Use of Artificial Intelligence for the Interpretable Prediction of the Pathologic Diagnosis and Molecular Abnormalities of Flat Urothelial Lesions.

Flat urothelial lesions are important because of their potential for carcinogenesis and development into invasive urothelial carcinomas. However, it is difficult for pathologists to detect early flat urothelial changes and accurately diagnose flat urothelial lesions. To predict the pathologic diagnosis and molecular abnormalities of flat urothelial lesions from pathologic images, artificial intelligence with an interpretable method was used. Next-generation sequencing on 110 hematoxylin and eosin-stained slides of normal urothelium and flat urothelial lesions, including atypical urothelium, dysplasia, and carcinoma in situ, detected 17 types of molecular abnormalities. To generate an interpretable prediction, a new method for segmenting urothelium and a new pathologic criteria-based artificial intelligence (PCB-AI) model was developed. κ Statistics and accuracy measurements were used to evaluate the ability of the model to predict the pathologic diagnosis. The likelihood ratio test was performed to evaluate the logistic regression models for predicting molecular abnormalities. The diagnostic prediction of the PCB-AI model was almost in perfect agreement with the pathologists' diagnoses (weighted κ = 0.98). PCB-AI significantly predicted some molecular abnormalities in an interpretable manner, including abnormalities of TP53 (P = 0.02), RB1 (P = 0.04), and ERCC2 (P = 0.04). Thus, this study developed a new method of obtaining accurate urothelial segmentation, interpretable prediction of pathologic diagnosis, and interpretable prediction of molecular abnormalities.

Double Negativity of MRI-Detected and Pathologically-Diagnosed Extramural Venous Invasion is a Favorable Prognostic Factor for Rectal Cancer.

BACKGROUND: Extramural venous invasion (EMVI) is a prognostic factor in rectal cancer. There are two types: EMVI detected by magnetic resonance imaging (MRI) (mr-EMVI) and EMVI detected by pathology (p-EMVI). They have been separately evaluated, but they have not yet been concurrently evaluated. We therefore evaluate both mr-EMVI and p-EMVI in rectal cancer at the same time and clarify their association with prognosis. PATIENTS AND METHODS: Included were the 186 consecutive patients who underwent complete radical resection of tumors ≤ stage III at Wakayama Medical University Hospital, Japan, between 2010 and 2018. All underwent preoperative MRI examination, and were reassessed for EMVI by a radiologist. Surgically resected specimens were then reassessed for EMVI by a pathologist. We assessed the correlation between positivity of mr-EMVI and p-EMVI and prognosis, and the clinicopathological background behind them. RESULTS: Patients with double negativity for mr-EMVI and p-EMVI had better prognosis than patients with mr-EMVI or p-EMVI positivity (p < 0.0001). Positivity for mr-EMVI or p-EMVI was a poor independent prognostic factor in multivariate analysis. CONCLUSIONS: Combined analysis of mr-EMVI and p-EMVI may enable prediction of postoperative prognosis of rectal cancer. Patients with double negativity of mr-EMVI and p-EMVI had better prognosis than patients with some form of positivity. Stated differently, patients with positivity of mr-EMVI, p-EMVI, or both had a poorer prognosis than those with double negativity. Postoperative adjuvant chemotherapy may improve poor prognosis. Combined evaluation of mr-EMVI and p-EMVI may be used to predict clinical outcomes and may be an effective prognostic predictor of rectal cancer.

Clinicopathological and molecular features of renal cell carcinomas with haemangioblastoma-like features distinct from clear cell renal cell carcinoma.

