Impact of Istradefylline on Levodopa Dose Escalation in Parkinson's Disease: ISTRA ADJUST PD Study, a Multicenter, Open-Label, Randomized, Parallel-Group Controlled Study.

INTRODUCTION: A higher levodopa dose is a risk factor for motor complications in Parkinson's disease (PD). Istradefylline (IST) is used as adjunctive treatment to levodopa in PD patients with off episodes, but its impact on levodopa dose titration remains unclear. The objective of this study was to investigate the effect of IST on levodopa dose escalation in PD patients with wearing-off. METHODS: This was a multicenter, open-label, randomized, parallel-group controlled study (ISTRA ADJUST PD) in which PD patients experiencing wearing-off (n = 114) who were receiving levodopa 300-400 mg/day were randomized to receive IST or no IST (control). Levodopa dose was escalated according to clinical severity. The primary endpoint was cumulative additional levodopa dose, and secondary endpoints were changes in symptom rating scales, motor activity determined by a wearable device, and safety outcomes. RESULTS: The cumulative additional levodopa dose throughout 37 weeks and dose increase over 36 weeks were significantly lower in the IST group than in the control group (both p < 0.0001). The Movement Disorder Society Unified Parkinson's Disease Rating Scale Part I and device-evaluated motor activities improved significantly from baseline to 36 weeks in the IST group only (all p < 0.05). Other secondary endpoints were comparable between the groups. Adverse drug reactions (ADRs) occurred in 28.8% and 13.2% of patients in the IST and control groups, respectively, with no serious ADRs in either group. CONCLUSION: IST treatment reduced levodopa dose escalation in PD patients, resulting in less cumulative levodopa use. Adjunctive IST may improve motor function more objectively than increased levodopa dose in patients with PD. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180248.

Electrosurgical knife with the water-jet function of tip-type during endoscopic treatment injection.

Objectives: This study aimed to objectively evaluate the water-jet-functioned electrosurgical knife injection performances in a desktop experiment. Methods: Five types of water-jet-functioned electrosurgical knives, including two injection styles of sheath-type (A: DualKnife J, KD-655L; B: FlushKnife, DK2620-J-B20S; C: Splash M-Knife, DN-D2718B; D: ISSEN, SN1650-20) and tip-type (E: ORISE ProKnife, M00519361) were evaluated. These knives were compared with an injection needle (Control: SuperGrip 25G) as a control. The injection speed under constant pressure and the injection efficiency for each knife against prepared porcine stomach mucosa were evaluated. The additional clear gel injections using an injection needle were observed using an indigo blue-colored gel to evaluate the difference between the locations of water-jet holes. Results: Four types of knives, except for A, showed significantly higher water-jet speeds (A: 0.79 ± 0.03 g/20 s, B: 2.56 ± 0.05 g/20 s, C: 3.09 ± 0.06 g/20 s, D: 2.86 ± 0.05 g/20 s, and E: 1.79 ± 0.03 g/20 s) compared to that of the control (1.21 ± 0.03 g/20 s). Meanwhile, significantly higher efficacy of injection was found in the tip-type water-jet function knife, second to the injection needle (Control: 37.2% ± 35.5%, A: 20.9% ± 20.2%, B: 1.1% ± 2.2%, C: 6.2% ± 12.6%, D: 12.5% ± 15.6%, and E: 33.3% ± 32.2%). An additional injection experiment revealed that the injection with a piercing tip into the gel could achieve sufficient additional injection inside the stacked clear gel. Conclusions: The tip-type water-jet function electrosurgical knife is preferable for effective submucosal injection during endoscopic treatments.

[A geriatric case of hyperosmolar hyperglycemic state with osmotic demyelination syndrome that manifested with dysphagia].

