Telepathology in intraoperative frozen section consultation of breast cancer sentinel node biopsy in Fukushima, Japan following the 2011 triple disaster: diagnostic accuracy and required time during the early implementation phase.

In breast cancer surgery, some medical facilities lack the necessary resources to conduct sentinel lymph node biopsy and its intraoperative frozen section consultation. In the coastal rural area of Fukushima, Japan, which has suffered from physician undersupply following the 2011 triple disaster of earthquake, tsunami and nuclear disaster, we explored the feasibility of telepathology by evaluating the diagnostic accuracy in remote intraoperative frozen section consultation of sentinel lymph node biopsy and its required time. Although examination time has room for improvement, telepathology can be one possible solution in resource-limited areas.

Whole circumferential endoscopic submucosal dissection of superficial adenocarcinoma in long-segment Barrett's esophagus: A case report.

BACKGROUND: Esophageal adenocarcinoma (EAC) derived from long-segment Barrett's esophagus (LSBE) is extremely rare in Asia. LSBE-related EAC is often difficult to diagnose in the horizontal extent. If the tumor has spread throughout the LSBE, whole circumferential endoscopic submucosal dissection (ESD) should be performed, which is difficult to complete safely. Additionally, whole circumferential ESD can bring refractory postoperative stenosis. We hereby report a case of EAC involving the whole circumference of the LSBE, achieving complete endoscopic removal without complications. CASE SUMMARY: An 85-year-old man with the chief complaint of dysphagia underwent esophagogastroduodenoscopy. We suspected a flat-type cancerous lesion that extended the whole circumference of the LSBE (C 3.5, M 4.0) using narrow-band imaging magnification endoscopy (NBI-M). We achieved circumferential en bloc resection of the lesion safely with special ESD techniques. Histology of the ESD specimens demonstrated that the superficial EAC extended the whole circumference of the LSBE, and papillary or well-differentiated tubular adenocarcinoma was confined in the lamina propria mucosa showing a vertical negative margin. To prevent post-ESD stenosis, we performed endoscopic local injection of steroids, followed by oral administration of steroids. There was no evidence of esophageal refractory stenosis or tumor recurrence 30 mo after ESD. In summary, we experienced a rare case of LSBE-related EAC. The horizontal tumor extent was accurately diagnosed by NBI-M. Additionally, we achieve whole circumferential ESD safely without postoperative refractory stenosis. CONCLUSION: NBI-M, ESD, and steroid therapy enabled the curative resection of superficial full circumferential LSBE-related EAC without refractory postoperative stenosis.

Association between Endoscopic Milk-White Mucosa, Epithelial Intracellular Lipid Droplets, and Histological Grade of Superficial Non-Ampullary Duodenal Epithelial Tumors.

We previously reported that superficial non-ampullary duodenal tumors (SNADETs) commonly had a whitish mucosal surface, named milk-white mucosa (MWM). The aim of this study was to evaluate the association of MWM with epithelial intracellular lipid droplets (immunohistochemically stained by adipose differentiation-related protein (ADRP)) and histological tumor grades. We reviewed endoscopic images and the histopathology of SNADETs resected en bloc endoscopically. We analyzed the correlation between the positive rates of endoscopic MWM in preoperative endoscopy and resected specimens, and ADRP-positive rates in the resected specimens. Associations between the MWM-positive rates and tumor grades, high-grade intraepithelial neoplasia (HGIN)/intramucosal carcinoma (IC), and low-grade intraepithelial neoplasia (LGIN) were analyzed. All the 92 SNADETs analyzed were <20 mm and histologically classified into 39 HGIN/IC and 53 LGIN. Spearman's rank correlation coefficient showed a significant correlation between MWM-positive and ADRP-positive rates (p < 0.001). MWM-positive rates were significantly lower in the HGIN/IC than in the LGIN in preoperative endoscopy (p < 0.001) and resected specimens (p = 0.02). Our results suggest that endoscopic MWM is closely associated with epithelial intracellular lipid droplets and that the MWM-positive rate may be a predictor of histological grade in small SNADETs.

