Inhibition of ß-Catenin Activity Abolishes LKB1 Loss-Driven Pancreatic Cystadenoma in Mice.

Pancreatic cancer (PC) is the seventh leading cause of cancer death worldwide, and remains one of our most recalcitrant and dismal diseases. In contrast to many other malignancies, there has not been a significant improvement in patient survival over the past decade. Despite advances in our understanding of the genetic alterations associated with this disease, an incomplete understanding of the underlying biology and lack of suitable animal models have hampered efforts to develop more effective therapies. LKB1 is a tumor suppressor that functions as a primary upstream kinase of adenine monophosphate-activated protein kinase (AMPK), which is an important mediator in the regulation of cell growth and epithelial polarity pathways. LKB1 is mutated in a significant number of Peutz-Jeghers syndrome (PJS) patients and in a small proportion of sporadic cancers, including PC; however, little is known about how LKB1 loss contributes to PC development. Here, we report that a reduction in Wnt/ß-catenin activity is associated with LKB1 tumor-suppressive properties in PC. Remarkably, in vivo functional analyses of ß-catenin in the Pdx-1-Cre LKB1L/L ß-cateninL/L mouse model compared to LKB1 loss-driven cystadenoma demonstrate that the loss of ß-catenin impairs cystadenoma development in the pancreas of Pdx-1Cre LKB1L/L mice and dramatically restores the normal development and functions of the pancreas. This study further determined the in vivo and in vitro therapeutic efficacy of the ß-catenin inhibitor FH535 in suppressing LKB1 loss-driven cystadenoma and reducing PC progression that delineates the potential roles of Wnt/ß-catenin signaling in PC harboring LKB1 deficiency.

Inactivation of APC Induces CD34 Upregulation to Promote Epithelial-Mesenchymal Transition and Cancer Stem Cell Traits in Pancreatic Cancer.

Pancreatic cancer (PC) is a highly lethal malignancy due to the cancer routinely being diagnosed late and having a limited response to chemotherapy. Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic malignant tumor, representing more than 85% of all pancreatic cancers. In the present study, we characterized the phenotypes of concomitant P53 and APC mutations in pancreatic neoplasms driven by the oncogene KRAS in genetically modified mice (GEMM). In this GEMM setting, APC haploinsufficiency coupled with P53 deletion and KRASG12D activation resulted in an earlier appearance of pancreatic intraepithelial neoplasia (PanIN) lesions and progressed rapidly to highly invasive and metastatic PDAC. Through a microarray analysis of murine PDAC cells derived from our APC-deficient PDAC model, we observed that APC loss leads to upregulated CD34 expression in PDAC. CD34 is a member of a family of single-pass transmembrane proteins and is selectively expressed in hematopoietic progenitor cells, vascular endothelial cells, interstitial precursor cells, and various interstitial tumor cells. However, the functional roles of CD34 in pancreatic cancer remain unclear. Thus, in this study, we explored the mechanisms regarding how CD34 promotes the deterioration of pancreatic malignancy. Our results demonstrated that the increased expression of CD34 induced by APC inactivation promotes the invasion and migration of PDAC cells, which may relate to PDAC metastasis in vivo. Collectively, our study provides first-line evidence to delineate the association between CD34 and the APC/Wnt pathway in PDAC, and reveals the potential roles of CD34 in PDAC progression.

Loss of the transcriptional repressor TGIF1 results in enhanced Kras-driven development of pancreatic cancer.

BACKGROUND: The TG-interacting factor 1 (TGIF1) gene, which encodes a nuclear transcriptional corepressor of the TGFß1/Smad signaling pathway, has been implicated in the pathogenesis of various types of human cancer; however, its role in pancreatic ductal adenocarcinoma (PDAC) has yet to be elucidated. METHODS: The expression of TGIF1 in human and murine PDAC specimens were detected by IHC analysis. The functions of TGIF1 in in vivo PDAC growth, dissemination, and metastasis were assessed using conditional inactivation of TGIF1 in well-established autochthonous mouse models of PDAC. Primary cells from TGIF1 null or wild type PDAC mice were examined by assays for cell proliferation, migration, invasion, soft agar and xenograft tumorigenesis. Gene expression profiling, pathway analyses, epigenetic changes associated with TGIF1 loss, and in vitro and in vivo effects of 4-MU were assessed. RESULTS: Conditional deletion of TGIF1 in the mouse pancreas had no discernible effect on pancreatic development or physiology. Notably, TGIF1 loss induced KrasG12D-driven PDAC models exhibited shorter latency and greater propensity for distant metastases. Deciphering the molecular mechanisms highlighted the TGIF1 loss-induced activation of the hyaluronan synthase 2 (HAS2)-CD44 signaling pathway and upregulation of the immune checkpoint regulator PD-L1 to facilitate the epithelial-mesenchymal transition (EMT) and tumor immune suppression. We also founded that TGIF1 might function as an epigenetic regulator and response for aberrant EMT gene expression during PDAC progression. CONCLUSIONS: Our results imply that targeting the HAS2 pathway in TGIF1 loss of PDAC could be a promising therapeutic strategy for improving the clinical efficacy against PDAC metastasis.

