Smoothness of gait in healthy older females and patients with postoperative proximal femur fracture.

[Purpose] This study aimed to investigate the usefulness of a quality index in gait for proximal femur fractures. [Participants and Methods] In this study, 20 females with postoperative proximal femur fracture in the preparation phase for discharge (femur fracture group) aged ≥60 years (63.0 ± 3.0 years) and 20 healthy older females (healthy group) participated (75.7 ± 7.7 years) (n=40). Measurements were conducted at comfortable and maximal gait speeds. Power spectrum entropy (PSE), harmonic ratio (HR), and modified HR (mHR), which are smoothness indices, were calculated from the measured data in each of the three axial directions and compared. [Results] The healthy and femur fracture groups showed significant differences in the PSE, HR, and mHR for comfortable and maximal gait speed in the lateral and vertical directions. Furthermore, all directions between the HR and mHR in the femur fracture group had significant differences. [Conclusion] The usefulness of the PSE, HR, and mHR as quality evaluation indices of gait was demonstrated in patients with postoperative femur fractures after unilateral disability.

Validation of smoothness evaluation during standing and sitting motions using an accelerometer.

[Purpose] To quantitatively evaluate smoothness during standing and sitting motion analysis using an accelerometer and to clarify the relationship between indices. [Participants and Methods] Seventeen healthy males participated in this study. We attached a 9-axis motion sensor to the spinous process of the third lumbar spine and measured the acceleration of standing and sitting motions under normal and unstable conditions. We estimated and compared the root mean square and entropy in the lateral, vertical, longitudinal, and triaxial composite directions. [Results] On comparing both conditions, the unstable condition indices were significantly high, except for the lateral direction of entropy. The root mean square was significantly negatively correlated with entropy under normal conditions. [Conclusion] The study results suggested that the acceleration index quantitatively evaluates motion smoothness. Since each index had different characteristics, the motion-specific index was observed to be significant.

A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response.

Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.

Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy.

The EGFR T790M mutation has been identified in tumors from lung cancer patients that eventually develop resistance to erlotinib. In this study, we generated a mouse model with doxycycline-inducible expression of a mutant EGFR containing both L858R, an erlotinib-sensitizing mutation, and the T790M resistance mutation (EGFR TL). Expression of EGFR TL led to development of peripheral adenocarcinomas with bronchioloalveolar features in alveoli as well as papillary adenocarcinomas in bronchioles. Treatment with an irreversible EGFR tyrosine kinase inhibitor (TKI), HKI-272, shrunk only peripheral tumors but not bronchial tumors. However, the combination of HKI-272 and rapamycin resulted in significant regression of both types of lung tumors. This combination therapy may potentially benefit lung cancer patients with the EGFR T790M mutation.

Suppression of heat shock protein 27 induces long-term dormancy in human breast cancer.

The mechanisms underlying tumor dormancy have been elusive and not well characterized. We recently published an experimental model for the study of human tumor dormancy and the role of angiogenesis, and reported that the angiogenic switch was preceded by a local increase in VEGF-A and basic fibroblast growth factor. In this breast cancer xenograft model (MDA-MB-436 cells), analysis of differentially expressed genes revealed that heat shock protein 27 (HSP27) was significantly up-regulated in angiogenic cells compared with nonangiogenic cells. The effect of HSP27 down-regulation was further evaluated in cell lines, mouse models, and clinical datasets of human patients with breast cancer and melanoma. Stable down-regulation of HSP27 in angiogenic tumor cells was followed by long-term tumor dormancy in vivo. Strikingly, only 4 of 30 HSP27 knockdown xenograft tumors initiated rapid growth after day 70, in correlation with a regain of HSP27 protein expression. Significantly, no tumors escaped from dormancy without HSP27 expression. Down-regulation of HSP27 was associated with reduced endothelial cell proliferation and decreased secretion of VEGF-A, VEGF-C, and basic fibroblast growth factor. Conversely, overexpression of HSP27 in nonangiogenic cells resulted in expansive tumor growth in vivo. By clinical validation, strong HSP27 protein expression was associated with markers of aggressive tumors and decreased survival in patients with breast cancer and melanoma. An HSP27-associated gene expression signature was related to molecular subgroups and survival in breast cancer. Our findings suggest a role for HSP27 in the balance between tumor dormancy and tumor progression, mediated by tumor-vascular interactions. Targeting HSP27 might offer a useful strategy in cancer treatment.

