Hiroyuki Kato

Guidelines for Diagnosis and Treatment of Carcinoma of the Esophagus April 2012 edited by the Japan Esophageal Society

Purpose nThese guidelines are intended for doctors who are engaged in the diagnosis and treatment of esophageal carcinoma, for the following purposes: (1) to present the standard practice for the diagnosis and treatment of esophageal carcinoma with a high regard for the principles of evidence-based medicine (EBM); (2) to improve the safety and results of treatment, thereby reducing the difference in treatment results among different institutions; (3) to reduce unnecessary costs and efforts; (4) help enable people to undergo treatment without anxiety. n nThese guidelines provide only guidance on the indications for treatment and do not restrict or prohibit the use of any treatment deviating from those described herein.

MiR‐150 is associated with poor prognosis in esophageal squamous cell carcinoma via targeting the EMT inducer ZEB1

The association of microRNAs (miRs) with cancer progression has been established in many cancers including esophageal squamous cell carcinoma (ESCC). A public microarray database showed that the expression of miR‐150 was lower in ESCC than in normal esophageal mucosa. Here, we focused on ZEB1, epithelial‐mesenchymal‐transition (EMT)‐inducer, as a target gene of miR‐150 based on in silico predictions. The purpose of this study was to clarify the clinicopathological significance of miR‐150 in ESCC, and to investigate miR‐150′s EMT‐regulatory ability. Quantitative RT‐PCR was used to evaluate miR‐150 expression in 108 curative resected ESCC samples to determine the clinicopathological significance. Moreover, we examined the in vitro and in vivo function of miR‐150 via degradation of ZEB1. MiR‐150 expression was significantly lower in cancer tissues compared to adjacent non‐cancerous tissues (P < 0.001). Low expression of miR‐150 in ESCC contributed to malignant potential, such as tumor depth, lymph node metastasis, lymphatic invasion, venous invasion, clinical staging, and poor prognosis (P < 0.05). In vitro assays showed that EMT‐inducer‐ZEB1 is a new direct target of miR‐150. Moreover, miR‐150 induced MET‐like changes in TE‐8 cells through ZEB1 degradation (e.g., E‐cadherin expression, vimentin repression, epithelial morphology, and suppression of migration ability), and significantly inhibited tumorigenicity and tumor growth in a mouse xenograft model. Analysis of the regulation of ZEB1 by miR‐150 could provide new insights into preventing metastasis and also suggests novel targeted therapeutic strategies in ESCC. (Cancer Sci 2013; 104: 48–54)

Clinical validation of the gastrointestinal NET grading system: Ki67 index criteria of the WHO 2010 classification is appropriate to predict metastasis or recurrence.

BackgroundIn the WHO 2010 classification, the neuroendocrine tumors (NETs) are subdivided by their mitotic index or Ki67 index into either G1 or G2 NETs. Tumors with a Ki67 index of <2% are classified as G1 and those with 3—20% are classified as G2. However, the assessment of tumors with Ki67 index of greater than 2% and less than or equal to 3% is still unclear. To resolve the problem, we validated the Ki67 index criteria of gastrointestinal NETs of the WHO 2010 classification.MethodsThe medical records of 45 patients who were pathologically diagnosed as having NET G1/G2 of the gastrointestinal tract were analyzed retrospectively. According to the WHO 2010 classification, Ki67 index were calculated. Computer-assisted cytometrical analysis of Ki67 immunoreactivity was performed using the WinRooF image processing software. Receiver operating characteristic (ROC) curves were generated to determine the best discriminating Ki67 index. To clarify the assessment of tumors with Ki67 index between 2—3%, the calculated cutoff of Ki67 index was evaluated using Fisher’s exact test.ResultsROC curve analysis confirmed that 2.8% was the best Ki67 index cutoff value for predicting metastasis or recurrence. The sensitivity of the new Ki67 index cutoff was 42.9%, and the specificity was 86.8%.ConclusionsDivision of NETs into G1/G2 based on Ki67 index of 3% was appropriate to predict metastases or recurrences. The WHO grading system may be the most useful classification to predict metastases or recurrences.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1553036118943799

CD47 expression regulated by the miR-133a tumor suppressor is a novel prognostic marker in esophageal squamous cell carcinoma

