Prediction of pathological response to preoperative chemotherapy for pancreatic ductal adenocarcinoma using 2-[18F]-fluoro-2-deoxy-d-glucose positron-emission tomography.

AIM: To determine whether the pathological response to preoperative chemotherapy for pancreatic ductal adenocarcinoma (PDAC) can be predicted using 2-[18F]-fluoro-2-deoxy-d-glucose positron-emission tomography (F-18 FDG-PET). MATERIALS AND METHODS: Twenty-eight patients with PDAC who underwent only neoadjuvant chemotherapy (NAC) before surgery were enrolled in the study. All patients had F-18 FDG-PET examinations before NAC. The resected specimen was pathologically evaluated according to the Classification of Pancreatic Carcinoma (7th edn). Patients were categorised into a non-response group and a response group based on the pathological findings. The non-response group (Grades 1a and 1b) showed ≤50% necrosis in the specimen, while the specimens of the response group (Grades 2-3) showed >50% necrosis. The maximum standardised uptake values (SUVmax) of the tumours on F-18 FDG-PET were measured. The mean values of SUVmax were compared between the two groups. The diagnostic performance of SUVmax in distinguishing the two groups was also evaluated using receiver operating characteristic analysis. RESULTS: The mean SUVmax of the response group was higher than that of the non-response group (9.00 ± 1.78 versus 4.26 ± 2.35; p<0.001). The optimal cut-off value of SUVmax was 9.28 for distinguishing the two groups. The sensitivity, specificity, and accuracy for the prediction in the response group were 80%, 95.7%, and 92.9%, respectively. CONCLUSIONS: SUVmax on F-18 FDG-PET may be useful as a biomarker to predict the pathological response to NAC in patients with PDAC.

Local and systemic responses following intravitreous injection of AAV2-encoded modified Volvox channelrhodopsin-1 in a genetically blind rat model.

We previously designed a modified channelrhodopsin-1 (mVChR1) protein chimera with a broader action than that of Chlamydomonas channelrhodopsin-2 and reported that its transduction into retinal ganglion cells can restore visual function in genetically blind, dystrophic Royal College of Surgeons (RCS) rats, with photostimuli ranging from 486 to 640 nm. In the current study, we sought to investigate the safety and influence of mVChR1 transgene expression. Adeno-associated virus type 2 encoding mVChR1 was administered by intravitreous injection into dystrophic RCS rats. Reverse-transcription PCR was used to monitor virus and transgene dissemination and the results demonstrated that their expression was restricted specifically within the eye tissues, and not in non-target organs. Moreover, examination of the blood, plasma and serum revealed that no excess immunoreactivity was present, as determined using standard clinical hematological parameters. Serum antibodies targeting the recombinant adeno-associated virus (rAAV) capsid increased after the injection; however, no increase in mVChR1 antibody was detected during the observation period. In addition, retinal histological examination showed no signs of inflammation in rAAV-injected rats. In conclusion, our results demonstrate that mVChR1 can be exogenously expressed without harmful immunological reactions in vivo. These findings will aid in studies of AAV gene transfer to restore vision in late-stage retinitis pigmentosa.

A phase II trial of stereotactic body radiotherapy in 4 fractions for patients with localized prostate cancer.

PURPOSE/OBJECTIVE(S): To report results from our phase II study of stereotactic body radiotherapy (SBRT) delivering 36 Gy in 4 fractions for patients with localized prostate cancer. MATERIALS/METHODS: We enrolled 55 patients treated with SBRT delivering 36 Gy in 4 fractions between 2015 to 2018. All patients were categorized as low-risk (n = 4), intermediate-risk (n = 31) or high-risk (n = 20) according to National Comprehensive Cancer Network criteria. Median age was 73 years (range 54-86 years). Two-thirds of patients (n = 37) had received androgen-deprivation therapy for 3-46 months (median, 31 months). Median duration of follow-up was 36 months (range 1-54 months). We used Radiation Therapy Oncology Group and National Cancer Institute-Common Toxicity Criteria version 4 for toxicity assessments. Quality of life (QOL) outcomes were also evaluated using the Expanded Prostate Cancer Index Composite (EPIC). RESULTS: Protocol treatments were completed for all patients. Six patients experienced biochemical failures. Among these six patients, three patients experienced clinical failure. One patient showed bone metastasis before biochemical failure. One patient died of gastric cancer. The 3-year biochemical control rate was 89.8%. Acute grade 2 genitourinary (GU) and gastrointestinal (GI) toxicities were observed in 5 patients (9%) and 6 patients (11%), respectively. No grade 3 or higher acute toxicities were observed. Late grade 2 GU and GI toxicities were observed in 7 patients (13%) and 4 patients (7%), respectively. Late grade 3 GU and GI toxicities were observed in 1 patient (1.8%) each. EPIC scores decreased slightly during the acute phase and recovered within 3 months after treatment. CONCLUSION: Our phase II study showed that SBRT delivering 36 Gy in 4 fractions was safe and effective with favorable QOL outcomes, although this regimen showed slightly more severe toxicities compared to current standards.

