[A Case of Adenosquamous Carcinoma of Pancreas Treated with Conversion Surgery after Systemic Chemotherapy].

CASE: A man in his 60s reported upper abdominal pain; close examination revealed a tumor in the body-tail of the pancreas that was suspected to be infiltrating the stomach. Multiple liver lesions(S3, S4)were also detected. Histological examination by EUS-FNA showed poorly-differentiated carcinoma; thus, this case was diagnosed with unresectable pancreatic cancer with liver metastases(cT3, cN1[No. 7], cM1[P0, H1], cStage Ⅳ: JPS 7th). After 2 kinds of systemic chemotherapy(9 courses of GEM plus nab-PTX and 9 courses of modified FOLFIRINOX), obvious distant metastases or local progression did not appear and conversion surgery was scheduled. Although a metastatic lesion was identified at S5 of the liver just before the surgery, it was assumed that an R0 resection could be achieved; therefore, the operation(distal pancreatectomy with combined proximal gastrectomy, left adrenalectomy, lymph node dissection, partial hepatectomy of S5, and cholecystectomy)was performed. Histopathological examination showed squamous metaplasia of the epithelial tissue combined with glandular formation. This case was, thus, diagnosed as adenosquamous carcinoma of pancreas. This patient was discharged 90 days after the operation. The patient is still alive 2 years and 2 months since the first diagnosis.

Characterization of the Pathogenicity of Streptococcus intermedius TYG1620 Isolated from a Human Brain Abscess Based on the Complete Genome Sequence with Transcriptome Analysis and Transposon Mutagenesis in a Murine Subcutaneous Abscess Model.

Streptococcus intermedius is known to cause periodontitis and pyogenic infections in the brain and liver. Here we report the complete genome sequence of strain TYG1620 (genome size, 2,006,877 bp; GC content, 37.6%; 2,020 predicted open reading frames [ORFs]) isolated from a brain abscess in an infant. Comparative analysis of S. intermedius genome sequences suggested that TYG1620 carries a notable type VII secretion system (T7SS), two long repeat regions, and 19 ORFs for cell wall-anchored proteins (CWAPs). To elucidate the genes responsible for the pathogenicity of TYG1620, transcriptome analysis was performed in a murine subcutaneous abscess model. The results suggest that the levels of expression of small hypothetical proteins similar to phenol-soluble modulin ß1 (PSMß1), a staphylococcal virulence factor, significantly increased in the abscess model. In addition, an experiment in a murine subcutaneous abscess model with random transposon (Tn) mutant attenuation suggested that Tn mutants with mutations in 212 ORFs in the Tn mutant library were attenuated in the murine abscess model (629 ORFs were disrupted in total); the 212 ORFs are putatively essential for abscess formation. Transcriptome analysis identified 37 ORFs, including paralogs of the T7SS and a putative glucan-binding CWAP in long repeat regions, to be upregulated and attenuated in vivo This study provides a comprehensive characterization of S. intermedius pathogenicity based on the complete genome sequence and a murine subcutaneous abscess model with transcriptome and Tn mutagenesis, leading to the identification of pivotal targets for vaccines or antimicrobial agents for the control of S. intermedius infections.

Three-dimensional registration of images obtained before and after radiofrequency ablation of hepatocellular carcinoma to assess treatment adequacy.

OBJECTIVE: The aim of our study was to evaluate the value of 3D registration images reconstructed by fusion of pre- and posttreatment CT or MRI for the assessment of ablative margins after percutaneous radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: From January 2007 to May 2011, we performed RFA in 84 patients to treat 139 HCC nodules, the margins of which had been assessed by comparing pre- and postablation images side by side. The same nodules were retrospectively assessed again with 3D registration images after classification into four margin grades. We analyzed the cumulative local recurrence rate for each grade and reviewed the origin of recurrence. RESULTS: Three-dimensional registration images predicted local recurrences more accurately than did the conventional side-by-side method (area under the curve, 0.678 and 0.536, respectively; p = 0.0144). The cumulative rates of local recurrence were significantly different among the margin grades assessed with 3D registration images (p = 0.0088). Three-dimensional registration images detected that the major origins of recurrence (n = 22) were residuals (n = 13) and sites of no margin (n = 6), especially proximate to blood vessels more than 3 mm in diameter. CONCLUSION: Three-dimensional registration of pre- and postablation CT or MRI more accurately assesses the ablative margin than the conventional method. It can predict a proclivity for local recurrence after RFA according to margin grade. It also indicated that residuals and sites of no margin proximate to blood vessels that are more than 3 mm in diameter are high-risk locations for local recurrence after ablation.