Predictors and long-term outcome of seizures after bacterial brain abscess.

BACKGROUND: Seizures are one of the most important neurological complications of bacterial brain abscesses. A better understanding of the risk factors of seizures following bacterial brain abscesses is needed to predict those who will require treatment. METHODS: A total of 205 patients were enrolled in this 22-year retrospective study. Prognostic variables were analysed based on Cox's proportional hazards model after a minimum of 18 months of follow-up. RESULTS: Seizures occurred in 48 patients who had bacterial brain abscesses, including acute symptomatic seizures in 17% (35/205) and unprovoked seizures in 6.4% (13/205). Altogether, 27 patients had early seizures and 21 had late seizures. The overall mortality rate in the seizure patients was 23% (11/48) and seven patients progressed to epilepsy. CONCLUSION: Cox's proportional hazards model demonstrated that valvular heart diseases as the underlying diseases and the presence of a fronto-parietal distribution of bacterial brain abscess were independently predictive of seizures, and the presence of late seizures was predictive of developing epilepsy. Most first seizures occurred within 3 y after bacterial brain abscesses.

Cerebrotendinous xanthomatosis patients with and without parkinsonism: clinical characteristics and neuroimaging findings.

Parkinsonism in cerebrotendinous xanthomatosis (CTX) is rare. There are no published studies with imaging findings of dopamine transporter using (99m)Tc-[2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo [3,2,1] oct-2-yl] methyl] (2-mercaptoethyl) amino] ethyl] amino]-ethanethiolato(3-)-N2,N2,S2,S2]oxo-[1R-(exo-exo)] ((99m)Tc-TRODAT-1) SPECT in CTX patients. This report is on the clinical details of five genetically-proven CTX patients (two with and three without parkinsonism). Imaging findings using cranial magnetic resonance (MR) imaging and (99m)Tc-TRODAT-1 SPECT are also shown. Clinical correlation of neuroimaging findings and clinical presentations was made. A literature review of the clinical and neuroimaging features of eight CTX patients with parkinsonism reported in the English literature is also presented. The parkinsonian features of our two cases and the other eight reported cases occurred before the age of 50 years. The MR imaging study showed variable findings, in which, besides the common diffuse cerebral and cerebellar white matter lesions shown in CTX, several focal brain lesions were also noted. Of the focal lesions, substantia nigra abnormalities were seen only in the two cases with parkinsonism. The (99m)Tc-TRODAT-1 SPECT study showed different degrees of unilateral or bilateral abnormalities in the striatal binding in both visual and semiquantitative assessments. parkinsonism can be one of the neurologic presentations of CTX. Even though abnormal findings of the substantia nigra were detected in both of our CTX patients with parkinsonism, basal ganglion lesions have not been uniformly described in MR imaging findings of reported CTX patients with parkinsonism. (99m)Tc-TRODAT-1 SPECT study can be of value in the detection of striatal involvement, and the study results also suggest pre-synaptic dopamine neuron involvement in CTX patients with parkinsonism.

Evaluation of the pathophysiology of classical trigeminal neuralgia by blink reflex study and current perception threshold testing.

We recruited 49 patients with classical trigeminal neuralgia (TN) according to the latest guidelines of the International Classification of Headache Disorders, and divided them into an acute (30 days onset; 36 patients) group. We used blink reflex study and current perception threshold (CPT) testing to evaluate the painful facial areas and contralateral non-painful areas of patients with classical TN. CPT 5 Hz examinations, which correlate with unmyelinated fiber function, showed significantly decreased CPTs in the acute stage (11.62 +/- 6.99 vs. 18.69 +/- 9.66, P = 0.025), but significantly increased CPTs in the chronic stage (26.67 +/- 18.65 vs. 19.69 +/- 13.70, P = 0.010) on the painful side when compared with the contralateral non-painful side. However, CPTs at 250 Hz (Adelta) and 2000 Hz (Abeta) examinations did not show significant differences between the painful and non-painful sides. In contrast, only three (3/49) patients showed an abnormal trigeminal nerve stimulation on the ipsilateral painful side by blink reflex study. The findings suggest that classical TN is not a simple large-myelinated nerve fiber dysfunction but a more complex process with a main dysfunction of unmyelinated nerve fibers.