AIMS: Haemangioblastomas arise in the central nervous system. Rarely, haemangioblastomas may develop in extra-neural sites, such as the kidneys. A few reported cases of renal cell carcinomas (RCCs) with haemangioblastoma-like features have exhibited both clear cell renal cell carcinoma (CCRCC)- and haemangioblastoma-like components. The clinicopathological and molecular characteristics of RCCs with haemangioblastoma-like features were analysed, focusing on VHL alterations, in comparison with CCRCCs partially resembling haemangioblastoma. METHODS AND RESULTS: Four RCCs with haemangioblastoma-like features and five CCRCCs partially resembling haemangioblastoma were included. The RCCs with haemangioblastoma-like features were indolent and lacked adverse prognostic factors. All RCCs with haemangioblastoma-like features had a well-circumscribed appearance and a thick fibromuscular capsule, with fibromuscular bundles extending into the tumour to varying degrees in the three tumours. Each RCC with haemangioblastoma-like features exhibited CCRCC-like areas with indistinct tubular structures and foci of haemangioblastoma-like areas, in which vessels and short spindle cells overwhelmed tumour cells. Whereas haemangioblastoma-like areas in the CCRCCs partially resembling haemangioblastoma exhibited sparse vessels and spindle cells and distinct clear cells. The RCCs with haemangioblastoma-like features exhibited a unique immunohistochemical profile, with positive staining for inhibin-α, S100, carbonic-anhydrase-9, keratin7, and high molecular weight keratin and negative staining for (alpha-methylacyl-CoA racemase) AMACR. RCC with haemangioblastoma-like features did not display any VHL alterations, including VHL mutation, 3p LOH, and methylation of the VHL promoter region, and the two tumours harboured a likely oncogenic missense variant of MTOR (c.7280T>G). CONCLUSION: The histopathological, immunohistochemical, and molecular findings suggest that RCC with haemangioblastoma-like features is a distinct entity from CCRCC.

Subgroup characteristics in care workers with low back pain: cluster analysis-based severity of central sensitivity syndromes and low back pain.

PURPOSE: This multicentre, collaborative, cross-sectional study aimed to explore the characteristics of subgroups based on central sensitivity syndromes (CSSs) and low back pain (LBP) severity. Furthermore, we investigated the relationship between the classified subgroups and work status among the care workers. PATIENTS AND METHODS: In 660 care workers, we assessed LBP intensity, pain duration, pain sites, CSS (using the central sensitization inventory-9), psychological factors (using the pain catastrophizing scale and pain self-efficacy questionnaire), and work status (interference, amount of assistance, frequency of assistance, and work environment). We used hierarchical clustering analysis to divide the participants into subgroups based on CSS and LBP severity. We further performed multiple comparison analyzes and adjusted the residuals (chi-square test) to reveal differences between clusters. RESULTS: Care workers with LBP were divided into four subgroups (Cluster 1: no CSS and mild LBP, Cluster 2: mild CSS and severe LBP, Cluster 3: mild CSS and mild LBP, Cluster 4: severe CSS and moderate LBP). Cluster 4 tended to have a higher number of pain sites, severe pain catastrophizing, and poor pain self-efficacy. In addition, Cluster 4 showed a higher frequency of assistance and an inadequate working environment and equipment. By contrast, Cluster 2 tended to have low pain self-efficacy. In addition, Cluster 2 experienced the highest work-related interference compared with any of the subgroups. CONCLUSION: Our findings suggested that the severe LBP and severe CSS subgroups had common and different characteristics concerning psychological factors and work status, including interference with work. Our results may help to improve the management of care workers with LBP.

Implication of KMT2C and TSC2 variants in the tumorigenesis of acquired cystic disease-associated renal cell carcinomas.