Clinical Significance of Horizontal and Vertical Margin of En Bloc Resection for Nonmuscle Invasive Bladder Cancer.

PURPOSE: The primary advantage of en bloc resection of bladder tumors is to provide better diagnostic accuracy. However, the clinical significance of horizontal and vertical margin has not been demonstrated. We evaluated the clinical importance of surgical margins in patients who underwent en bloc resection of bladder tumors. MATERIALS AND METHODS: We retrospectively analyzed the records of 140 consecutive patients who underwent en bloc resection of bladder tumors for nonmuscle invasive bladder cancer. We analyzed perioperative and oncological outcome, and compared patient demographics and recurrence-free survival for horizontal findings. The relationship between surgical margin and second transurethral resection outcome in pT1 bladder cancer was also analyzed. RESULTS: Mean tumor diameter was 17.2±9.8 mm. Pathological stages were 93 cases in pTa and 47 cases in pT1. Diagnostic rates for the horizontal and vertical margins were 63% and 99%, respectively. The rates of sessile, carcinoma in situ, high grade, and pT1 tumors were significantly higher in the horizontal margin positive group (41) than in the negative group (47). There was no significant difference in 2-year recurrence-free survival based on horizontal margin findings (negative: 72.4%, positive: 75.4%, p=0.87). A second transurethral resection was performed in 31 of the 47 pT1 patients; pT1 residue was seen only in vertical margin positive cases, and 5 pTa/pTis residues at the transurethral resection scar were seen in 15 horizontal margin positive patients. CONCLUSIONS: Horizontal margin positive findings were not associated with recurrence-free survival, but careful assessment is warranted regarding residue at the original site. A second transurethral resection should be considered in patients with horizontal and vertical margin positive pT1 bladder cancer.

[Utility of core-needle biopsy as a primary diagnostic method for detecting aggressive B-cell lymphoma in the intensive care unit].

A 68-year-old male presented with appetite loss and abdominal distention. The whole-body computed tomography scan revealed an ileocecal mass with a large amount of ascites, which was consistent with malignant lymphoma. Due to the worsening of his general condition following admission, he was intubated and admitted to the intensive care unit (ICU). In the ICU, we performed a core-needle biopsy (CNB) on the left peritoneal mass, the findings of which showed a pathological diffuse infiltration of CD20+ middle-sized lymphoid cells. After chemotherapy was initiated, the patient showed complete response, suggesting that CNB can be performed immediately and safely even on a critically ill patient.

Cancerous pericarditis presenting as cardiac tamponade in a 68-year-old man with pancreatic adenocarcinoma: a case report.

INTRODUCTION: Pericardial effusion is a rare complication of pancreatic cancer. We report a case of cardiac tamponade secondary to pancreatic cancer. CASE PRESENTATION: A 68-year-old Japanese man was diagnosed as having pancreatic cancer during surgery and received chemotherapy for 28 months after the diagnosis. He was admitted to the emergency room with severe dyspnea. Echocardiography revealed pericardial effusion with severe hypofunction. Emergency pericardial drainage was performed to maintain hemodynamics, which resulted in the elimination of 450 mL of blood and the maintenance of circulatory dynamics. Cytological examination of the pericardial fluid revealed atypical cells and tumor cells suggesting adenocarcinoma. CONCLUSIONS: To our knowledge, pancreatic cancer complicated with cancerous pericarditis has not been previously documented. This case highlights the extreme severity of pericardial effusion, a sign of progressive disease, secondary to pancreatic cancer. In the case of neoplastic pericardial effusion, an extremely poor prognosis must be considered.

Impairment of DYRK2 by DNMT1­mediated transcription augments carcinogenesis in human colorectal cancer.

