis and glucose transporter-1 (Glut-1) expression or fluorine-18 fluorodeoxyglucose uptake using partial volume correction and dual-point imaging in surgically resected nonsmall cell lung cancer (NSCLC) patients.

Methods: Our patient population consisted of 108 NSCLC cases. The early maximum standardized uptake value (ESUVmax), delayed SUVmax (DSUVmax), partial volume correction SUVmax (cSUVmax) and retention index of primary lesions were calculated. Cox proportional hazard model was applied to evaluate the effects of PET parameters and Glut-1 expression. Overall survival (OS) and disease-free survival (DFS) were evaluated by Kaplan-Meier methods, and the difference in survival between subgroups was analyzed by log-rank test.

Results: On the Cox regression analysis, ESUVmax, DSUVmax, cSUVmax and Glut-1 were significantly related to DFS [ESUVmax, hazard ratio = 2.301, 95% confidential interval (CI) = 1.146-4.618, P = 0.019; DSUVmax, hazard ratio = 2.483, 95% CI = 1.257-4.905, P = 0.009; cSUVmax, hazard ratio = 2.205, 95% CI = 1.038-4.686, P = 0.04; Glut-1, hazard ratio = 2.095, 95% CI = 1.086-4.041, P = 0.001] and OS (ESUVmax, hazard ratio = 3.197, 95% CI = 1.339-7.633, P = 0.009; DSUVmax, hazard ratio = 3.599, 95% CI = 1.521-8.516, P = 0.004; cSUVmax, hazard ratio = 8.655, 95% CI = 2.048-36.658, P = 0.003; Glut-1, hazard ratio = 2.427, 95% CI = 5.140, P = 0.021). Retention index had no significant association with DFS or OS. On the Kaplan-Meier survival curves, the patients with high ESUVmax, DSUVmax, cSUVmax and Glut-1 showed significantly worse prognosis than those with low values (ESUVmax: DFS, P = 0.001, OS, P = 0.003; DSUVmax: DFS, P = 0.002, OS, P = 0.004; cSUVmax: DFS, P < 0.001, OS, P = 0.013; Glut-1: DFS, P = 0.012, OS, P = 0.002).

Conclusions: cSUVmax, ESUVmax, DSUVmax and Glut-1 may be more useful biomarkers than retention index for predicting outcomes in NSCLC patients.
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http://dx.doi.org/10.1097/MNM.0000000000001118DOI Listing
January 2020

Distinctive clinicopathological features and KRAS and IDH1/2 mutation status of cholangiolocellular carcinoma.

Hepatol Res 2020 Jan 8;50(1):84-91. Epub 2019 Dec 8.

Department of Pathology, Kurume University School of Medicine, Kurume, Japan.

Aim: Cholangiolocellular carcinoma (CLC) is classified as a subtype of combined hepatocellular cholangiocarcinoma with stem-cell features (CHC-SC) in the latest World Health Organization classification. This subclassification of CHC-SCs is controversial and the relevance of such classification is unclear.

Methods: We analyzed a series of CHC-SCs and intrahepatic cholangiocarcinoma (iCCA) to clarify the clinicopathological features and mutational status of each tumor.

Results: Background liver disease, fibrosis stage, microvascular invasion, nodal metastasis, and IDH1/2 mutation status were associated with their histology. Compared with the intermediate cell subtype of CHC-SC (CHCs-SC-int), CLCs were less frequently associated with chronic viral hepatitis, and showed lower levels of serum alpha-fetoprotein. Compared with iCCAs, CLCs showed lower levels of serum carbohydrate antigen 19-9 (CA19-9) and a lower frequency of expression of S100P. Patients with iCCA showed worse overall survival than those with CLC or CHC-SC-int. In patients with iCCA, CLC, or CHC-SC-int, a histology of iCCA, microvascular invasion, and serum CA19-9 value of >100 U/mL were significant poor prognostic factors for overall survival in univariate analysis. Multivariate analysis showed that a high serum CA19-9 value was an independent poor prognostic factor for overall survival.

Conclusions: Patients with CLC are likely to have a different etiology and mutational background from those with CHC-SC-int. Their clinicopathological manifestations are also different from those with classic iCCA. Our results suggest that CLC might be a distinct entity among primary liver carcinomas.
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http://dx.doi.org/10.1111/hepr.13428DOI Listing
January 2020
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