In 2020, acquired cystic disease-associated renal cell carcinomas (ACD-RCCs) were reported to harbor KMT2C and TSC2 variants: however, their carcinogenic implication has not yet been reported. This study aimed to explore the variant features of KMT2C and TSC2 in ACD-RCC and their implication in ACD-RCC tumorigenesis. Eleven ACD-RCCs, 10 ACD-RCC-like cysts, and 18 background kidneys were retrieved. The background kidneys consisted of atrophic thyroid follicle-like tubules. They included four with clustered cysts, two with eosinophilic changes, and one each with clear cell changes and sieve-like changes in the renal tubules. First, DNA-targeted sequencing of KMT2C and TSC2 whole exons was performed on eight ACD-RCC samples. Subsequently, a custom DNA panel was designed to include the recurrent KMT2C and TSC2 variants based on the sequencing results. Second, DNA-targeted sequencing was performed on the remaining samples using a custom panel targeting the recurrent variants. Additionally, immunohistochemistry was performed for KMTC, H3K4me1, H3K4me3, TSC2, and GPNMB on the ACD-RCCs. Six of the 11 ACD-RCC cases harbored KMT2C and TSC2 variants, including nine likely pathogenic variants. In contrast to ACD-RCC, 1 of the 9 ACD-RCC-like cysts harbored both variants. Immunohistochemical analysis did not support the loss of function in ACD-RCCs harboring KMT2C and TSC2 variants. KMT2C and TSC2 variant frequencies were higher in ACD-RCC than in other renal cell carcinomas. However, KMT2C and TSC2 are unlikely to be the primary drivers of ACD-RCC development.

[Association between depressive tendencies and oral diadochokinesis in the older adults in private residential nursing home].

AIM: This study aimed to investigate the relationship between depressive tendencies and oral diadochokinesis (ODK) in 24 older adults living in a private residential nursing home. ODK is an indicator of the oral function. METHODS: Depressive tendencies were assessed using the Geriatric Depression Scale 5, with scores of two or higher indicating probable depression. ODK was measured across four syllable tasks (/pa/, /ta/, /ka/, and /pataka/), which were evaluated using coefficient of variation (CV) values. Low CV values indicate superior performance. Potential confounders, including the cognitive function, sleep status, body mass index, instrumental activities of daily living, and physical function, were controlled. RESULTS: Five participants (20.8%) experienced depression. Individuals with depressive tendencies demonstrated significantly poor ODK performance (higher CV) in the /ta/ task and a marginally significant difference in the /ka/ task. No significant differences were observed between /pa/ and /pataka/. CONCLUSIONS: These findings suggest a link between depressive tendencies and reduced proficiency in specific ODK tasks among older nursing home residents. This finding implies that a decline in the oral function in articulating /ta/ and /ka/ syllables may precede other common depressive symptoms. Furthermore, depression monitoring could be a valuable tool for early detection of the oral function in this population, enabling timely interventions.

The Roles of Transient Receptor Potential Vanilloid 1 and 4 in Olfactory Regeneration.

Olfactory disorders, which are closely related to cognitive deterioration, can be caused by several factors, including infections, such as COVID-19; aging; and environmental chemicals. Injured olfactory receptor neurons (ORNs) regenerate after birth, but it is unclear which receptors and sensors are involved in ORN regeneration. Recently, there has been great focus on the involvement of transient receptor potential vanilloid (TRPV) channels, which are nociceptors expressed on sensory nerves during the healing of damaged tissues. The localization of TRPV in the olfactory nervous system has been reported in the past, but its function there are unclear. Here, we investigated how TRPV1 and TRPV4 channels are involved in ORN regeneration. TRPV1 knockout (KO), TRPV4 KO, and wild-type (WT) mice were used to model methimazole-induced olfactory dysfunction. The regeneration of ORNs was evaluated using olfactory behavior, histologic examination, and measurement of growth factors. Both TRPV1 and TRPV4 were found to be expressed in the olfactory epithelium (OE). TRPV1, in particular, existed near ORN axons. TRPV4 was marginally expressed in the basal layer of the OE. The proliferation of ORN progenitor cells was reduced in TRPV1 KO mice, which delayed ORN regeneration and the improvement of olfactory behavior. Postinjury OE thickness improved faster in TRPV4 KO mice than WT mice but without acceleration of ORN maturation. The nerve growth factor and transforming growth factor ß levels in TRPV1 KO mice were similar to those in WT mice, and the transforming growth factor ß level was higher than TRPV4 KO mice. TRPV1 was involved in stimulating the proliferation of progenitor cells. TRPV4 modulated their proliferation and maturation. ORN regeneration was regulated by the interaction between TRPV1 and TRPV4. However, in this study, TRPV4 involvement was limited compared with TRPV1. To our knowledge, this is the first study to demonstrate the involvement of TRPV1 and TRPV4 in OE regeneration.