The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies.

To understand the role of human epidermal growth factor receptor (hEGFR) kinase domain mutations in lung tumorigenesis and response to EGFR-targeted therapies, we generated bitransgenic mice with inducible expression in type II pneumocytes of two common hEGFR mutants seen in human lung cancer. Both bitransgenic lines developed lung adenocarcinoma after sustained hEGFR mutant expression, confirming their oncogenic potential. Maintenance of these lung tumors was dependent on continued expression of the EGFR mutants. Treatment with small molecule inhibitors (erlotinib or HKI-272) as well as prolonged treatment with a humanized anti-hEGFR antibody (cetuximab) led to dramatic tumor regression. These data suggest that persistent EGFR signaling is required for tumor maintenance in human lung adenocarcinomas expressing EGFR mutants.

[A case of post-operative recurrence of pancreatic cancer in the residual pancreas treated by resection of the residual pancreas following radiological complete response achieved with second-line FOLFIRINOX].

A 65-year-old woman with carcinoma of the pancreatic body underwent Whipple's operation. After surgery, adjuvant chemotherapy with gemcitabine alone, and S-1 combined with gemcitabine was conducted. But one year later, a recurrent tumor was detected in the pancreatic tail. We administered FOLFIRINOX treatment for the recurrent tumor. After 6 courses, FOLFIRINOX treatment resulted in a partial response, and after 9 courses, a radiological complete response was achieved. We could then perform total pancreatotectomy and resection of the metastatic liver tumor. FOLFIRINOX as a second-line treat- ment was effective and safe in this case. In cases of gemcitabine and/or S-1 failure, FOLFIRINOX treatment should be considered.

Deciphering fibroblast-induced drug resistance in non-small cell lung carcinoma through patient-derived organoids in agarose microwells.

Patient-derived organoids (PDOs) serve as invaluable 3D tumor models, retaining the histological complexity and genetic heterogeneity found in primary tumors. However, the limitation of small sample volumes and the lack of tailored platforms have hindered the research using PDOs. Within the tumor microenvironment, cancer-associated fibroblasts play a pivotal role in influencing drug sensitivity. In this study, we introduce an agarose microwell platform designed for PDO-based tumor and tumor microenvironment models, enabling rapid drug screening and resistance studies with small sample volumes. These microwells, constructed using 3D printing molds, feature a U-shaped bottom and 200 µm diameter. We successfully generated co-culture spheroids of non-small cell lung carcinoma (NSCLC) cells, including NCI-H358 or A549, and NSCLC PDOs F231 or F671 with fibroblast cell line, WI-38. Our results demonstrate the production of uniformly-sized spheroids (coefficient of variation <30%), high viability (>80% after 1 week), and fibroblast-induced drug resistance. The PDOs maintained their viability (>81% after 2 weeks) and continued to proliferate. Notably, when exposed to adagrasib, a KRASG12C inhibitor, we observed reduced cytotoxicity in KRASG12C-mutant spheroids when co-cultured with fibroblasts or their supernatant. The fibroblast supernatant sustained proliferative signals in tumor models. Taking into account the physical features, viability, and drug resistance acquired through supernatants from the fibroblasts, our platform emerges as a suitable platform for in vitro tumor modeling and the evaluation of drug efficacy using patient-derived tissues.

A novel scoring system for arterial invasion of pancreatic body and tail cancer based on multidetector row computed tomography and biomarkers.