Dual specificity tyrosine­phosphorylation­regulated kinase 2 (DYRK2) is a protein kinase that functions as a novel tumor suppressor. Previous studies have reported that DYRK2 expression is decreased in colorectal cancer compared with adjacent non­tumor tissues. However, the regulatory mechanisms by which the expression of DYRK2 is diminished remain unknown. The aim of the present study was to determine the regulatory mechanisms of DYRK2 expression. The present study identified the promoter regions of the DYRK2 gene and demonstrated that they contained CpG islands in human cancer cells. In addition, the DYRK2 promoter region exhibited a higher level of methylation in colorectal cancer tissues compared with healthy tissues from clinical samples. DYRK2 expression was increased at the mRNA and protein level in colorectal cancer cell lines by treatment with 5­Azacytidine, a demethylating agent. The results further demonstrated that knockdown of DNA methyltransferase (DNMT) 1 elevated DYRK2 expression in colorectal cancer cell lines. A colitis­related mouse carcinogenesis model also exhibited a lower DYRK2 level in colorectal cancer tissues compared with adjacent non­tumor tissues. In this model, nuclear staining of DNMT1 was detected in colorectal cancer cells, whereas a cytoplastic distribution pattern of DNMT1 staining was exhibited in healthy tissue. Overall, these findings suggested that DYRK2 expression was downregulated via transcriptional regulation by DNMT1 to elevate the proliferation of colorectal cancer cells.

Effect of Vitamin D on Relapse-Free Survival in a Subgroup of Patients with p53 Protein-Positive Digestive Tract Cancer: A Post Hoc Analysis of the AMATERASU Trial.

BACKGROUND: The AMATERASU randomized trial of vitamin D3 supplementation (2,000 IU/day; UMIN000001977) showed the potential benefit of vitamin D in a subgroup of patients with digestive tract cancer. By conducting post hoc analyses of this trial, we further explored whether subgroups stratified by expression levels of p53, vitamin D receptor (VDR), and Ki-67 modify the effect of vitamin D supplementation. METHODS: The primary outcome was relapse-free survival (RFS). On IHC using pathologic specimens, the degree of p53 protein expression parallel with TP53 missense mutations was classified as p53 positive (>10%) and p53 negative (≤10%). In addition, VDR and Ki-67 expression levels were divided into quartiles. RESULTS: The p53 status of 372 patients' pathologic specimens was evaluated. In a subgroup of patients with p53-positive cancer (n = 226), 5-year RFS was 79% in the vitamin D group, which was significantly higher than the 57% in the placebo group (HR, 0.52; 95% confidence interval, 0.31-0.88; P = 0.02). In the subgroup of patients with p53-negative cancer, 5-year RFS in the vitamin D group versus placebo group was 72% versus 84% (not significantly different), respectively. Effect modification by p53 positivity was significant (P interaction = 0.02). However, no significant effect modification by either VDR or Ki-67 was observed. CONCLUSIONS: These results generate a hypothesis that vitamin D supplementation may improve RFS in patients with p53-positive digestive tract cancer. IMPACT: The results are still preliminary, but potentially important, because TP53 is the most frequently mutated gene across cancers at all sites.

Forced expression of DYRK2 exerts anti-tumor effects via apoptotic induction in liver cancer.

Liver cancer is highly aggressive and globally exhibits a poor prognosis. Therefore, the identification of novel molecules that can become targets for future therapies is urgently required. We have reported that dual-specificity tyrosine-regulated kinase 2 (DYRK2) functions as a tumor suppressor by regulating cell survival, differentiation, proliferation and apoptosis. However, the research into its clinical application as a molecular target has remained to be explored. Here we showed that DYRK2 knockdown enhanced tumor growth of liver cancer cells. Conversely and more importantly, adenovirus-mediated overexpression of DYRK2 resulted in inhibition of cell proliferation and tumor growth, and induction of apoptosis both in vitro and in vivo. Furthermore, we found that liver cancer patients with low DYRK2 expression had a significantly shorter overall survival. Given the findings that DYRK2 regulates proliferation and apoptosis of cancer cells, DYRK2 expression could be a promising predictive marker of the prognosis in liver cancer. Stabilized or forced expression of DYRK2 may become thus a potential target for novel gene therapy against liver cancer.

Desmoid-type fibromatosis arising in a bifid rib chest wall.