Targeted Next-Generation Sequencing of Flat Urothelial Lesions Reveals Putative Pathobiological Pathways, Potential Biomarkers, and Rational Therapeutic Targets.

Flat urothelial lesions are controversial diagnostic and prognostic urologic entities whose importance relies mainly on their ability to progress to muscle-invasive tumors via urothelial carcinoma in situ (CIS). However, the carcinogenetic progression of preneoplastic flat urothelial lesions is not well established. Moreover, predictive biomarkers and therapeutic targets of the highly recurrent and aggressive urothelial CIS lesion are lacking. Using a targeted next-generation sequencing (NGS) panel of 17 genes directly involved in bladder cancer pathogenesis, we investigated alterations of genes and pathways with clinical and carcinogenic implications on 119 samples of flat urothelium, including normal urothelium (n = 7), reactive atypia (n = 10), atypia of unknown significance ( n = 34), dysplasia ( n = 23), and CIS (n = 45). The majority of the flat lesions were tumor-associated but grossly/microscopically or temporally separated from the main tumor. Mutations were compared across flat lesions and concerning the concomitant urothelial tumor. Associations between genomic mutations and recurrence after intravesical bacillus Calmette-Guerin treatment were estimated with Cox regression analysis. TERT promoter mutations were highly prevalent in intraurothelial lesions but not in the normal or reactive urothelium, suggesting that it is a critical driver mutation in urothelial tumorigenesis. We found that synchronous atypia of unknown significance-dysplasia-CIS lesions without concomitant papillary urothelial carcinomas had a similar genomic profile that differed from atypia of unknown significance-dysplasia lesions associated with papillary urothelial carcinomas, which harbored significantly more FGFR3, ARID1A, and PIK3CA mutations. KRAS G12C and ERBB2 S310F/Y mutations were exclusively detected in CIS and were associated with recurrence after bacillus Calmette-Guerin treatment (P = .0006 and P = .01, respectively). This targeted NGS study revealed critical mutations involved in the carcinogenetic progression of flat lesions with putative pathobiological pathways. Importantly, KRAS G12C and ERBB2 S310F/Y mutations were identified as potential prognostic and therapeutic biomarkers for urothelial carcinoma.

Feasibility of the Glue-in-Plug Technique Using a Novel Liquid Embolic Material in a Swine Model.

PURPOSE: To evaluate the feasibility of the glue-in-plug (GIP) technique using n-butyl-2-cyanoacrylate‒Lipiodol (NL)-iopamidol (NLI) for short-segment embolization in swine. MATERIALS AND METHODS: The renal arteries, left external iliac artery, subclavian arteries, and common carotid arteries were each embolized in 4 swine using the GIP technique under general anesthesia. First, a type I Amplatzer vascular plug (AVP) (1-2 times the target vessel diameter) was deployed in the target artery. Next, the AVP was filled with NL mixture prepared at a ratio of 1:2 (NL12) (n = 11) or with NLI mixture prepared at a ratio of 2:3:1 (NLI231) (n = 11). Angiography was performed before, immediately after, and 1 hour after embolization to assess embolization and migration of the embolic materials. The embolized arteries were also evaluated histopathologically. RESULTS: The migration distance of the embolic material beyond the plug tip was significantly shorter in the NLI231 group than in the NL12 group immediately after embolization (6.5 mm ± 4.5 vs 1.0 mm ± 1.8, P = .0024) and 1 hour after embolization (8.4 mm ± 5.6 vs 1.0 mm ± 1.8, P = .0013). Angiography revealed no sign of recanalization of the target vessels in any artery in either group. Mild inflammatory cell infiltration was observed around the arterial wall at the embolization site in all arteries in both groups. CONCLUSIONS: The GIP technique using NLI231 may be a feasible procedure for short-segment embolization based on these short-term results.