Factors related to shift from hepatic borderline lesion to overt HCC diagnosed by CT.

BACKGROUND/AIMS: Factors contributing to the shift from the hepatic borderline lesion to overt hepatocellular carcinoma (HCC) were investigated. METHODOLOGY: Ninety-five borderline nodules from 69 patients were followed-up for 6-55 (median 24) months. The borderline lesion was diagnosed when the CT image demonstrated low density in the portal phase and lacked enhancement in the arterial phase. RESULTS: The shift to overt HCC was seen in 32 nodules from 27 patients. Using multivariate analysis, only size was a significant factor contributing to the shift to overt HCC (p = 0.009). The cumulative incidence of the shift to overt HCC was higher in nodules of ≥13 mm in size than in those of < 13 mm (p = 0.034). Among nodules of ≥13 mm, nodules showing iso density in the arterial phase and low density in the portal phase had a higher cumulative incidence of the shift to overt HCC than those showing low density in the arterial and portal phases on CT (p=0.007). CONCLUSIONS: In hepatic borderline nodules diagnosed by CT, greater size, and iso density in the arterial phase and low density in the portal phase may be risk factors associated with the shift to overt HCC.

Is sense of coherence helpful in coping with caregiver burden for dementia?

BACKGROUND: Sense of coherence (SOC) is associated with a reduced risk of various health problems and is thought to be a major factor related to the ability to cope with stress. In the present study, we examined the association between caregiver burden and SOC among caregivers to persons with dementia. METHODS: Participants included 274 caregivers or family members of community-dwelling elderly dementia patients. To assess the cognitive function of patients, neuropsychological tests (e.g. Mini-Mental State Examination, Clinical Dementia Rating) were conducted by a clinical psychologist who was well trained in interviewing participants; the tests used a semi-structured interview protocol. Senior neurologists and psychiatrists also independently evaluated the dementia status of patients. To assess the SOC and caregiver burden, a social welfare counsellor asked questions from a 13-item version of the SOC scale and the short, eight-item Japanese version of the Zarit Caregiver Burden Interview (ZBI). RESULTS: Among 78 caregivers of elderly subjects with cognitive impairment due to dementia, the ZBI score was significantly associated with SOC (r = -0.38, P = 0.001). Multiple regression analyses revealed that SOC scores (ß = -0.42, P < 0.001) and Mini-Mental State Examination scores (ß = -0.28, P = 0.009) were significantly associated with ZBI scores (F(2, 76) = 10.51, P < 0.001). SOC was closely associated with personal strain in the ZBI (ß = -0.41, P < 0.001; F(3, 75) = 8.53, P < 0.001). CONCLUSION: Caregivers with a strong SOC may be less prone to experiencing personal strain from their burden. These results suggest that reinforcement of SOC would contribute to reducing the personal strain.

The usefulness of monitoring sleep talking for the diagnosis of Dementia with Lewy bodies.

BACKGROUND: Dementia with Lewy bodies (DLB) is the second most common type of neurodegenerative dementia. It is frequently difficult to differentiate DLB from Alzheimer's disease (AD) and other types of dementia. This study examined the usefulness of monitoring sleep talking for the diagnosis of DLB. METHODS: A total of 317 patients with dementia were selected from a consecutive series at the Dementia Clinic of Kumamoto University Hospital. Diagnostic categories consisted of probable DLB (n = 55), probable AD (n = 191), frontotemporal lobar degeneration (FTLD) (n = 16), vascular dementia (VaD) (n = 18), and other/unspecified dementia (n = 37). We evaluated sleep talking in all dementia patients and normal elderly subjects (n = 32) using an originally designed sleep talking questionnaire. RESULTS: Sleep talking occurred most frequently in the DLB group (61.8%), followed by the VaD group (33.3%), other/unspecified dementia group (27.0%), AD group (18.8%), FTLD group (12.5%), and normal elderly subjects group (6.3%). The prevalence of sleep talking in the DLB group was significantly higher than in other groups, except in the VaD group. The sleep talking yielded high specificity (81.2%) and some sensitivity (61.8%) for the differential diagnosis of DLB from AD. Furthermore, loud sleep talking may improve the specificity (96.9%). For the differentiation of DLB from all other dementia types, the specificity of sleep talking and loud sleep talking was also high (79.4% and 95.8% respectively). CONCLUSIONS: Assessing sleep talking, especially the volume of sleep talking, may be useful in the clinical discrimination of DLB from not only AD but also from all other types of dementia.