The patient was an 84-year-old man who had been on insulin therapy for type 2 diabetes mellitus for 55 years. He had undergone bile duct stenting to avoid obstruction due to adenocarcinoma of the bile duct. The patient had suffered from fever and anorexia for two weeks, and had subsequently stopped insulin therapy. Since he showed signs of impaired consciousness, he was taken to the emergency room, and was diagnosed with a hyperosmotic hyperglycemic state (HHS) based on the following laboratory findings: blood glucose, 632 mg/dL; plasma osmolality, 391 mOsm/kg·H2O; and serum Na, 163 mEq/L, with urine ketone bodies±and sepsis (Klebsiella pneumoniae). He was therefore admitted to the hospital. His blood glucose and serum Na levels slowly improved following the administration of fluids, insulin, and antibiotics. The patient's consciousness disturbance also improved. However, on the third day after admission, dysphagia was newly observed when the patient resumed eating, and swallowing endoscopy revealed a delayed gag reflex and pharyngeal retention of saliva. Cranial magnetic resonance imaging showed a high-intensity area in the central pontine, which was considered to be caused by osmotic demyelination syndrome (ODS). The patient's oral intake ability recovered with swallowing rehabilitation. ODS is a rare complication of HHS. We report a case of HHS with ODS, in which the patient's chief complaint was dysphagia, which should be distinguished from other diseases.

Evaluating the impact of adjunctive istradefylline on the cumulative dose of levodopa-containing medications in Parkinson's disease: study protocol for the ISTRA ADJUST PD randomized, controlled study.

BACKGROUND: Levodopa remains the most effective symptomatic treatment for Parkinson's disease (PD) more than 50 years after its clinical introduction. However, the onset of motor complications can limit pharmacological intervention with levodopa, which can be a challenge when treating PD patients. Clinical data suggest using the lowest possible levodopa dose to balance the risk/benefit. Istradefylline, an adenosine A2A receptor antagonist indicated as an adjunctive treatment to levodopa-containing preparations in PD patients experiencing wearing off, is currently available in Japan and the US. Preclinical and preliminary clinical data suggested that adjunctive istradefylline may provide sustained antiparkinsonian benefits without a levodopa dose increase; however, available data on the impact of istradefylline on levodopa dose titration are limited. The ISTRA ADJUST PD study will evaluate the effect of adjunctive istradefylline on levodopa dosage titration in PD patients. METHODS: This 37-week, multicenter, randomized, open-label, parallel-group controlled study in PD patients aged 30-84 years who are experiencing the wearing-off phenomenon despite receiving levodopa-containing medications ≥ 3 times daily (daily dose 300-400 mg) began in February 2019 and will continue until February 2022. Enrollment is planned to attain 100 evaluable patients for the efficacy analyses. Patients will receive adjunctive istradefylline (20 mg/day, increasing to 40 mg/day) or the control in a 1:1 ratio, stratified by age, levodopa equivalent dose, and presence/absence of dyskinesia. During the study, the levodopa dose will be increased according to symptom severity. The primary study endpoint is the comparison of the cumulative additional dose of levodopa-containing medications during the treatment period between the adjunctive istradefylline and control groups. Secondary endpoints include changes in efficacy rating scales and safety outcomes. DISCUSSION: This study aims to clarify whether adjunctive istradefylline can reduce the cumulative additional dose of levodopa-containing medications in PD patients experiencing the wearing-off phenomenon, and lower the risk of levodopa-associated complications. It is anticipated that data from ISTRA ADJUST PD will help inform future clinical decision-making for patients with PD in the real-world setting. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031180248 ; registered 12 March 2019.

Frequency of FMR1 Premutation Alleles in Patients with Undiagnosed Cerebellar Ataxia and Multiple System Atrophy in the Japanese Population.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder caused by FMR1 premutation expansion of CGG repeats. FXTAS can be misdiagnosed with many neurodegenerative disorders manifesting with cerebellar ataxias owing to their overlapping clinical and radiological features. The frequency of the FMR1 premutation allele in Japan has not been fully determined. Herein, we aimed to determine the frequency of FMR1 premutation alleles in Japanese patients with undiagnosed cerebellar ataxia and multiple system atrophy, using repeat-primed PCR in 186 patients with adult onset of undiagnosed cerebellar ataxia and 668 patients with multiple system atrophy, to identify expanded CGG repeats as well as to detect AGG interruptions within the expanded alleles. The size of expansions was estimated using fragment length analysis of PCR products obtained by conventional PCR employing a pair of unique primers flanking the repeat sequence. We identified FMR1 premutation alleles in three male patients. One patient revealed 84 repeat units with one AGG interruption and another patient showed 103 repeat units. Both had presented with sporadic cerebellar ataxia, giving an estimated frequency of 3.7% among Japanese male patients with sporadic cerebellar ataxia with age at onset above 50 years. One patient with the clinical diagnosis of multiple system atrophy harbored 60 repeat units with four AGG interruptions. FMR1 intermediate alleles were observed in two males and one female among the multiple system atrophy patients. We found that genetic tests for FMR1 premutation should be considered in Japanese male patients with cerebellar ataxia with the age at onset above 50 years.