Desmoid-type fibromatosis is a rare soft tissue tumor and the chest wall is one of the common sites of its extra-abdominal occurrence. A bifid rib is one of the congenital rib abnormalities. We report a case of desmoid-type fibromatosis arising in a chest wall's bifid rib. A 42-year-old female complained of right chest pain without remarkable medical, traumatic, or familial history. Chest-computed tomography revealed a chest wall tumor located adjacent to a bifid costal cartilage of third rib. We performed chest wall resection of second and third ribs. Pathologically, the tumor was diagnosed a desmoid-type fibromatosis of the chest wall. We surmise mechanical stimulation due to the bifid rib may be related to the occurrence of the tumor. In case of desmoid-type fibromatosis without somatic gene mutation, traumatic history, wound, implants, or use of female hormonal agents, we should search also local congenital abnormality.

Short- and long-term outcomes of endoscopically treated superficial non-ampullary duodenal epithelial tumors.

BACKGROUND: It is widely recognized that endoscopic resection (ER) of superficial non-ampullary duodenal epithelial tumors (SNADETs) is technically challenging and may carry high risks of intraoperative and delayed bleeding and perforation. These adverse events could be more critical than those occurring in other levels of the gastrointestinal tract. Because of the low prevalence of the disease and the high risks of severe adverse events, the curability including short- and long-term outcomes have not been standardized yet. AIM: To investigate the curability including short- and long-term outcomes of ER for SNADETs in a large case series. METHODS: This retrospective study included cases that underwent ER for SNADETs at our university hospital between March 2004 and July 2017. Short-term outcomes of ER were measured based on en bloc and R0 resection rates as well as adverse events. Long-term outcomes included local recurrence detected on endoscopic surveillance and disease-specific mortality in patients followed up for ≥ 12 mo after ER. RESULTS: In the study, 131 patients with 147 SNADETs were analyzed. The 147 ERs consisted of 136 endoscopic mucosal resections (EMRs) (93%) and 11 endoscopic submucosal dissections (ESDs) (7%). The median tumor diameter was 10 mm. The pathology diagnosis was adenocarcinoma (56/147, 38%), high-grade intraepithelial neoplasia (44/147, 30%), or low-grade intraepithelial neoplasia (47/147, 32%). The R0 resection rate was 68% (93/136) in the EMR group and 73% (8/11) in the ESD group, respectively. Cap-assisted EMR (known as EMR-C) showed a higher rate of R0 resection compared to the conventional method of EMR using a snare (78% vs 62%, P = 0.06). No adverse event was observed in the EMR group, whereas delayed bleeding, intraoperative perforation, and delayed perforation in 3, 3, and 5 patients occurred in the ESD group, respectively. One patient with perforation required emergency surgery. In the 43 mo median follow-up period, local recurrence was found in four EMR cases and all cases were treated endoscopically. No patient died due to tumor recurrence. CONCLUSION: Our findings suggest that ER provides good long-term outcomes in the patients with SNADETs. EMR is likely to become the safe and reliable treatment for small SNADETs.

Diagnostic efficacy of dual-focus endoscopy with narrow-band imaging using simplified dyad criteria for superficial esophageal squamous cell carcinoma.