Tumor growth and metastasis suppression by Glipr1 gene-modified macrophages in a metastatic prostate cancer model.

We previously identified the mouse and human Glipr1 and GLIPR1/RTVP-1 genes, respectively, as direct p53 targets with proapoptotic activities in various cancer cell lines, including prostate cancer (PCa). Intratumoral injection of an adenoviral vector capable of efficient transduction and expression of Glipr1 (AdGlipr1) yielded promising therapeutic results in an orthotopic, metastatic mouse model of PCa. AdGlipr1-transduced macrophages (Mφ/Glipr1) generated greater surface expression of CD40, CD80 and major histocompatibility complex class II molecules and greater production of interleukin 12 (IL-12) and IL-6 in vitro than control macrophages did. Mechanistic analysis indicated that increased production of IL-12 in Mφ/Glipr1 depends on activation of the p38 signaling cascade. Mφ/Glipr1 injected into orthotopic 178-2BMA tumors in vivo resulted in significantly suppressed prostate tumor growth and spontaneous lung metastases and longer survival relative to those observed in control-treated mice. Furthermore, these preclinical data indicate the generation of systemic natural killer cell activity and tumor-specific cytotoxic T lymphocyte responses. Trafficking studies confirmed that intratumorally injected Mφ/Glipr1 could migrate to draining lymph nodes. Overall, our data suggest that this novel gene-modified cell approach is an effective treatment avenue that induces antitumor immune responses in preclinical studies.

Use of ultrasound in assessment of necrotic tissue in pressure ulcers with adjacent undermining.

OBJECTIVE: To reveal the specific ultrasonic imaging findings of non-visible necrotic tissue in pressure ulcers (PUs) with undermining and describe the images objectively. The predictive validity of the specific images of the undermined necrotic tissue was also determined. METHOD: Using digital ultrasonography (12 MHz linear transducer, MyLab25; Hitachi Medical Corporation), we imaged PUs with undermining every 2 weeks. PUs were also monitored by DESIGN-R, a PU assessment tool, at the same time. RESULTS: Ten patients had 11 PUs with undermining and all ulcers were located in the sacral region. The necrotic tissue showed high echogenicity with no layers, unclear borders and an uneven gray level (cloud-like image). Granulation tissue appeared as a low echoic image which had no layers, was of coarse resolution and an even gray level. There were significant differences between the pixel uniformity of the necrotic tissue (84.0) and granulation tissue (53.9) compared with uninjured tissue (65.5; p=0.000 and 0.005, respectively). The sensitivity, specificity, and positive and negative predictive values of cloud-like image were 87.5%, 91.7%, 77.8% and 95.6%, respectively. CONCLUSION: The results suggest that cloud-like image is the most useful diagnostic indicator for non-visible necrotic tissue in PUs with undermining and is the best prognostic indicator for PU healing. DECLARATION OF INTEREST: The authors have no conflicts of interest to declare. There were no external sources of funding for this study.

[Extended thymectomy and intraoperative-intrapleural perfusion hyperthermo-chemotherapy for stage IVa invasive thymoma with myasthenia gravis].

A 37-year-old woman diagnosed with ocular myasthenia gravis was referred to our department. Chest computed tomography (CT) showed anterior mediastinal tumor and right pleural dissemination. Extended thymectomy and right intraoperative-intrapleural perfusion hyperthermo-chemothrapy (IPHC) were performed. Pathological diagnosis was invasive thymoma type B2 and stage IVa based on Masaoka's classification. The post operative course was uneventful. The patient underwent 4 cycles of adjuvant chemotherapy with doxorubicin, cisplatin, vincristine, and cyclophosphamide (ADOC), and is free from recurrence at 12 months postoperatively.