BACKGROUND/OBJECTIVES: The absence of major-vessel involvement is a crucial factor in the resectability and prognosis of pancreatic cancer. However, arterial invasion cannot be evaluated adequately using imaging findings alone. We therefore developed a scoring system to assess arterial invasion by pancreatic adenocarcinoma using multidetector row computed tomography (MDCT) and serum tumor markers. METHODS: Twenty patients who underwent distal pancreatectomy and splenectomy for pancreatic adenocarcinoma were examined retrospectively using 4-, 16- or 64-row MDCT and serum tumor markers. Splenic arterial invasion was evaluated in terms of length of tumor contact, circumferential involvement (<180° or ≥180°) and deformity of vascular diameter. Preoperative expression of carbohydrate antigen 19-9 (CA19-9), DUPAN-2 and S-Pancreas-1 antigen (SPan-1) were also evaluated. The presence or absence of arterial invasion was confirmed histopathologically in all 20 cases. RESULTS: In 11 of 20 cases invasion into splenic arteries was observed histopathologically, mostly involving the external elastic lamina and periarterial nerves. Sensitivity, specificity and accuracy were 100%, 88.9% and 95%, respectively, for length of tumor contact (<16 mm or ≥16 mm), 90.9%, 77.8% and 85% for circumferential involvement (<180° or ≥180°), and 100%, 66.7% and 85% for deformity of vascular diameter. Furthermore, the sensitivity, specificity and accuracy were all increased to 100% when tumor markers were included in the score. CONCLUSIONS: MDCT is a useful technique for diagnosing arterial invasion of pancreatic body and tail cancer, even in comparison with pathological examination; however, this new scoring system can be further complemented and made more reliable by measurements of serous tumor markers.

LKB1 modulates lung cancer differentiation and metastasis.

Germline mutation in serine/threonine kinase 11 (STK11, also called LKB1) results in Peutz-Jeghers syndrome, characterized by intestinal hamartomas and increased incidence of epithelial cancers. Although uncommon in most sporadic cancers, inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines. Here we used a somatically activatable mutant Kras-driven model of mouse lung cancer to compare the role of Lkb1 to other tumour suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 or Ink4a/Arf (also known as Cdkn2a) in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1-deficient tumours demonstrated shorter latency, an expanded histological spectrum (adeno-, squamous and large-cell carcinoma) and more frequent metastasis compared to tumours lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34% and 19% of 144 analysed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes, such as NEDD9, VEGFC and CD24, as targets of LKB1 repression in lung cancer. These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis.

Smoothness Evaluation Indices during Sit-to-Stand-to-Sit Motions in Healthy Older Females and after Hip Fracture Using an Accelerometer: A Pilot Study.

BACKGROUND: Studies that quantify the quality of sit-to-stand-to-sit (STS) motions, particularly in terms of smoothness, are limited. Thus, this study aimed to investigate the possibility and usefulness of quality evaluation during STS motions. METHODS: This cross-sectional study enrolled 36 females aged >60 years, including 18 females each in the healthy and hip fracture groups. Measurements were performed at two different speeds: five STS as fast as possible (STSF) and two seconds for each motion (STS2s). Indices of smoothness, including harmonic ratio (HR) and power spectrum entropy (PSE), were calculated and compared from the measured data in each of the three axial directions. RESULTS: HR in the vertical direction was significantly higher in the healthy group (STSF: 3.65 ± 1.74, STS2s: 3.42 ± 1.54) than in the hip fracture group (STSF: 2.67 ± 1.01, STS2s: 2.58 ± 0.83) for STSF and STS2s. Furthermore, PSE for all directions and triaxial composites were significantly lower for STS2s (the healthy group (mediolateral (ML): 7.63 ± 0.31, vertical (VT): 7.46 ± 0.22, anterior-posterior (AP): 7.47 ± 0.15, triaxial: 7.45 ± 0.25), the hip fracture group (ML: 7.82 ± 0.16, VT: 7.63 ± 0.16, AP: 7.61 ± 0.17, triaxial: 7.66 ± 0.17)). CONCLUSIONS: This study suggests the usefulness of HR and PSE as quality evaluations for STS motions.

Myo1e overexpression in lung adenocarcinoma is associated with increased risk of mortality.