CD47 inhibits phagocytosis and its overexpression is correlated with poor prognosis in patients with several types of cancer. It has also been reported that CD47 expression in multiple sclerosis is regulated by microRNAs. However, the regulatory mechanism of CD47 in cancer tissues has not been yet clarified. Re-analysis of a public microarray database revealed that miR-133a is downregulated in esophageal squamous cell carcinoma (ESCC). Moreover, inxa0silico algorithms predicted that miR-133a is a regulator of CD47. The purpose of this study was to clarify the clinical significance of CD47 and its regulatory mechanism by miR-133a in ESCC. Quantitative real-time RT-PCR was used to evaluate CD47 and miR-133a expression in 102 cases of curative resected ESCC and adjacent non-cancerous tissue. The regulation of CD47 by miR-133a was examined with precursor miR-133a-transfected cells. A mouse xenograft model was used to investigate the ability of miR-133a to suppress tumor progression. High expression levels of CD47 were associated with lymph node metastasis (P=0.049). Multivariate analysis showed that CD47 expression was an independent prognostic factor (P=0.045). miR-133a expression was significantly lower in cancer tissues compared to adjacent non-cancerous tissues (P<0.001). Inxa0vitro assays showed that miR-133a is a direct regulator of CD47. miR‑133a significantly inhibited tumorigenesis and growth inxa0vivo. CD47 expression is a novel prognostic marker in ESCC that is directly inhibited by the miR-133a tumor suppressor. This correlation could provide new insight into the mechanism of cancer progression and a promising candidate for target therapy in ESCC.

Treatments for esophageal cancer: a review.

Esophageal cancer is the eighth most common form of cancer worldwide. The treatments for esophageal cancer depend on its etiology. For mucosal cancer, endoscopic mucosal resection and endoscopic submucosal dissection are standard, while for locally advanced cancer, esophagectomy remains the mainstay. The three most common techniques for thoracic esophagectomy are the transhiatal approach, the Ivor Lewis esophagectomy (right thoracotomy and laparotomy), and the McKeown technique (right thoracotomy followed by laparotomy and neck incision with cervical anastomosis). Surgery for carcinoma of the cervical esophagus requires an extensive procedure with laryngectomy in many cases. When the tumor is more advanced, neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy is added. The theoretical advantages of adding chemotherapy to the treatment of esophageal cancer are potential tumor down-staging prior to surgery, as well as targeting micrometastases and, thus, decreasing the risk of distant metastasis. Cisplatin- and 5-fluorouracil-based regimes are used worldwide. Chemoradiotherapy is the standard for unresectable esophageal cancer and could also be considered as an option for resectable tumors. For patients who are medically or technically inoperable, concurrent chemoradiotherapy should be the standard of care. Although neoadjuvant chemoradiotherapy followed by surgery or salvage surgery after definitive chemoradiotherapy is a practical treatment; judicious patient selection is crucial. It is important to have a thorough understanding of these therapeutic modalities to assist in this endeavor.

Prognostic significance of CD151 expression in esophageal squamous cell carcinoma with aggressive cell proliferation and invasiveness.

BackgroundCD151 is a member of the tetraspanins and has recently been reported as a promoter of the malignant progression of cancer. The purpose of this study was to clarify the clinicopathological outcome and prognostic significance of the immunohistochemical expression of CD151 in esophageal squamous cell carcinoma (ESCC).MethodsWe evaluated the significance of CD151 expression by immunohistochemistry in 138 surgically resected ESCC and the association of CD151 expression with clinicopathological features.ResultsSeventy-five (51.7%) ESCC showed a positive expression of CD151, which indicated a significant association with tumor depth (Pxa0=xa00.004), lymph node metastasis (Pxa0=xa00.002), distant metastasis (Pxa0=xa00.025), and lymphatic invasion (Pxa0=xa00.046), as well as the Ki-67 labeling index (Pxa0=xa00.011). The 5-year survival rate of ESCC patients with CD151-positive expression was significantly lower than with CD151-negative expression (positive, 43.1%; negative, 63.8%; Pxa0=xa00.003). Multivariate analysis showed that positive CD151 expression was not an independent factor for poor survival (Pxa0=xa00.096).ConclusionsCD151 expression is associated with tumor proliferation and invasiveness in ESCC.

Treatment options for esophageal squamous cell carcinoma

Introduction: The treatment for esophageal squamous cell carcinoma (SCC) depends on its etiology. For mucosal cancer, endoscopic resection is standard; while for locally advanced cancer, esophagectomy is the main treatment. When the tumor is more advanced, neoadjuvant or adjuvant therapy is added. For unresectable cancer, concurrent chemoradiotherapy is the standard therapy. Areas covered: The standard chemotherapy for esophageal SCC is a cisplatin- and 5-fluorouracil (CF)-based regimen. Chemoradiotherapy (CRT) is the standard treatment for unresectable esophageal SCC and is also an option for resectable tumors. For patients who are inoperable, concurrent CRT should be the standard of care. Docetaxel, cisplatin and 5-fluorouracil (DCF) therapy is a promising candidate for chemotherapy with or without radiotherapy because an excellent local control rate and pathological remission rate have been reported. Although salvage surgery after definitive CRT is a practical treatment, judicious patient selection is crucial. Expert opinion: Presently, the standard regimen for esophageal SCC is CF. DCF is expected to be the next standard regimen. In the near future, some new therapeutic options, such as molecular targeted therapy or particle beam therapy, may confer further advantages. A thorough understanding of these therapeutic modalities is important to achieve this endeavor.