Large-scale production of UDP-galactose and globotriose by coupling metabolically engineered bacteria.

A large-scale production system of uridine 5'-diphospho-galactose (UDP-Gal) has been established by the combination of recombinant Escherichia coli and Corynebacterium ammoniagenes. Recombinant E. coli that overexpress the UDP-Gal biosynthetic genes galT, galK, and galU were generated. C. ammoniagenes contribute the production of uridine triphosphate (UTP), a substrate for UDP-Gal biosynthesis, from orotic acid, an inexpensive precursor of UTP. UDP-Gal accumulated to 72 mM (44 g/L) after a 21 h reaction starting with orotic acid and galactose. When E. coli cells that expressed the alpha1,4-galactosyltransferase gene of Neisseria gonorrhoeae were coupled with this UDP-Gal production system, 372 mM (188 g/L) globotriose (Galalpha1-4Galbeta1-4Glc), a trisaccharide portion of verotoxin receptor, was produced after a 36 h reaction starting with orotic acid, galactose, and lactose. No oligosaccharide by-products were observed in the reaction mixture. The production of globotriose was several times higher than that of UDP-Gal. The strategy of producing sugar nucleotides by combining metabolically engineered recombinant E. coli with a nucleoside 5'-triphosphate producing microorganism, and the concept of producing oligosaccharides by coupling sugar nucleotide production systems with glycosyltransferases, can be applied to the manufacture of other sugar nucleotides and oligosaccharides.

Adenoviral vector-mediated RTVP-1 gene-modified tumor cell-based vaccine suppresses the development of experimental prostate cancer.

We previously identified a novel p53 target gene, RTVP-1, that possesses unique cytotoxic and immunostimulatory activities which make it potentially useful for cancer gene therapy. To test the therapeutic potential of RTVP-1 in a gene-modified tumor cell-based vaccine model, we used an adenoviral vector capable of efficient transduction and expression of RTVP-1 (AdRTVP-1), together with a highly metastatic mouse prostate cancer cell line (178-2 BMA). A vaccine was prepared with 178-2 BMA cells transduced with AdRTVP-1 or a control adenoviral vector expressing beta-galactosidase (Adbetagal). After irradiation of the cells, syngeneic 129/Sv mice were vaccinated three times at weekly intervals. After 3 weeks, they were challenged with orthotopic 178-2 BMA cells. After 21 days, fewer than 60% of the RTVP-1-cell-vaccinated mice developed tumors compared to 100% of the control mice. The RTVP-1-cell vaccine significantly reduced primary tumor wet weight compared with control Adbetagal-cell vaccine (P<0.0001 at 7 and 14 days). Experimental metastasis to lung was also significantly reduced (P=0.0377), and survival significantly increased (P=0.0002). In addition, significantly increased NK and CTL activities were demonstrated in the AdRTVP-1-cell-vaccinated mice. These findings indicate that RTVP-1 gene-modified cell-based vaccines may be useful in the prevention of recurrent prostate cancer.

Cloning of a cDNA encoding a putative metal-transporting P-type ATPase from Arabidopsis thaliana.

Metal-transporting P-type ATPases were recently proposed to constitute a newly emerged sub-family of cation-transporting P-type ATPases, and are known to occur widely in prokaryotes and eukaryotes. However, no instance has been reported for higher plants. A cDNA clone encoding a metal-transporting P-type ATPase was thus searched for, if present, and was identified in Arabidopsis thaliana. The amino acid sequence, predicted from the determined nucleotide sequence for the cloned cDNA, shows all the critical features common to known metal-transporting P-type ATPases. This plant P-type ATPase has a typical metal-binding motif at its N-terminal portion. The newly isolated Arabidopsis gene, named PAA1, provides us with the first instance of putative metal-transporting P-type ATPases in higher plants. Some results of genomic analyses for this gene are also presented.

Physical map of the extremely thermophilic bacterium Thermus thermophilus HB27 chromosome.

The physical map of the chromosome of Thermus thermophilus HB27 was constructed using three restriction enzymes; EcoRI, SspI and MunI by applying pulsed-field gel electrophoresis techniques. Although the genome size of 1.82 Mb was almost the same as that (1.74 Mb) reported for T. thermophilus HB8 [Borges, K.M., and P.L. Bergquist. (1993) J. Bacteriol. 175, 103-110], the MunI cleavage maps were different. A 240 kb plasmid was detected in HB27, and its physical map was also constructed. In addition, several genes were located on the chromosomal physical map.