This study aims to perform a comprehensive genomic analysis to assess the influence of overexpression of MYO1E in non-small cell lung carcinoma (NSCLC) and whether there are differences in survival and mortality risk in NSCLC patients depending on both DNA methylation and RNA expression of MYO1E. The DNA methylation probe cg13887966 was inversely correlated with MYO1E RNA expression in both LUAD and LUSC subpopulations showing that lower MYO1E RNA expression was associated with higher MYO1E DNA methylation. Late stages of lung cancer showed significantly lower MYO1E DNA methylation and significantly higher MYO1E RNA expression for LUAD but not for LUSC. Low DNA methylation as well as high RNA expression of MYO1E are associated with a shorter median survival time and an increased risk of mortality for LUAD, but not for LUSC. This study suggests that changes in MYO1E methylation and expression in LUAD patients may have an essential role in lung cancer's pathogenesis. It shows the utility of MYO1E DNA methylation and RNA expression in predicting survival for LUAD patients. Also, given the low normal expression of MYO1E in blood cells MYO1E DNA methylation has the potential to be used as circulating tumor marker in liquid biopsies.

In vivo metabolomics identifies CD38 as an emergent vulnerability in LKB1 -mutant lung cancer.

LKB1/STK11 is a serine/threonine kinase that plays a major role in controlling cell metabolism, resulting in potential therapeutic vulnerabilities in LKB1-mutant cancers. Here, we identify the NAD + degrading ectoenzyme, CD38, as a new target in LKB1-mutant NSCLC. Metabolic profiling of genetically engineered mouse models (GEMMs) revealed that LKB1 mutant lung cancers have a striking increase in ADP-ribose, a breakdown product of the critical redox co-factor, NAD + . Surprisingly, compared with other genetic subsets, murine and human LKB1-mutant NSCLC show marked overexpression of the NAD+-catabolizing ectoenzyme, CD38 on the surface of tumor cells. Loss of LKB1 or inactivation of Salt-Inducible Kinases (SIKs)-key downstream effectors of LKB1- induces CD38 transcription induction via a CREB binding site in the CD38 promoter. Treatment with the FDA-approved anti-CD38 antibody, daratumumab, inhibited growth of LKB1-mutant NSCLC xenografts. Together, these results reveal CD38 as a promising therapeutic target in patients with LKB1 mutant lung cancer. SIGNIFICANCE: Loss-of-function mutations in the LKB1 tumor suppressor of lung adenocarcinoma patients and are associated with resistance to current treatments. Our study identified CD38 as a potential therapeutic target that is highly overexpressed in this specific subtype of cancer, associated with a shift in NAD homeostasis.

Apoptosis induced by JAK2 inhibition is mediated by Bim and enhanced by the BH3 mimetic ABT-737 in JAK2 mutant human erythroid cells.

The activating mutation JAK2 V617F plays a central role in the pathogenesis of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Inhibition of JAK2 activity leads to growth inhibition and apoptosis in cells with mutated JAK2. However, the proapoptotic proteins involved in JAK2 inhibition-induced apoptosis remain unclear. In this study, we show that JAK2 inhibition-induced apoptosis correlated with up-regulation of the nonphosphorylated form of the BH3-only protein Bim in hematopoietic cell lines bearing JAK2 mutations. Knockdown of Bim dramatically inhibited apoptosis induced by JAK2 inhibition, which was reversed by the BH3 mimetic agent ABT-737. In addition, ABT-737 enhanced the apoptosis induced by JAK2 inhibition in JAK2 V617F(+) HEL and SET-2 cells. The combination of JAK inhibitor I and ABT-737 reduced the number of erythroid colonies derived from CD34(+) cells isolated from JAK2 V617F(+) polycythemia vera patients more efficiently than either drug alone. These data suggest that Bim is a key effector molecule in JAK2 inhibition-induced apoptosis and that targeting this apoptotic pathway could be a novel therapeutic strategy for patients with activating JAK2 mutations.