Papillary thyroid carcinoma with aggressive fused follicular and solid growth pattern: A unique histological subtype with high-grade malignancy?

Papillary thyroid carcinoma (PTC) is usually indolent; however, some rare subtypes of PTCs, such as columnar cell and hobnail subtypes, carry poor prognosis as an intermediate malignancy between differentiated carcinoma and anaplastic carcinoma. We present the case of a 56-year-old Japanese woman having PTC with aggressive behavior showing characteristic histological features of a predominantly fused follicular and focally solid (FFS) pattern. The fused follicular pattern is cribriform-like without intermingled vessels. This PTC with FFS pattern included frequent mitotic figures, necrosis, lymphovascular invasion, and metastases with high clinical stage. The tumor cells were broadly positive for antibodies to TTF-1, PAX8, and bcl-2, and negative for cyclin D1. Ki-67 labeling index was approximately 10%, and there was occasional positivity of p53. Targeted next generation sequencing analysis only detected a NRAS mutation (Q61K); there was no mutation and no translocation of other genes including BRAF and RET/PTC. To our knowledge, this is first report that PTC shows aggressive FFS growth pattern. The tumor is possibly included in the new category of differentiated high-grade thyroid carcinoma in the World Health Organization 2022 classification, or in a novel subtype of PTC owing to its characteristic histological feature and intermediate malignancy between differentiated carcinoma and anaplastic carcinoma.

Ultrasonographic diagnosis of cystitis glandularis with severe intestinal metaplasia.

This study presents the case of man who underwent ultrasonography (US) for the diagnosis and follow-up of cystitis glandularis with severe intestinal metaplasia. We believe that our study makes a significant contribution to the literature because the findings of cystitis glandularis that forms a mass is relatively rare.

Chondroma Arising from the Temporomandibular Joint: A Case Report.

Periarticular chondromas are common in the humerus and femur but rarely occur in the temporomandibular joint. We report a case of a chondroma in the anterior part of the ear. One year prior to his visit, a 53-year-old man became aware of swelling in the right cheek region which gradually increased in size. In the anterior part of the right ear, there was a palpable 25 mm tumor, elastic and hard, with poor mobility and without tenderness. A contrast-enhanced computed tomography CT showed a mass lesion with diffuse calcification or ossification in the upper pole of the parotid gland and areas of poor contrast within. A magnetic resonance imaging showed a low-signal mass lesion at the parotid gland with some high signals in both T1 and T2. Fine-needle aspiration cytology did not lead to diagnosis. Using a nerve monitoring system, the tumor was resected with normal tissue of the upper pole of the parotid gland in the same way as for a benign parotid tumor. Distinguishing between pleomorphic adenoma, including diffuse microcalcification of the parotid gland and cartilaginous tumors of the temporomandibular joint, may be sometimes difficult. In such cases, surgical resection may be a beneficial treatment option.

Comparison of Soluble Gelatin Sponge Particles and Tris-acryl Gelatin Microspheres for Bariatric Arterial Embolization in Swine.

The purpose of this study was to compare complications and the number of ghrelin-expressing cells (GECs) after bariatric arterial embolization (BAE) using soluble gelatin sponge particles (SGSs) or tris-acryl gelatin microspheres (MSs) in swine. Twelve swine underwent embolization of gastric fundal arteries with SGSs (n = 4) or MSs (n = 4) or underwent saline infusion (n = 4, control group). One week later, the number of gastric ulcers and the percentage of GECs were compared among the 3 groups. There were no ulcers in the SGS and control groups. Two swine in the MS group had 4 large ulcers (12-50 mm in size). The mean percentages of GECs were significantly lower in the SGS (2.7% ± 0.9%) and MS (2.5% ± 1.0%) groups compared with the control group (3.7% ± 1.3%; P = .038 and P = .016, respectively). SGSs may be safer than MSs for BAE while inducing a similar reduction of GECs in swine.