A carotenogenic gene cluster exists on a large plasmid in Thermus thermophilus.

In Thermus thermophilus HB27, the crtB gene encoding phytoene synthase was found to exist on the large plasmid, pTT27. One of the carotenoid under-producing mutants, Crt31, carried a derivative of pTT27 (pTT27') in which deletion and inversion were observed near the crtB gene. T. thermophilus HB8 also contained a large plasmid which showed homology to pTT27 and the crtB gene. These results suggested that genes for carotenoid biosynthesis occurred as a cluster on a large plasmid in Thermus thermophilus. This is the first report to show directly that carotenogenesis is plasmid-encoded in microorganisms.

Transmission of Helicobacter pylori infection via flexible fiberoptic endoscopy.

BACKGROUND: Public concern has been raised with regard to the possibility of transmission of instrument mediated Helicobacter pylori infection after upper gastrointestinal endoscopy. METHODS: Disinfection procedures for gastrointestinal endoscopes were surveyed in 20 Japanese institutions, and in vitro bactericidal activities of seven disinfectants against H. pylori were determined. RESULTS: Screening tests for infection before endoscopy were not consistently performed; only 11 institutions always screened for hepatitis B virus, nine for hepatitis C virus, and two for tuberculosis. All 20 institutions used the same flexible fiberoptic endoscope on more than one patient in succession, with minimal cleanings only. Only two used glutaraldehyde for disinfection. Most used ethyl alcohol, benzalkonium chloride, or alkyldiaminoethylglycine hydrochloride as an external wipe. Bactericidal testing of nine strains of H. pylori against disinfectants revealed that ethyl alcohol (80%) and glutaraldehyde (0.5%) killed all nine strains within 15 seconds, whereas chlorhexidine gluconate (0.05%, 0.1%), benzalkonium chloride (0.025%, 0.1%), alkyldiaminoethylglycine hydrochloride (0.1%), povidone-iodine (0.1%), and sodium hypochlorite (150 ppm) killed all nine strains within 30 seconds. CONCLUSION: H. pylori is readily killed by many common disinfectants and antiseptics. However, practices for disinfection of flexible fiberoptic endoscope were not appropriate.

Molecular cloning and sequence analysis of the proBA operon from an extremely thermophilic eubacterium Thermus thermophilus.

A 3.6 kb DNA fragment carrying the Thermus thermophilus proBA region, which encodes the first two steps in the proline biosynthetic pathway, was cloned from the Thermus thermophilus gene library, and its complete nucleotide sequence was determined. The deduced amino acid sequence of gamma-glutamyl kinase (40,657 Da), the product of proB gene, and gamma-glutamyl phosphate reductase (48,747 Da), the product of proA gene, showed 44.1% and 44.4% identity to those of Escherichia coli, respectively. The termination codon of the proB gene and the initiation codon of the proA gene overlapped by 2 bp. A possible transcriptional termination structure was found downstream of the proA gene but not downstream of the proB gene. These results indicate that the proBA genes of T. thermophilus form a single operon as in E. coli.

Evaluation of the efficacy of a 3.2% glutaraldehyde product for disinfection of fibreoptic endoscopes with an automatic machine.

The efficacy of 'Cidex Plus' 3.2% alkaline glutaraldehyde was evaluated for the disinfection of fibreoptic endoscopes. The glutaraldehyde concentration in 'Cidex Plus', stored in an automatic machine (Olympus EW-20), remained higher than 2% (2.21%) even after a total of 102 disinfection cycles during 28 consecutive days. The results of the in-vitro study on antimicrobial activity showed that this alkaline glutaraldehyde product had a greater activity against 20 test organisms, including vegetative bacteria, bacterial spores, mycobacteria, and fungi, than 2% glutaraldehyde alone. The presence of 10 or 30% human serum did not appear to affect the activity of glutaraldehyde adversely. Instrument samples made from a variety of materials such as stainless steel, glass, teflon, etc. were not damaged after 168 h of immersion in alkaline glutaraldehyde, although it contained approximately 1.7 times more glutaraldehyde than 2% glutaraldehyde alone. Based on these results, 3.2% alkaline glutaraldehyde is considered to be a more effective disinfectant for fibreoptic endoscopes, with the use of an automatic machine, than 2% glutaraldehyde.

Brain SPECT with 123I-IMP for the early diagnosis of Creutzfeldt-Jakob disease.