Cytological scoring for pancreatic specimens obtained by endoscopic ultrasound-guided fine needle aspiration.

OBJECTIVE: Cytological diagnosis of pancreatic specimens obtained by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is often challenging because of the small sample size or well-differentiated adenocarcinoma with weak cytological atypia. Therefore, the sensitivity and specificity of cytological diagnosis for pancreatic cancer should be improved. Hence, we aimed to clarify the utility of cytological scoring to distinguish malignant from benign lesions for cytological diagnosis of pancreatic EUS-FNA specimens. METHODS: Seven reviewers, including four cytotechnologists and three medical doctors, evaluated 20 morphological indices in pancreatic specimens obtained by EUS-FNA (malignant, n = 111; benign, n = 31). Statistical analyses were performed using Fisher's exact test, logistic regression analysis, the area under the receiver operating characteristic curve, and Youden index. RESULTS: Among the 20 indices, there was a high incidence rate (>40%) of the following 13 indices in malignant cases: irregular structure, hyperchromatic nucleus, irregular cell polarity, unclear cell boundaries, nuclear membrane thickening, anisonucleosis, overlapping, irregular nuclei, high nuclear-cytoplasmic ratio, binding decline, the simultaneous appearance of malignant and benign cells, enlarged nucleoli, and background necrosis. When we diagnosed pancreatic specimens using these 13 cytological indices, the cut-off value of 8/9 showed the highest Youden index (0.950) as well as high sensitivity and specificity in distinguishing malignant from benign specimens (98% and 97%, respectively). CONCLUSION: Thirteen cytological indices showed high sensitivity and specificity in differentiating malignant and benign lesions using pancreatic EUS-FNA samples. All 13 indices were important for diagnosing malignancy in the pancreatic cytology smear of EUS-FNA. Further validation studies are required.

Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy.

Accumulated experience supports the efficacy of allogenic haematopoietic stem cell transplantation in arresting the progression of childhood-onset cerebral form of adrenoleukodystrophy in early stages. For adulthood-onset cerebral form of adrenoleukodystrophy, however, there have been only a few reports on haematopoietic stem cell transplantation and the clinical efficacy and safety of that for adulthood-onset cerebral form of adrenoleukodystrophy remain to be established. To evaluate the clinical efficacy and safety of haematopoietic stem cell transplantation, we conducted haematopoietic stem cell transplantation on 12 patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy in a single-institution-based prospective study. Through careful prospective follow-up of 45 male adrenoleukodystrophy patients, we aimed to enrol patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy at early stages. Indications for haematopoietic stem cell transplantation included cerebral form of adrenoleukodystrophy or cerebello-brainstem form of adrenoleukodystrophy with Loes scores up to 13, the presence of progressively enlarging white matter lesions and/or lesions with gadolinium enhancement on brain MRI. Clinical outcomes of haematopoietic stem cell transplantation were evaluated by the survival rate as well as by serial evaluation of clinical rating scale scores and neurological and MRI findings. Clinical courses of eight patients who did not undergo haematopoietic stem cell transplantation were also evaluated for comparison of the survival rate. All the patients who underwent haematopoietic stem cell transplantation survived to date with a median follow-up period of 28.6 months (4.2-125.3 months) without fatality. Neurological findings attributable to cerebral/cerebellar/brainstem lesions became stable or partially improved in all the patients. Gadolinium-enhanced brain lesions disappeared or became obscure within 3.5 months and the white matter lesions of MRI became stable or small. The median Loes scores before haematopoietic stem cell transplantation and at the last follow-up visit were 6.0 and 5.25, respectively. Of the eight patients who did not undergo haematopoietic stem cell transplantation, six patients died 69.1 months (median period; range 16.0-104.1 months) after the onset of the cerebral/cerebellar/brainstem lesions, confirming that the survival probability was significantly higher in patients with haematopoietic stem cell transplantation compared with that in patients without haematopoietic stem cell transplantation (P = 0.0089). The present study showed that haematopoietic stem cell transplantation was conducted safely and arrested the inflammatory demyelination in all the patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy when haematopoietic stem cell transplantation was conducted in the early stages. Further studies are warranted to optimize the procedures of haematopoietic stem cell transplantation for adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy.