[Autism spectrum disorders in elderly].

Autism spectrum disorders (ASD) have been largely neglected in the field of elderly psychiatry. ASD were characterized by a triad of qualitative impairments in the aspects of social interaction, communication, and restricted patterns of behavior and interests. The prevalence of ASD was not clearly estimated in elderly. In clinical practice, elderly patients with confirmed ASD were not usually diagnosed properly earlier in life for various reasons. However, the understanding of characteristic with ASD is useful for clinicians, because we can arrange a suitable environment for patients with ASD. We tend to make overdiagnoses of ASD because of paying attention to only frontal lobe syndrome. We should exclude neurodegenerative disease, especially frontotemporal lobar degeneration.

[Survey of integrated medical care for dementia in Hyogo Prefecture: comparison in two areas].

OBJECTIVE: To assess the attitude of medical care for dementia among the primary care physicians (PCP) in two different areas in Hyogo Prefecture and compare it. METHODS: A 15-item questionnaire related medical care for dementia was developed and sent it by mail to the PCP in December, 2011. RESULTS: One area is an urban area and the other is a rural area. The response rates were 42.9% and 36.7%, respectively. The rate of the PCP in the urban area who was interested to care dementia elderly was higher, compared to the rural area. The integrated medical care net work was well functioning in the urban area. The rate of PCP in the urban area who wanted to have training for dementia care was higher than in the rural area. CONCLUSIONS: Although the rate of elderly in the population in the rural area is higher, the PCP in the rural area seemed not to be interested in dementia care.

[Case of dementia with Lewy bodies showing cervical dystonia after donepezil administration].

We reported a patient with probable dementia with Lewy bodies (DLB) showing cervical dystonia during treatment with donepezil. A 78-year-old female had been treated with donepezil 5 mg/day for 18 months. The patient admitted to our hospital because of severe antecollis. Antecollis disappeard three weeks after discontinuation of donepezil. Five months later the patient received donepezil 3-5 mg/day for disease progression. The patient showed laterocollis again after a month-treatment with donepezil. Physical examination and labolatory tests were nomal. Magnetic resonance imaging of the neck showed no abnormal finding, but electromyography revealed dystonic changes in the neck muscles. Three weeks after discontinuation of donepezil, laterocollis disappeared. These findings suggest that treatment with donepezil induced cervical dystona in a patient with DLB.

Development of a thrombus in the superior mesenteric artery associated with sequential therapy with tyrosine kinase inhibitors for hepatocellular carcinoma.

Tyrosine kinase inhibitors (TKIs) are widely used for systemic chemotherapy of hepatocellular carcinoma (HCC). Arterial thromboembolism (ATE) has been reported to be an adverse event associated with TKI therapy, but its incidence is rare. Here, we report a case of an HCC patient who developed a thrombus in the superior mesenteric artery (SMA) while on TKI therapy. The patient was a 78-year-old Japanese man with hepatitis C virus-associated HCC with multiple nodules. Several sessions of transarterial chemoembolization therapy caused him to become refractory to the treatment. Sorafenib and regorafenib therapy had also been previously performed, but his disease continued to progress gradually. Therefore, we started lenvatinib therapy. When a contrast-enhanced computed tomography (CT) examination was performed 2 months later, we found a thrombus in the SMA. Retrospective analysis of the CT images revealed that the thrombus formed during the sorafenib-regorafenib sequential therapy and it developed rapidly, especially during the lenvatinib therapy. An HCC patient developed a thrombus in the SMA during TKI therapy. The incidence of ATE is rare in TKI treatment; however, long-term or sequential TKI therapy may increase the frequency of ATE. Further study is needed.

Clinical Impact of Vitamin K Dosing on Sorafenib Treatment for Hepatocellular Carcinoma.