Intestinal Mucosa-Associated Lymphoid Tissue Lymphoma Transforming into Diffuse Large B-Cell Lymphoma in a Young Adult Patient with Neurofibromatosis Type 1: A Case Report.

Background: Neurofibromatosis type 1 (NF1) is a hereditary cancer syndrome characterized by multiple café-au-lait macules on the skin. Lymphoproliferative malignancies associated with NF1 are limited, although the most common are brain tumors. Case presentation: A 22-year-old woman with NF1 was admitted due to abdominal pain and bloody diarrhea. Her laboratory data exhibited macrocytic anemia and elevated IgA levels. Image studies showed diffuse increased wall thickening in the transverse and descending colon without lymphadenopathy and hepatosplenomegaly. A colonoscopy revealed a hemorrhagic ulcerated mass. Pathological analysis of the tumor tissues confirmed IgA-expressing mucosa-associated lymphoid tissue (MALT) lymphoma with histological transformation. Moreover, whole-exome sequencing in tumor tissues and peripheral blood mononuclear cells identified a somatic frameshift mutation of the A20 gene, which represents the loss of function. The patient responded well to R-CHOP chemotherapy, but the disease relapsed after 1 year, resulting in a lethal outcome. Conclusions: MALT lymphoma in children and young adults is extremely rare and is possibly caused by acquired genetic changes. This case suggests a novel association between hereditary cancer syndrome and early-onset MALT lymphoma.

The relationship between children's somatotypes, motor examination results, and motor skills: assessing 6- to 10-year-olds.

[Purpose] Childhood motor disorders and obesity are major health problems and concerns in children today. We performed a physical examination to test the motor system and motor ability of elementary school children based on their body types. [Participants and Methods] The obesity levels of 161 elementary school students aged six to ten were calculated based on the gender, age, and standard weight for each height category to classify them into somatotype groups, and analyze the relationships among the results of four motor examination items, Physical Fitness Test, and body composition analysis for two groups. [Results] More obese children were unable to reach the floor while performing a standing forward bend compared to non-obese children. In addition, a significant difference was found in the assessment of motor performance while performing side-to-side jumping, and obese children showed better values. Many endomorphic children were also unable to touch the floor with their hands when performing the standing forward bend. Among the items from a physical fitness test, the side-to-side hops revealed significant differences. There were no somatotype-related differences in the results of the body composition analysis. [Conclusion] In children aged six to ten years, somatotype differences were not associated with motor skill or body composition.

Paneth-like cells in renal cell carcinomas and in cysts associated with acquired cystic kidney disease: Clinicopathologic analysis, comparative study and description of precursor lesions.

Paneth-like cells (PLCs) are different from Paneth cells (PCs) and contain Paneth-like granules, which have been reported in non-neoplastic conditions and in neoplasms of various organs. PLCs have been reported in clear cell renal cell carcinoma (CCRCC), but not in non-CCRCC, including acquired cystic disease-associated renal cell carcinoma (ACD-RCC). We analyzed clinicopathological features of 24 acquired cystic disease-associated renal cell carcinoma (ACD-RCC) with PLCs (ACD-RCCP+) and compared with those of 23 ACD-RCCs without PLCs (ACD-RCCP-). Approximately half of ACD-RCCs had PLCs and that almost all kidneys harboring ACD-RCC had cysts with PLCs. The fact that many ACD-RCCs and the cysts had PLCs is further evidence that the cyst with vacuoles and complex architecture might be a precursor lesion for ACD-RCC. The presence of PLCs may provide additional morphologic clue for distinguishing ACD-RCC from PRCC in challenging differential diagnostic workup in acquired cystic disease of the kidney setting.