Severe Acute Pancreatitis in Autopsies Associated With Surgeries and Severe Inflammatory Diseases.

OBJECTIVE: We clarified clinicopathological characteristics of acute pancreatitis in terminal patients. METHODS: Pathological changes in the entire pancreas from serial autopsies (N = 183) classified lesions into the following 3 categories: focal neutrophil infiltration, focal necrotizing pancreatitis, and diffuse necrotizing pancreatitis. The former two are possible precursors of diffuse necrotizing pancreatitis. Immunohistochemical staining was performed to analyze pancreatic stellate cells and inflammatory cells. RESULTS: There were pathologically acute pancreatitis in 45 patients (24.6%), and no patients were diagnosed with it before autopsy. Focal neutrophil infiltration was present in 22 cases, focal necrotizing pancreatitis in 18 cases, and diffuse necrotizing pancreatitis in 5 cases. Severe inflammatory disease and surgery were associated with acute pancreatitis. Sepsis due to viral or bacterial infection was the most common cause of acute pancreatitis. Patients with diffuse necrotizing pancreatitis showed low white blood cell counts, while amylase levels were not increased. Increase in α-smooth muscle actin and nestin-positive stellate cell numbers in acute pancreatitis was correlated to increase in numbers of CD34-positive vascular endothelium, CD68- or CD163-positive macrophages, CD138-positive plasmacytes, CD3-positive T lymphocytes, and myeloperoxidase-positive leucocytes. CONCLUSIONS: Necrotizing pancreatitis without typical clinical signs was frequently detected in autopsy samples. Clinicians must be mindful of necrotizing pancreatitis in terminal patients.

[Acyclovir encephalopathy in a peritoneal dialysis patient despite adjusting the dose of oral acyclovir: a case report].

We report a case of acyclovir encephalopathy in a 77-year-old man who was introduced to peritoneal dialysis three years earlier. He developed herpes zoster and was treated with acyclovir (ACV) at 800 mg daily per oral. Two days later, he developed consciousness disturbance, hallucinations and asterixis. Acyclovir was stopped and continuous ambulatory peritoneal dialysis (CAPD) was switched to hemodialysis, which resulted in the resolution of his symptoms. Because the optimal dose of ACV varies among individuals depending on the bioavailability of ACV and metabolic enzyme activity, ACV encephalopathy can occur even when the acyclovir dose is modified according to the renal function of the affected patient. Because CAPD provides a poorer ACV clearance than hemodialysis, CAPD patients tend to have a higher risk of developing ACV encephalopathy and to recover more slowly. If CAPD patients develop ACV encephalopathy, a temporary change in the type of dialysis to hemodialysis should be considered.

Overexpression of carbohydrate sulfotransferase 15 in pancreatic cancer stroma is associated with worse prognosis.