Background: Some researchers have suggested that vitamin K enhances the antitumor effect of sorafenib for hepatocellular carcinoma (HCC) in vitro and in vivo. In this study, we examined the clinical impact of vitamin K dosing for sorafenib treatment. Methods: Twenty-nine out of 65 patients treated with sorafenib for HCC were simultaneously dosed with vitamin K. We retrospectively investigated progression-free survival (PFS) and overall survival (OS) in the vitamin K-dosed group and sorafenib alone group. We also examined the changes in serum des-γ-carboxy prothrombin (DCP) levels, which vitamin K is involved with. Results: The median PFS was prolonged in the sorafenib + vitamin K group compared with the sorafenib alone group (6.0 months and 2.0 months, respectively; P<0.001, hazard ratio〔HR〕: 0.25). The median OS was also significantly extended (12.5 months vs. 10.0 months; P=0.009, HR: 0.47). Despite suppressed tumor growth, serum DCP levels had increased in cases of disease-controlled patients in the sorafenib alone group 8 weeks after the beginning of treatment, (2.28±0.91 to 2.64±1.03, P= 0.048). In contrast, the serum DCP levels of the sorafenib + vitamin K group had declined both in patients with controlled disease and in patients with progressive disease (1.97±0.57 to 1.29±0.28, P=0.002 and 2.90±1.32 to 1.78±0.53, P=0.034, respectively). Conclusions: To the best of our knowledge, this is the first clinical report showing enhanced antitumor action of sorafenib by vitamin K. Our clinical findings suggest that vitamin K may have the synergistic effect by suppressing production of DCP, a tumor growth and angiogenesis factor.

Malnutrition in Alzheimer's Disease, Dementia with Lewy Bodies, and Frontotemporal Lobar Degeneration: Comparison Using Serum Albumin, Total Protein, and Hemoglobin Level.

Malnutrition among dementia patients is an important issue. However, the biochemical markers of malnutrition have not been well studied in this population. The purpose of this study was to compare biochemical blood markers among patients with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD). A total of 339 dementia outpatients and their family caregivers participated in this study. Low serum albumin was 7.2 times more prevalent among patients with DLB and 10.1 times more prevalent among those with FTLD than among those with AD, with adjustment for age. Low hemoglobin was 9.1 times more common in female DLB patients than in female AD patients, with adjustment for age. The levels of biochemical markers were not significantly correlated with cognitive function. Family caregivers of patients with low total protein, low albumin, or low hemoglobin were asked if the patients had loss of weight or appetite; 96.4% reported no loss of weight or appetite. In conclusion, nutritional status was worse in patients with DLB and FTLD than in those with AD. A multidimensional approach, including blood testing, is needed to assess malnutrition in patients with dementia.

Progressive degeneration of stereocilia in cochlear hair cells in hearing-impaired kuru2 mice.

BACKGROUND: We previously isolated a mouse strain, kuru2, which exhibits abnormal behavior and hearing impairment. To investigate the etiology of this impairment, the ultrastructure of the inner ear was examined. MATERIALS AND METHODS: The morphologies of the cochlea and the vestibule of control (Jcl:ICR) and mutant mice were analyzed by electron microscopy. In some experiments, the mice were cross-mated and their offspring examined. RESULTS: The mutant mice displayed progressive degeneration of the stereocilia in the cochlea. The stereocilia started to degenerate on post-natal day 10 and, subsequently, the hair bundles continued to degenerate. On day 18, degeneration of the stereocilia was complete. In contrast, the vestibule was intact. DISCUSSION: Many mutant mice display hearing impairment These mice demonstrate a characteristic morphology of the inner ear and, since correlations may be made with corresponding human diseases, the current results could contribute to the further understanding of hearing impairment mechanisms.

Monoclonal anti-idiotype antibodies recognizing the variable region of a high-affinity antibody against 11-deoxycortisol. Production, characterization and application to a sensitive noncompetitive immunoassay.