Novel endoscopic ultrasonography imaging technique for visualizing microcirculation without contrast enhancement in subepithelial lesions: Prospective study.

OBJECTIVES: Detective flow imaging for endoscopic ultrasonography (DFI?EUS) is a new imaging modality developed for detecting fine vessels without using ultrasound contrast agents. This study aimed to evaluate its utility by comparing it with a type of directional power Doppler (eFLOW) for subepithelial lesions (SELs). METHODS: Between January 2019 and January 2020, 28 patients with SELs undergoing DFI?EUS and eFLOW?EUS were enrolled. DFI?EUS and eFLOW?EUS assessing the vascularity in SELs were compared in terms of the rates of identification of intratumoral vessels. We also investigated how large vessels were depicted in both modalities based on surgical specimens as well as the detection rates of intratumoral vessels in gastrointestinal stromal tumors (GISTs) and non?GISTs using either DFI?EUS or eFLOW?EUS. RESULTS: Among 28 patients, 23 with pathological confirmation by EUS?guided fine?needle aspiration biopsy (EUS?FNAB) specimens were included. Of those 23 patients, the 10 who underwent surgical resection were selected for analysis. The rate of detection of intratumoral vessels in SELs was significantly higher on DFI?EUS (80%) than on eFLOW?EUS (30%) (P\xA0=\xA00.03). Comparison with surgical specimens revealed that detection rate for vessels with maximum size of less 1000\xA0µm was higher in DFI?EUS (66%) than that in eFLOW?EUS (0%). GIST patients had significantly higher positive rates (90%) of intratumoral vessels than non?GIST patients (31%) on DFI in 23 cases including EUS?FNAB specimens (P\xA0=\xA00.045). CONCLUSIONS: Detective flow imaging?EUS is more sensitive for depicting intratumoral vessels than eFLOW?EUS. Evaluation of intratumoral vessels on DFI?EUS is useful for identifying GISTs without contrast agents.

Adipophilin expression in cutaneous malignant melanoma is associated with high proliferation and poor clinical prognosis.

Adipophilin (ADP) is a primary protein component of lipid droplets (LDs). For more than half a century, certain types of cancer cells have been known to contain LDs in their cytoplasm. However, the pathological significance of ADP or LDs in cancer remains unclear. In the present study, we investigated the association between ADP and other pathological characteristics in cutaneous malignant melanomas to clarify the role of ADP in melanoma cells. We immunostained whole paraffin sections of primary cutaneous melanomas obtained from 90 cases for ADP, after which we analyzed the correlation between ADP immunohistochemistry (IHC) and patient survival data. We also studied the relationship between the ADP IHC score and in situ hybridization (ISH) score of ADP mRNA, and the Ki67-labeling index (Ki67-LI) by using tissue microarrays consisting of 74 primary cutaneous malignant melanomas, 19 metastasizing melanomas, and 29 melanocytic nevi. Finally, we analyzed the relationship between ADP expression and cell proliferation in cutaneous melanoma cell lines. We found that high ADP expression was associated with poor metastasis-free survival, disease-specific survival, and overall survival rates of patients with cutaneous melanomas (P < 0.05). By linear regression analysis, ADP IHC was correlated with increasing ADP mRNA ISH H-scores and Ki67-LI scores in melanocytic lesions (P < 0.01). ADP IHC and ADP ISH H-scores and Ki67-LI scores were greater in pT3-4 melanomas than in pT1-2 melanomas. In cell-based assays, cells with increased ADP expression showed higher proliferation rates compared with those of low-ADP cells. Thus, ADP expression in malignant melanoma was significantly associated with high cell proliferation and poor clinical prognosis. Our results thus indicate a significant association between ADP and melanoma progression, and we propose that ADP may be a novel marker of aggressive cutaneous melanoma with a lipogenic phenotype.