Carbohydrate sulfotransferase 15 (CHST15) synthesizes matrix proteoglycan that regulates various pathogenic mediators and contributes to tissue remodeling and fibrosis during injury. CHST15 has been reported to promote tumor growth and invasion in various types of cancer. Our previous study reported the safety and efficacy of EUS-guided fine-needle injection (EUS-FNI) of STNM01, a double-stranded RNA oligonucleotide that specifically represses CHST15, for use in patients with pancreatic cancer. The present study aimed to determine the expression and clinicopathological characteristics of CHST15 in pancreatic cancer. Immunohistochemical staining was performed for CHST15 using pancreatic tissues from 64 patients (28 males and 36 females; age, 69.0±9.6 years) with pancreatic cancer who underwent surgery. For the evaluation of fibrosis, two categories were defined (mature and immature), based on the existence of collagen, myxoid stroma and fibroblasts, using hematoxylin and eosin specimens. The positive percentage of CHST15 was quantified, patients were divided into two groups according to high and low CHST15 expression in both the cancer and stroma tissues, and the association between CHST15 expression in cancer cells and the stroma was analyzed. Additionally, the present study analyzed the association between CHST15 expression and clinicopathological information, including overall and disease-free survival. The expression levels of CHST15 were detected in the cytoplasm of pancreatic cancer cells and fibroblasts in the cancer stroma. CHST15 expression in cancer cells was not identified to be associated with overall survival (P=0.52). However, patients with high CHST15 expression in the stroma exhibited worse overall survival compared with patients with low CHST15 expression (P=0.02). CHST15 expression in the stroma exhibited a positive association with that in cancer cells (P=0.01). High CHST15 expression in the stroma group was associated with a higher incidence of immature fibrosis (P=0.02) compared with mature fibrosis. CHST15 expression in cancer cells was associated with Union for International Cancer Control stage (P=0.02) and invasive front. Age and sex were not associated with CHST15 expression. The present study revealed that overexpression of CHST15 in stroma was associated with worse overall survival and immature fibrosis. Overexpression of CHST15 in cancer cells was associated with tumor stage. These results suggested that targeting therapy for CHST15 may be useful for stroma fibroblasts and cancer cells.

Association Between Pancreatic Cystic Lesions and High-grade Intraepithelial Neoplasia and Aging: An Autopsy Study.

OBJECTIVES: This study aimed to clarify clinicopathological features of pancreatic cysts. METHODS: Pancreata from 280 autopsies (median, 83 years; male, 146; female, 134) were sectioned every 5 mm. Cysts (<10 mm) were diagnosed as a simple cyst or low-grade, intermediate-grade, or high-grade dysplasia. RESULTS: We found 236 cysts in 93 patients (33.2%). The number and diameter of cysts increased according to the age. Of the 236 cysts, 9 (3.8%) were with high-grade dysplasia. Cysts with high-grade dysplasia arose in the pancreata of older patients with larger numbers of cysts. In contrast, 15 noncystic lesions with high-grade dysplasia were also detected. Hence, in total, 24 high-grade dysplastic lesions in 15 patients (5.4%) were noted. Of the 15 patients with high-grade dysplastic lesions, in 10 patients, the condition was accompanied by pancreatic cysts, whereas 5 patients did not have any cysts in the pancreas; therefore, patients with cyst showed higher incidence of high-grade dysplasia (10.8%; P = 0.0047) than patients without cyst (2.7%). All cysts with high-grade dysplasia were located in the branch duct of the pancreatic head/body, whereas 20% of noncystic lesions with high-grade dysplasia were located in the main pancreatic duct. CONCLUSIONS: Cystic lesions with high-grade dysplasia may have different characteristics compared with noncystic high-grade dysplasia.

Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease.

Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.

Abnormal immunolabelling of SMAD4 in cell block specimens to distinguish malignant and benign pancreatic cells.

BACKGROUND: Accurate diagnosis of malignant and benign pancreatic lesions can be challenging, especially with endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) samples that are small and/or degraded. In the present study, we determined how to best evaluate abnormal SMAD4 expression by immunohistochemical staining on cell block specimens from EUS-FNA samples. RESULTS: In surgically resected pancreas, when abnormal SMAD4 immunolabelling was evaluated as negative SMAD4 expression, the sensitivity was low (33%), but when it was evaluated as decreased SMAD4 expression, the sensitivity improved (53%). Specificity and positive predictive value were high for both evaluations. There were no false-positive cases. In cell block specimens, decreased SMAD4 expression showed 47% sensitivity and 72% specificity, while negative SMAD4 expression showed lower sensitivity (20%) and higher specificity (100%). Both evaluations in cell block specimens showed lower sensitivity and specificity compared to resected specimens. False-positive and -negative rates were higher for cell blocks than for resected specimens. CONCLUSIONS: Decreased SMAD4 immunolabelling provided improved sensitivity as compared to negative SMAD4 immunolabelling; therefore, it is important to compare SMAD4 expression in a sample to its expression in normal cells. Abnormal SMAD4 labelling showed low sensitivity and high specificity; therefore, SMAD4 staining using EUS-FNA samples might be helpful to detect malignancies that possess SMAD4 gene abnormalities.