Anti-idiotype antibodies recognizing the variable regions of a particular anti-hapten antibody are valuable tools, which can be used in sensitive hapten immunoassays based on a noncompetitive format. Here, we describe the production and characterization of monoclonal anti-idiotype antibodies against idiotopes on the variable regions of an antibody showing high affinity and specificity to 11-deoxycortisol (11-DC). 11-DC is the biosynthetic precursor of cortisol and a diagnostic index for the assessment of pituitary-adrenal function. BALB/c or A/J mice were repeatedly immunized with the anti-11-DC antibody conjugated with keyhole limpet hemocyanin and their spleen cells were then fused with P3/NS1/1-Ag4-1 myeloma cells. Seven kinds of anti-idiotype antibodies were generated, one of which was a beta-type antibody recognizing the paratope and others which were alpha-type antibodies recognizing the framework region. A noncompetitive ELISA based on idiotype-anti-idiotype reactions was established using one of these alpha-type antibodies in combination with the beta-type antibody and with the anti-11-DC antibody. This noncompetitive assay system provided improved sensitivity (detection limit: 1.0 pg=2.9 fmol), which is approximately 10 times higher than the corresponding competitive enzyme immunoassay, and offered a practical specificity for clinical use. Appropriate serum 11-DC levels were obtained for normal subjects [0.16+/-0.09 (S.D.) microg/l (n=6), ranging from 0.086 to 0.316 microg/l] using the present assay system.

Mutant ICR mouse, kuru2, manifests hearing impairment and abnormal behavior.

BACKGROUND: Establishment of mutant animals presents valuable information on corresponding human diseases. We established a mutant mouse, kuru2, from the previously reported Ascites ICR Mouse. MATERIALS AND METHODS: Epileptic individuals of Ascites ICR Mouse were mated and maintained with sibling mating. This mouse was characterized by hearing impairment and abnormal behavior such as ataxic gait, disturbance of positional sense, hyperirritability, head-tossing and circling movement. RESULTS: No detectable auditory brain stem response was evoked from an early stage of life. Abnormal behavior started from 4 to 12 weeks of age. Microscopic examination revealed no major abnormalities in the central nervous system. In the inner ear, the vestibule and cochlea were well developed, however degeneration of the spiral ganglions was observed at a late age. The genetic mode was autosomal recessive. DISCUSSION: Since this mouse has a distinctive phenotype, the animal may provide an understanding of hereditary hearing impairment and abnormal behavior.

Patient-related factors associated with depressive state in caregivers of patients with dementia at home.

OBJECTVES: To identify patient-related factors associated with depressive state in caregivers of patients with dementia, we investigated the caregivers' and patients' characteristics in relation to the depressive state in their caregivers. DESIGN: Prospective hospital-based cohort study. SETTING: Two memory clinics in Japan. PARTICIPANTS: Outpatients with dementia (n = 135) and their caregivers at home. MEASUREMENTS: The outpatients and their caregivers were divided into 2 groups according to the Center for Epidemiologic Studies Depression Scale for caregivers. To identify the patient-related factors that cause depressive state in caregivers, Mini-Mental State Examination (MMSE), the Physical Self-Maintenance Scale for fundamental activities of daily living (ADL), and the instrumental ADL scale (IADL) scores for instrumental ADL and the neuropsychiatric inventory (NPI) subscale score for behavioral and psychological symptoms of dementia were compared between the 2 groups. We used logistic regression to determine the independent predictors of caregiver depressive state. RESULTS: There was no significant difference in MMSE score between the 2 groups. Logistic regression analysis revealed that the depressive state in caregivers was related with IADL score and delusion in NPI subscale of patients. CONCLUSIONS: Depressive state in caregivers was independent of the decline in cognitive function in patients with dementia but was associated with decline in instrumental ADL and severity of delusion.

Spontaneous mutant ICR kuru2 might be another shaker-2 deaf mouse.

BACKGROUND: We have established a mouse model of spontaneous deafness by sib-inbreeding over 10 years. The mouse was designated as kuru(2) and has been previously reported in this Journal. MATERIALS AND METHODS: In order to identify the genetic abnormality, the mouse was back-crossed to Mus musculus castaneus (CAST), and myosine 15 or myoXV on chromosome 11 was assumed to be the responsive gene. The background abnormality was identified by gene sequencing. RESULTS: Deletion of 2446 base pairs occurred in the mouse (from 28795 to 31241 in the complete sequence of the Mus musculus unconventional myosin-15 gene; NCBI accession: AF144093). DISCUSSION: The myosin ATP-binding site is present in the deleted area. Considering the function that the affected area regulates and previous reports, hearing loss of the examined mouse is attributable to the abnormality of the myoXV gene and this mouse might be another type of shaker-2 deaf mouse.