Prediction, clinical characteristics and prognosis of intracerebral hemorrhage in hepatocellular carcinoma patients with intracerebral metastasis.

The clinical characteristics of intracerebral hemorrhage (ICH) in hepatocellular carcinoma (HCC) patients with intracerebral metastasis (IcM) have not been reported on extensively. We compared the clinical characteristics between patients with ICH (w-ICH, 18 patients) and without ICH (wo-ICH, 24 patients) in HCC patients with IcM. Using multivariate logistic regression, only habitual alcohol consumption is a significant predictor of ICH in HCC patients with IcM (adjusted odds ratio [OR]=4.7, 95% CI=1.26-17.71, p=0.022). Patients with ICH also had lower Glasgow Coma Scale scores at the time of admission (p=0.032) and lower incidence of infratentorial metastasis (p=0.014). Using correlation analysis, only blood platelet count on admission was positively correlated with survival duration after the diagnosis of IcM in the wo-ICH group (p=0.000) but not in the w-ICH group.

Clinical characteristics of spinal involvement in hepatocellular carcinoma.

PURPOSE: To analyze the clinical characteristics of hepatocellular carcinoma (HCC) with spinal metastasis. METHODS: During a period of 14 years, 42 HCC patients with cranial and/or spinal metastasis were identified. Among them, 12 had spinal involvement and thus were included for study. The clinical, laboratory and neuroimaging data of these 12 cases were analyzed. RESULTS: The 12 cases were all male, aged 36-65 years. The time interval from the diagnosis of HCC to the finding of spinal involvement was 0-38 months. Among these 12 cases, four had the features of spinal involvement in the initial presentation of their HCC. Low back pain was the most common symptom followed by weakness and numbness in the lower limbs. A serum biochemical study did not show unique findings. All 12 cases died within nine months after the diagnosis of the HCC spinal involvement. CONCLUSIONS: 28.6% (12/42) of the HCC patients with nervous system metastasis had spinal involvement and the exact incidence rate can be increased by more extensive neuroimaging studies. Viral hepatitis and liver cirrhosis are common preceding events in patients with HCC with spinal involvement. T- and L-spine are the most commonly involved segments and back pain is the most common complaint in patients with HCC with spinal metastasis. The prognosis in this group of patients is grave and most of the patients died soon after the development the HCC's spinal involvement. No specific biomarker can predict the development of spinal involvement in HCC patients and diagnostic consideration can only be emphasized, especially in HCC hyperendemic areas such as Taiwan.

Clinical characteristics of fusobacterial brain abscess.

We retrospectively reviewed 122 patients with culture-proven bacterial brain abscesses (BBA) at our hospital over a period of 20 years and identified seven fusobacterial brain abscess patients. Here we describe the therapeutic experience in fusobacterial BBA cases and compare the clinical features of patients with single pathogen infection between fusobacterial and non-fusobacterial brain abscesses. Fusobacterium spp. accounted for 6% of the implicated pathogens of monomicrobial BBA. All seven fusobacterial brain abscess patients contracted the infection spontaneously, and two cases had important preceding events. F. nucleatum was the commonest one of the species described. Clinical presentations and laboratory data of these seven patients were similar to those of non-fusobacterial BBA, and in these patients the diagnosis was only confirmed by positive culture results. All seven patients were successfully treated with combined surgical and antimicrobial therapy. Although the average age tends to be older and there is a higher prevalence of multiloculated brain abscesses in patients with this type of BBA, the therapeutic outcome can be favorable with early diagnosis and prompt treatment.

Clinical characteristics of post-neurosurgical Klebsiella pneumoniae meningitis in adults and a clinical comparison to the spontaneous form in a Taiwanese population.

A total of 46 patients (nine post-neurosurgical, 37 spontaneous) with adult bacterial meningitis (ABM) caused by Klebsiellapneumoniae infection were included in this study. The nine patients in the post-neurosurgical K. pneumoniae ABM group (seven male, two female) had a mean age of 48.9 years. Two patients in this group also had diabetes mellitus (DM) and one had liver disease. The most common presentation of patients in post-neurosurgical K. pneumoniae ABM group was fever (nine patients), followed by altered consciousness (seven patients) and hydrocephalus (six patients). With medical and/or surgical treatment, a mortality of 22.2% (2/9) occurred. Compared to patients who had spontaneous K. pneumoniae ABM, those with the post-neurosurgical form had a lower incidence of community-acquired infection, seizure and DM, but had a higher incidence of leukocytosis, hydrocephalus, cerebrospinal fluid leak and bacterial strains with extended-spectrum beta-lactamase. Univariate analysis found these clinical differences to be statistically significant, however they were not significant on multivariate analysis. This study reveals that there are clinical differences between the post-neurosurgical and spontaneous presentations of K. pneumoniae ABM.