BACKGROUND: Our previous studies have shown the diagnostic utility of a newly developed dual-focus endoscope with narrow-band imaging (DF-NBI) and simplified dyad criteria for detection of superficial esophageal squamous cell carcinoma (SESCC). This clinical trial aimed to study the diagnostic efficacy of DF-NBI with dyad criteria for detecting SESCC compared to white light imaging (WLI). METHODS: This was a single-arm prospective comparative trial. We enrolled 170 consecutive high-risk patients for esophageal squamous cell carcinoma. Patients were initially examined with WLI by one independent endoscopist and then the other performed DF-NBI blinded to the WLI diagnosis to avoid a carry-over effect. Lesions showing proliferation and/or various shapes of intrapapillary capillary loops (IPCL) under DF-NBI (i.e., dyad criteria) were endoscopically diagnosed as SESCC including high-grade intraepithelial neoplasia. The primary endpoint was sensitivity of WLI and DF-NBI for detecting SESCC. The secondary endpoints were the diagnostic performance (i.e., specificity and accuracy) and inter/intra-observer concordance of DF-NBI with dyad criteria. RESULTS: A total 77 SESCCs were detected. The sensitivity of DF-NBI for SESCC was significantly higher than that of WLI (91% vs. 51%, P < 0.001). The specificity and accuracy of WLI and DF-NBI using dyad criteria were 100% vs. 84%, and 86% vs. 86%, respectively. Various shapes and proliferation of IPCL showed the highest value in inter-observer and intra-observer agreements (κ = 0.77 and 0.82, respectively). CONCLUSION: DF-NBI combined with dyad criteria may be a promising technique with a high sensitivity for diagnosis of SESCC and high inter/intra-observer agreement.

Downregulation of dual-specificity tyrosine-regulated kinase 2 promotes tumor cell proliferation and invasion by enhancing cyclin-dependent kinase 14 expression in breast cancer.

Tumor progression is the main cause of death in patients with breast cancer. Accumulating evidence suggests that dual-specificity tyrosine-regulated kinase 2 (DYRK2) functions as a tumor suppressor by regulating cell survival, differentiation, proliferation and apoptosis. However, little is known about the mechanisms of transcriptional regulation by DYRK2 in cancer progression, particularly with respect to cancer proliferation and invasion. Here, using a comprehensive expression profiling approach, we show that cyclin-dependent kinase 14 (CDK14) is a target of DYRK2. We found that reduced DYRK2 expression increases CDK14 expression, which promotes cancer cell proliferation and invasion in vitro, in addition to tumorigenicity in vivo. CDK14 and DYRK2 expression inversely correlated in human breast cancer tissues. We further identified androgen receptor (AR) as a candidate of DYRK2-dependent transcription factors regulating CDK14. Taken together, our findings suggest a mechanism by which DYRK2 controls CDK14 expression to regulate tumor cell proliferation and invasion in breast cancer. Targeting of this pathway may be a promising therapeutic strategy for treating breast cancer.

Dual-specificity tyrosine-regulated kinase 2 is a suppressor and potential prognostic marker for liver metastasis of colorectal cancer.

Colorectal cancer is a common cancer and a leading cause of cancer-related death worldwide. The liver is a dominant metastatic site for patients with colorectal cancer. Molecular mechanisms that allow colorectal cancer cells to form liver metastases are largely unknown. Activation of epithelial-mesenchymal transition is the key step for metastasis of cancer cells. We recently reported that dual-specificity tyrosine-regulated kinase 2 (DYRK2) controls epithelial-mesenchymal transition in breast cancer and ovarian serous adenocarcinoma. The aim of this study is to clarify whether DYRK2 regulates liver metastases of colorectal cancer. We show that the ability of cell invasion and migration was abrogated in DYRK2-overexpressing cells. In an in vivo xenograft model, liver metastatic lesions were markedly diminished by ectopic expression of DYRK2. Furthermore, we found that patients whose liver metastases expressed low DYRK2 levels had significantly worse overall and disease-free survival. Given the findings that DYRK2 regulates cancer cell metastasis, we concluded that the expression status of DYRK2 could be a predictive marker for liver metastases of colorectal cancer.

Clinicopathological characteristics of duodenal epithelial neoplasms: Focus on tumors with a gastric mucin phenotype (pyloric gland-type tumors).