Endoscopic ultrasonographic findings predict the risk of carcinoma in branch duct intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND: The preoperative diagnosis of branch duct intraductal papillary mucinous neoplasm (IPMN) of the pancreas can be very difficult, since low-risk and high-risk lesions can be difficult to differentiate even after cytological analysis. The purpose of this study was to evaluate the preoperative diagnostic value of endoscopic ultrasonography (EUS) in differentiating low-risk and high-risk IPMNs. METHODS: We retrospectively identified 36 patients who underwent preoperative EUS for branch duct IPMNs. The pathological diagnosis after surgical resection was low-grade dysplasia (n = 26), moderate dysplasia (n = 1), high-grade dysplasia or carcinoma in situ (n = 5), and invasive carcinoma (n = 4). We divided the patients into two groups: low risk (low-grade dysplasia or moderate dysplasia) and high risk (high-grade dysplasia or carcinoma). We focused on the diameter of the cystic dilated branch duct, the main pancreatic duct, and the mural nodule as measured using the EUS findings. RESULTS: The cystic dilated branch duct diameter (31.5 mm vs. 41.9 mm, P = 0.0225) was significantly correlated with low-risk and high-risk IPMNs, but the main pancreatic duct diameter (5.37 mm vs. 5.44 mm, P = 0.9418) was not significantly correlated with the low-risk and high-risk IPMNs. The mural nodule diameter of the papillary protrusions (4.3 mm vs. 16.4 mm, P < 0.0001) and the width diameter of the mural nodule (5.7 mm vs. 23.2 mm, P < 0.0001) were significantly correlated with low-risk and high-risk IPMNs. CONCLUSIONS: The mural nodule of papillary protrusions diameter and width diameter observed using EUS was a reliable preoperative diagnostic finding capable of distinguishing low-risk and high-risk IPMNs.

HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy.

Mutations in the HER2 kinase domain have been identified in human clinical lung cancer specimens. Here we demonstrate that inducible expression of the most common HER2 mutant (HER2(YVMA)) in mouse lung epithelium causes invasive adenosquamous carcinomas restricted to proximal and distal bronchioles. Continuous expression of HER2(YVMA) is essential for tumor maintenance, suggesting a key role for HER2 in lung adenosquamous tumorigenesis. Preclinical studies assessing the in vivo effect of erlotinib, trastuzumab, BIBW2992, and/or rapamycin on HER2(YVMA) transgenic mice or H1781 xenografts with documented tumor burden revealed that the combination of BIBW2992 and rapamycin is the most effective treatment paradigm causing significant tumor shrinkage. Immunohistochemical analysis of lung tumors treated with BIBW2992 and rapamycin combination revealed decreased phosphorylation levels for proteins in both upstream and downstream arms of MAPK and Akt/mTOR signaling axes, indicating inhibition of these pathways. Based on these findings, clinical testing of the BIBW2992/rapamycin combination in non-small cell lung cancer patients with tumors expressing HER2 mutations is warranted.

Non-small cell lung carcinoma spheroid models in agarose microwells for drug response studies.

There is a growing interest in developing personalized treatment strategies for each cancer patient, especially those with non-small cell lung carcinoma (NSCLC) which annually accounts for the majority of cancer related deaths in the US. Yet identifying the optimal NSCLC treatment strategy for each cancer patient is critical due to a multitude of mutations, some of which develop following initial therapy and can result in drug resistance. A key difficulty in developing personalized therapies in NSCLC is the lack of clinically relevant assay systems that are suitable to evaluate drug sensitivity using a minuscule amount of patient-derived material available following biopsies. Herein we leverage 3D printing to demonstrate a platform based on miniature microwells in agarose to culture cancer cell spheroids. The agarose wells were shaped by 3D printing molds with 1000 microwells with a U-shaped bottom. Three NSCLC cell lines (HCC4006, H1975 and A549) were used to demonstrate size uniformity, spheroid viability, biomarker expressions and drug response in 3D agarose microwells. Results show that our approach yielded spheroids of uniform size (coefficient of variation <22%) and high viability (>83% after 1 week-culture). Studies using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKIs) drugs gefitinib and osimertinib showed clinically relevant responses. Based on the physical features, cell phenotypes, and responses to therapy of our spheroid models, we conclude that our platform is suitable for in vitro culture and drug evaluation, especially in cases when tumor sample is limited.