Optic neuropathy and decorticate-like posture as presenting symptoms of Bickerstaff's brainstem encephalitis: A case report and literature review.

A 72-year-old woman with a 10-day history of bilateral visual impairment after respiratory tract infection showed decorticate-like posture and progressive deterioration of consciousness leading to coma. Ophthalmoplegia was also noted and anti-GQ1b antibodies were positive, consistent with Bickerstaff's brainstem encephalitis. After intravenous immunoglobulin and steroid pulse therapy, her consciousness gradually improved. However, severe visual impairment at the level of hand motion was noticed, which gradually normalized after second steroid pulse therapy. Atypical findings including optic neuropathy and decorticate-like posture can be seen in patients with Bickerstaff's brainstem encephalitis, and early diagnosis is essential for adequate management.

Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy.

Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.

Effects of EUS-guided intratumoral injection of oligonucleotide STNM01 on tumor growth, histology, and overall survival in patients with unresectable pancreatic cancer.

BACKGROUND AND AIMS: Carbohydrate sulfotransferase 15 (CHST15) promotes tumor growth and invasion and is considered to be an emergent therapeutic target for pancreatic cancer. The aim of this study was to evaluate the safety and efficacy of EUS-guided fine-needle injection (EUS-FNI) of STNM01, the double-stranded RNA oligonucleotide that specifically represses CHST15, for use in patients with pancreatic cancer. METHODS: Six patients with unresectable pancreatic cancer, treated at Tokyo Metropolitan Geriatric Hospital, were used in this open-labeled, investigator-initiated trial. A total of 16 mL STNM01 (250 nM) was injected into the tumor through EUS-FNI. The study's primary endpoint was safety, with a secondary endpoint of tumor response 4 weeks after the initial injection. Some patients received a series of infusions as extensions. The local expression of CHST15 and overall survival (OS) were also evaluated. RESULTS: There were no adverse events. The mean tumor diameter changed from 30.7 to 29.3 mm 4 weeks after injection. Four patients exhibited necrosis of tumor in biopsy specimens. CHST15 was highly expressed at baseline, with 2 patients showing large reductions of CHST15 at week 4. The mean OS of these 2 patients was 15 months, whereas it was 5.7 months for the other 4 patients. CONCLUSIONS: EUS-FNI of STNM01 in pancreatic cancer is safe and feasible. The CHST15 reduction could predict tumor progression and OS. Injections of STNM01 during the beginning of treatment may reduce CHST15 and warrants further investigation.

Two Cases of Liver Abscesses Derived from Dental Disease in Patients with Alcoholic Chronic Pancreatitis.

Among the etiologies of pyogenic liver abscess (PLA), bacterial spread from the biliary tract or portal flow is the major cause, while the onset of PLA due to arterial bacterial transmission is rare. We herein report two cases of PLA thought to be caused by arterial transmission from dental disease. In both cases, there was benign biliary stricture as a result of alcoholic chronic pancreatitis, although normal oral flora was detected as the causative bacteria and oral hygiene was poor in both patients. We presumed that the origin of PLA was dental disease and successfully treated the patients with percutaneous drainage, antibiotics and dental procedures.

Risk factors for post-ERCP pancreatitis in wire-guided cannulation for therapeutic biliary ERCP.