Expression of Lysyl Oxidase Is Correlated with Lymph Node Metastasis and Poor Prognosis in Esophageal Squamous Cell Carcinoma

BackgroundLysyl oxidase (LOX), an extracellular matrix-remodeling enzyme, has been reported to regulate tumor metastasis. We investigated the clinical significance of LOX expression in esophageal squamous cell carcinoma (ESCC).MethodsWe examined LOX expression in ESCC cell lines by real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and Western blotting. We also examined LOX expression by real-time RT-PCR in 39 surgically resected ESCC and by immunohistochemistry in 122 surgically resected ESCC.ResultsLOX messenger RNA (mRNA) was expressed at a high level in TTn (originating from an ESCC metastatic lesion); at a moderate level in TE-2 and TE-15; and at a low level in TE-1, TE-8, and TE-13. In Western blotting, all cell lines expressed the catalytically inactive 50-kDa LOX at approximately the same levels, but catalytically active 32-kDa LOX was overexpressed only in TTn. LOX mRNA levels in ESCC tissues were significantly higher than those observed in normal esophageal tissues (Pxa0<xa00.001) and had no significant correlation with tumor–node–metastasis (TNM) factors. High LOX protein expression had a significant correlation with presence of lymph node metastasis (Pxa0=xa00.009) and number of lymph node metastases (Pxa0=xa00.047). Overall and cancer-specific survival rates of patients with ESCC with high LOX expression were significantly lower than those of patients with ESCC with low LOX expression (Pxa0=xa00.024 and Pxa0=xa00.012). Univariate and multivariate analyses revealed that high LOX protein expression was an independent prognostic factor for ESCC.ConclusionsOur findings suggest that LOX can serve as a predictive marker of lymph node metastasis and prognosis in ESCC.

18F-FAMT-PET Is Useful for the Diagnosis of Lymph Node Metastasis in Operable Esophageal Squamous Cell Carcinoma

BackgroundThe role and potential usefulness of positron emission tomography (PET) scanning in certain tumors has been widely investigated in recent years. 18F-FAMT (L-[3-18F]-α-methyltyrosine) is an amino acid tracer for PET. This study investigated whether PET/CT with 18F-FAMT provides additional information for preoperative diagnostic workup of esophageal squamous cell carcinoma compared with that obtained by 18F-FDG (fluorodeoxyglucose) PET or CT.MethodsPET/CT studies with 18F-FAMT and 18F-FDG were performed as a part of the preoperative workup in 21 patients with histologically confirmed esophageal squamous cell carcinoma.ResultsFor the detection of primary esophageal cancer, 18F-FAMT-PET exhibited a sensitivity of 76.2%, whereas the sensitivity for 18F-FDG-PET was 90.5% (Pxa0=xa00.214). 18F-FAMT uptake in primary tumors showed significant correlation with depth of invasion (Pxa0=xa00.005), lymph node metastasis (Pxa0=xa00.045), stage (Pxa0=xa00.031), and lymphatic invasion (Pxa0=xa00.029). In the evaluation of individual lymph node groups, 18F-FAMT-PET exhibited 18.2% sensitivity, 100% specificity, 71.9% accuracy, 100% positive predictive value, and 70.0% negative predictive value, compared with 24.2%, 93.7%, 69.8%, 66.6%, and 70.2%, respectively, for 18F FDG-PET. CT exhibited 39.4% sensitivity, 85.7% specificity, 69.8% accuracy, 59.1% positive predictive value, and 73.0% negative predictive value. The specificity of 18F-FAMT-PET is significantly higher than that of 18F-FDG-PET (Pxa0=xa00.042) and CT (Pxa0=xa00.002). 18F-FAMT-PET did not have any false-positive findings compared to those with 18F-FDG-PET.ConclusionsOur findings suggest that the addition of 18F-FAMT-PET to 18F-FDG-PET and CT would permit more precise staging of esophageal cancer.

MUTYH-associated colorectal cancer and adenomatous polyposis

MUTYH-associated polyposis (MAP) was first described in 2002. MUTYH is a component of a base excision repair system that protects the genomic information from oxidative damage. When the MUTYH gene product is impaired by bi-allelic germline mutation, it leads to the mutation of cancer-related genes, such as the APC and/or the KRAS genes, via G to T transversion. MAP is a hereditary colorectal cancer syndrome inherited in an autosomal-recessive fashion. The clinical features of MAP include the presence of 10–100 adenomatous polyps in the colon, and early onset of colorectal cancer. Ethnic and geographical differences in the pattern of the MUTYH gene mutations have been suggested. In Caucasian patients, c.536A>G (Y179C) and c.1187G>A (G396D) mutations are frequently detected. In the Asian population, Y179C and G396D are uncommon, whereas other variants are suggested to be the major causes of MAP. We herein review the literature on MUTYH-associated colorectal cancer and adenomatous polyposis.