Semaphorin 4D, a lymphocyte semaphorin, enhances tumor cell motility through binding its receptor, plexinB1, in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor, for which the development of new biomarkers and therapeutic targets has become critical. The main cause of poor prognosis in PDAC patients is the high invasive and metastatic potential of the cancer. In the present study, we report a new signaling pathway that was found to mediate the enhanced tumor cell motility in pancreatic cancer. Semaphorin 4D (Sema4D) is a ligand known to be expressed on different cell types, and has been reported to be involved in the regulation of immune functions, epithelial morphogenesis, and tumor growth and metastasis. In this study, we revealed for the first time that the cancer tissue cells expressing Sema4D in PDAC are tumor-infiltrating lymphocytes. The overexpression of Sema4D and of its receptor, plexinB1, was found to be significantly correlated with clinical factors, such as lymph node metastasis, distant metastasis, and poor prognosis in patients with PDAC. Through in vitro analysis, we demonstrated that Sema4D can potentiate the invasiveness of pancreatic cancer cells and we identified the downstream molecules. The binding of Sema4D to plexinB1 induced small GTPase Ras homolog gene family, member A activation and resulted in the phosphorylation of MAPK and Akt. In addition, in terms of potential therapeutic application, we clearly demonstrated that the enhanced-cell invasiveness induced by Sema4D could be inhibited by knockdown of plexinB1, suggesting that blockade of plexinB1 might diminish the invasive potential of pancreatic cancer cells. Our findings provide new insight into possible prognostic biomarkers and therapeutic targets in PDAC patients.

Novel findings for the development of drug therapy for various liver diseases: Liver microsomal triglyceride transfer protein activator may be a possible therapeutic agent in non-alcoholic steatohepatitis.

The factors involved in the progression of non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH) are not fully understood and thus it is urgently needed to elucidate these factors. Steatosis is not causal in the development of NASH, but rather it sensitizes the liver to the damaging effects of second hits such that stressors innocuous to a healthy liver lead to the development of NASH in the steatotic liver. In the previous study, most of the hepatic lipid metabolite profiles were similar in the NAFL and NASH groups. However, very-low-density lipoprotein (VLDL) synthesis, especially hepatic microsomal triglyceride transfer protein (MTP) mRNA expression, was impaired in the NASH group. Moreover, NASH showed significantly higher incidence of minor alley appearance compared with NAFL, indicating the possibility of association between NASH pathogenesis and decreased congenital MTP activity. MTP is one of the enzymes that transfer triglycerides to nascent apolipoprotein B, producing VLDL and removing lipid from the hepatocyte. A growing body of literature suggests that the measurement of hepatic MTP expression may be helpful for diagnosis; and moreover, hepatic MTP activator may be a possible therapeutic agent for the treatment of NASH.

Discrimination between sclerosing cholangitis-associated autoimmune pancreatitis and primary sclerosing cholangitis, cancer using intraductal ultrasonography.

BACKGROUND AND AIM: Differentiation of sclerosing cholangitis-associated autoimmune pancreatitis (SC-AIP), primary sclerosing cholangitis (PSC) and cancer of the hilar part of the bile duct (CHB) has been challenging. The aim of the present study was to evaluate characteristic intraductal ultrasonography (IDUS) features that could be used to discriminate SC-AIP from PSC and CHB. METHODS: Six patients with SC-AIP, 10 patients with PSC and 12 patients with CHB were identified. We reviewed the following bile duct features observed using IDUS to determine their usefulness for differentiating SC-AIP from PSC and CHB: presence of symmetrical wall thickness, wall thickness, presence of homogeneous internal foci and presence of lateral mucosal lesions continuous to the hilar. RESULTS: IDUS results (SC-AIP, PSC, CHB) were as follows: wall thickness (mm), 3.7±0.9, 2.6 ±0.9, 2.8±0.0.6; presence of symmetrical wall thickness, 100% (6/6), 20% (2/10), 8.3% (1/12); presence of homogeneous internal foci, 100% (6/6), 10% (1/10), 8.3% (1/12); and presence of lateral mucosal lesions continuous to the hilar, 83.3% (5/6), 40%(4/10), 25% (3/12). Symmetrical wall thickness of the bile duct, homogeneous internal foci and lateral mucosal lesions continuous to the hilar were detected significantly more often among the patients with SC-PSC than among the patients with PSC or CHB (P<0.05). CONCLUSIONS: IDUS findings, such as symmetrical wall thickness, presence of homogeneous internal foci and presence of lateral mucosal lesions continuous to the hilar can facilitate the differential diagnosis of SC-AIP from PSC and CHB.