BACKGROUND: Wire-guided cannulation (WGC) was reported to decrease post-ERCP pancreatitis (PEP), but risk factors for PEP in WGC are not fully elucidated. OBJECTIVE: To evaluate the incidence and risk factors of PEP in WGC. DESIGN: Single-center retrospective study. SETTING: Academic center. PATIENTS: A total of 800 consecutive patients with a native papilla. INTERVENTIONS: Biliary therapeutic ERCP by using WGC. MAIN OUTCOME MEASUREMENTS: The rate of PEP and its risk factors. RESULTS: Biliary cannulation was successful by using WGC alone in 70.5%, and the final cannulation rate was 96.1%. Unintentional guidewire insertion and contrast material injection into the pancreatic duct (PD) during cannulation occurred in 55.3% and 21.8%, respectively. The incidence of PEP was 9.5% (mild 5.6%, moderate 2.9%, severe 1.0%). Multivariate analysis revealed a common bile duct (CBD) diameter of <9 mm (odds ratio [OR] 2.03; P = .006) and unintentional guidewire insertion into the PD (OR 2.25; P = .014) as risk factors for PEP. PD opacification was not a risk factor for PEP (OR 1.15; P = .642), but the incremental increase of the PEP rate was seen in patients with CBDs <9 mm: 4.6% without any PD manipulation, 8.3% with contrast material alone, 16.9% with guidewire alone, and 22.1% with both contrast material and guidewire. LIMITATIONS: Retrospective design in a single center. CONCLUSION: Unintentional PD manipulation was not uncommon in WGC. Guidewire insertion into the PD and a small CBD were risk factors for PEP in biliary therapeutic ERCP with the use of WGC.

Total cholesterol level for assessing pancreatic insufficiency due to chronic pancreatitis.

BACKGROUND/AIMS: To determine the nutritional markers important for assessing the degree of pancreatic insufficiency due to chronic pancreatitis in routine clinical practice. METHODS: A total of 137 patients with chronic pancreatitis were followed up for more than 1 year. They were divided into two groups: a pancreatic diabetes mellitus (DM) group, consisting of 47 patients undergoing medical treatment for DM of pancreatic origin, and a nonpancreatic DM group, consisting of 90 other patients (including 86 patients without DM). Serum albumin, prealbumin, total cholesterol, cholinesterase, magnesium, and hemoglobin were compared between the two groups. RESULTS: The total cholesterol was significantly lower in the pancreatic than the nonpancreatic DM group (164 mg/dL vs 183 mg/dL, respectively; p=0.0028). Cholinesterase was significantly lower in the former group (263 U/L vs 291 U/L, respectively; p=0.016). Among the 37 patients with nonalcoholic pancreatitis, there was no difference in the cholinesterase levels between the pancreatic and nonpancreatic (296 U/L vs 304 U/L, respectively; p=0.752) DM groups, although cholesterol levels remained lower in the former (165 mg/dL vs 187 mg/dL, respectively; p=0.052). CONCLUSIONS: Cholinesterase levels are possibly affected by concomitant alcoholic liver injury. The total cholesterol level should be considered when assessing pancreatic insufficiency due to chronic pancreatitis.

Possibilities of interventional endoscopic ultrasound.

Since endoscopic ultrasound (EUS) was developed in the 1990s, EUS has become widely accepted as an imaging tool. EUS is categorized into radial and linear in design. Radial endoscopes provide cross-sectional imaging of the mediastinum, gastrointestinal tract, liver, spleen, kidney, adrenal gland, and pancreas, which has highly accuracy in the T and N staging of esophageal, lung, gastric, rectal, and pancreatic cancer. Tumor staging is common indication of radial-EUS, and EUS-staging is predictive of surgical resectability. In contrast, linear array endoscope uses a side-viewing probe and has advantages in the ability to perform EUS-guides fine needle aspiration (EUS-FNA), which has been established for cytologic diagnosis. For example, EUS-FNA arrows accurate nodal staging of esophageal cancer before surgery, which provides more accurate assessment of nodes than radial-EUS imaging alone. EUS-FNA has been also commonly used for diagnose of pancreatic diseases because of the highly accuracy than US or computed tomography. EUS and EUS-FNA has been used not only for TNM staging and cytologic diagnosis of pancreatic cancer, but also for evaluation of chronic pancreatitis, pancreatic cystic lesions, and other pancreatic masses. More recently, EUS-FNA has developed into EUS-guided fine needle injection including EUS-guided celiac plexus neurolysis, celiac plexus block, and other "interventional EUS" procedures. In this review, we have summarized the new possibilities offered by "interventional EUS".