The usefulness of EUS-FNA with contrast-enhanced harmonic imaging of solid pancreatic lesions: A prospective study.

BACKGROUND AND AIM: Few studies have investigated endoscopic ultrasound-guided fine-needle aspiration with contrast-enhanced harmonic imaging (EUS-FNA-CHI) for diagnosing and adequately sampling pancreatic lesions. This study aimed to investigate the efficacy of EUS-FNA-CHI compared with that of endoscopic ultrasound-guided fine-needle aspiration with fundamental B mode imaging (EUS-FNA-FBI) for diagnosing solid pancreatic lesions. METHODS: Consecutive patients with solid pancreatic lesions were enrolled prospectively (UMIN 000024467). Only samples obtained during the first needle pass (EUS-FNA-FBI) and second needle pass (EUS-FNA-CHI) were used to compare the accuracy rate for diagnosing pancreatic lesions and rate of adequate sampling for histological evaluation. In patients with hypo-enhancing lesions on contrast-enhanced harmonic EUS (CH-EUS), subgroup analyses were performed. Patients were classified into those with a heterogeneous area in the whole lesion (whole group), those with a heterogeneous area with a non-enhancing area (non-enhancing group), and those with a heterogeneous area with a homogeneous area (homogeneous group). RESULTS: Ninety-three patients were enrolled. Overall, the rates of adequate sampling and sensitivity were significantly higher with EUS-FNA-CHI than with EUS-FNA-FBI (84.9% vs 68.8%, P = 0.003 and 76.5% vs 58.8%, P = 0.011, respectively). The adequate sampling rate and sensitivity were significantly higher with EUS-FNA-CHI than with EUS-FNA-FBI when the mass was > 15 mm. In the non-enhancing and homogeneous groups, the adequate sampling rate and sensitivity were significantly higher with EUS-FNA-CHI than with EUS-FNA-FBI. CONCLUSIONS: CH-EUS enables improved observation of pancreatic lesions and helps identify the target of EUS-FNA among different pathological areas of the lesions particularly of > 15 mm.

Expression of unfolded protein response markers in the pheochromocytoma with Waardenburg syndrome: a case report.

BACKGROUND: It is clinically emergent to further understand the pathological mechanism to advance therapeutic strategy for endocrine tumors. A high amount of secretory protein with tumorigenic triggers are thought to induce unfolded protein response in endoplasmic reticulum in endocrine tumors, but its evidence is limited. CASE PRESENTATION: A 40-year-old woman had an approximately 10-year history of intermittent headaches. After the incidental detection of a mass in her right adrenal gland by CT scan, she was admitted to our hospital. She had been diagnosed as type 1 Waardenburg syndrome with the symptoms of dystopia canthorum, blue iris, and left sensorineural hearing loss. Urinary catecholamine levels were markedly elevated. 123I-MIBG scintigraphy showed uptake in the mass in her adrenal gland. After the adrenalectomy, her headaches disappeared and urinary catecholamine levels decreased to normal range within 2 weeks. Genome sequencing revealed germline mutation of c.A175T (p.Ile59Phe) in transcription factor PAX3 gene and somatic novel mutation of c.1893_1898del (p. Asp631_Leu633delinsGlu) in proto-oncogene RET in her pheochromocytoma. RNA expression levels of RET were increased 139 times in her pheochromocytoma compared with her normal adrenal gland. Those of unfolded protein response markers, Bip/GRP78, CHOP, ATF4, and ATF6, were also increased in the pheochromocytoma. CONCLUSION: We report a rare case of pheochromocytoma with type 1 Waardenburg syndrome. This is the first case to show the activation of unfolded protein response in the pheochromocytoma with the novel somatic mutation in RET gene. Our findings may support that unfolded protein response is activated in endocrine tumors, which potentially could be a candidate of therapeutic target.