OBJECTIVE: Epithelial tumors less commonly occur in the duodenum than in the stomach or large intestine. The clinicopathological characteristics of duodenal epithelial tumors remain a matter of debate. We therefore studied resected specimens to investigate the clinicopathological characteristics of duodenal epithelial tumors. MATERIALS AND METHODS: Among duodenal epithelial tumors resected endoscopically or surgically in our hospital, we studied the clinicopathological characteristics of 110 adenomas or intramucosal carcinomas. The grade of atypia of all tumors was classified into 3 groups according to the World Health Organization (WHO) 2010 classification. The tumors were immunohistochemically evaluated to determine the frequency of differentiation toward fundic glands. RESULTS: As for patient characteristics, there were 76 men (75.2%) and 25 women (24.8%), with a median age of 65 years (range, 34 to 84). The tumors most commonly arose in the first to second part of the duodenum. Many lesions were flat, and the median tumor diameter was 8.0 mm. The lesions were classified into 2 types according to mucin phenotype: intestinal-type tumors (98 lesions, 89.1%) and gastric-type tumors (12 lesions, 10.9%). Intestinal-type tumors were subdivided into 2 groups: tubular-type tumors (91 lesions, 82.7%) and tubulovillous-type tumors (7 lesions, 6.4%). Gastric-type tumors were classified into 2 types: foveolar type (3 lesions, 2.7%) and pyloric gland-type (PG) tumors (9 lesions, 8.2%). The grade of atypia was significantly higher in gastric-type tumors (p<0.01). PG tumors were gastric-type tumors characterized by pyloric glands and findings suggesting differentiation toward fundic glands. CONCLUSIONS: About 10% of the duodenal tumors had a gastric-type mucin phenotype. Gastric-type tumors showed high-grade atypia. In particular, PG tumors showed similarities to PG tumors of the stomach, such as differentiation toward fundic glands.

Features of sinonasal hemangioma: A retrospective study of 31 cases.

OBJECTIVE: Although hemangiomas are common lesions of the head and neck, sinonasal hemangiomas are rare. The purpose of this study was to analyze the clinical features (sex, age, symptoms, and size and anatomical location of the lesion) and the histological findings of sinonasal hemangioma cases, to assess preoperative transarterial embolization, and to evaluate the outcome (recurrence or no recurrence) of endoscopic sinus surgery. METHODS: Clinical records of 31 patients who underwent endoscopic sinus surgery for resection of sinonasal hemangioma between January 2010 and June 2015 were retrospectively reviewed. RESULTS: The study group consisted of 19 men and 12 women. Mean age was 53.3±15.9years. The principal symptom was epistaxis (81%). Mean tumor size was 12.6±8.2mm. The most common origin of hemangioma was the inferior turbinate (45%), followed by the nasal septum (39%), and, in both locations, the origin had a tendency to be located in the anterior portion. Thirty-one specimens were histologically categorized as 9 cavernous hemangiomas and 22 capillary hemangiomas. Preoperative transarterial embolization was performed in 2 cases. Only one recurrence was observed among 31 cases. In the recurrent case, the hemangioma of the nasal septum was resected during pregnancy. CONCLUSION: According to our results, the transnasal endoscopic approach can be useful for the resection of sinonasal hemangioma. However, sinonasal hemangioma in connection with pregnancy must be addressed with care to decide the appropriate time for treatment.

Diminished DYRK2 sensitizes hormone receptor-positive breast cancer to everolimus by the escape from degrading mTOR.

Mammalian target of rapamycin (mTOR) inhibitor, everolimus, provides benefit for metastatic hormone receptor positive breast cancer after failure of the endocrine therapy. The present report highlights Dual Specificity Tyrosine Phosphorylation Regulated Kinase 2 (DYRK2) as a predictive marker for everolimus sensitivity. The key node and KEGG pathway analyses revealed that mTORC1 pathway is activated in DYRK2-depleted cells. Everolimus was more effective in DYRK2-depleted cells compared with control cells. In xenograft model, everolimus treatment significantly inhibited tumor growth compared with vehicle or eribulin treatment. In clinical analysis, patients with low DYRK2 expression acquired longer treatment period and had higher clinical benefit rate than those with high DYRK2 expression (171 vs 82 days; P < 0.05 and 50% vs 12.5%, respectively). We further investigated the underlying mechanism by which DYRK2 regulates mTORC1 pathway. The ectopic expression of DYRK2 promoted phosphorylation of Thr631 for the ubiquitination and degradation of mTOR. DYRK2 expression levels may thus predict clinical responses to everolimus.