We performed brain CT and single-photon emission computed tomography (SPECT) using N-isopropyl-p-[123I] iodoamphetamine (123I-IMP) as a tracer in the early stage of seven patients with Creutzfeldt-Jakob disease (CJD). In four of the patients, we determined absolute values of regional cerebral blood flow (rCBF) in the frontal, temporal, parietal and occipital lobes, thalamus and cerebellum using an autoradiographic method with a single blood sample. Brain CT demonstrated no abnormal findings other than a mild age-related atrophy in all patients except for one patient with a low-density area in the left cerebellar hemisphere due to an old hemorrhage, whereas SPECT revealed a decreased uptake of the tracer in various parts of the cerebral cortex of all patients, sometimes in an asymmetrical pattern. Absolute values of rCBF showed a significant decrease in all examined regions of the patients as against healthy controls (P<0.0001). In three patients, SPECT demonstrated a decreased uptake throughout the cerebral cortex on visual inspection, whereas absolute values of rCBF revealed an obvious decrease of the uptake also in the thalamus and cerebellum. These results suggest that SPECT with quantification of rCBF using 123I-IMP might be a sensitive and useful technique not only for detecting a focal metabolic dysfunction but also for diagnosis in the early stage of CJD.

Hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA): clinical and neuropathological features of a Japanese family.

We report clinicopathological features of a Japanese family with hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA). Four affected members from a single generation were examined. They shared common clinical features, including insidious onset in teenage, slowly progressive cerebellar ataxia, amyotrophy, sensory disturbance, and dementia. In addition, all the patients showed hypoalbuminemia and hyperlipidemia and a marked atrophy of the cerebellum on magnetic resonance images. Autopsy of the proband revealed a severe loss of Purkinje cells, degeneration of posterior columns and spinocerebellar tracts of the spinal cord, and a marked loss of myelinated and unmyelinated fibers in the peripheral nerves. We consider that HMSNCA is a distinct form of hereditary multisystem neuronal degeneration.

Multiple sclerosis with secondary syringomyelia. An autopsy report.

We report an elderly woman with multiple sclerosis who showed an extensive cavity formation in the midthoracic cord in addition to multiple abnormal intensity signals in the central nervous system on magnetic resonance imaging (MRI). The cavity decreased in size in response to corticosteroid therapy with an improvement in neurological symptoms. The autopsy demonstrated a slit-like cavity lined with no ependymal cells on the luminal surface in the lower cervical to midthoracic cord, with circumferentially distributed demyelinative lesions, leading to the pathological diagnosis of secondary syringomyelia. In this patient a limited necrosis formed in the spinal cord might have developed into a cavity formation with edematous fluid leading to subsequent episodes of neurological exacerbation.

Correlation between the antitumor activity of a polysaccharide schizophyllan and its triple-helical conformation in dilute aqueous solution.

Eight samples of a polysaccharide schizophyllan ranging in weight-average molecular weight Mw (in water) from 5 x 10(3) to 1.3 x 10(5) were prepared and their antitumor activity (expressed in terms of the tumor inhibition ratio) against Sarcoma 180 ascites, intrinsic viscosities [eta], and gel-filtration chromatograms in aqueous solution were determined. The tumor inhibition ratio was essentially unity for samples with Mw higher than 9 x 10(4), but reduced to zero or even to a negative value when Mw was lower than 10(4). The [eta] data combined with the chromatographic data showed that above Mw approximately 9 x 10(4) the predominant species of schizophyllan in aqueous solution is the previously found rigid triple helix, whereas below Mw approximately 9 x 10(4) both triple helices and single chains coexist in the solution and the fraction of triple helices decreases monotonically to zero as Mw is decreased to 5 x 10(3). From these findings it was concluded that the antitumor potency of schizophyllan in water is related to the amount of triple helices relative to that of single chains.

Correction note on "The demand for health with uncertainty and insurance".

This paper proves the non-existence of an optimal solution under the Liljas [Liljas, B. (1998). The demand for health with uncertainty and insurance. J. Health Econ., 17, 153-170] type of insurance. The reason for the non-existence is that the insurance induces the individual to increase his time input, relative to medical expenditure in the household production of health investment. Hence, it distorts the balance of inputs in the production of health investment. Moreover, it also distorts the household production for consumption goods through time constraints. Therefore, this paper proposes an alternative insurance that covers the time loss due to illness and has an optimal solution.