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.

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.

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.

Roles of microsomal prostaglandin E synthase-1 in lung metastasis formation in prostate cancer RM9 cells.

Cyclooxygenase-2 (COX-2) is known to correlate with a poor prognosis of prostate cancer and contribute to tumor metastasis. However, the precise mechanism of this phenomenon remains unknown. We have previously reported that host stromal microsomal prostaglandin E synthase-1 (mPGES-1) appeared critical for tumor-associated angiogenesis and tumor growth. Here, we tested whether or not mPGES-1 has a critical role in lung metastasis formation of prostate cancer. Murine prostate cancer cells (RM9) were intravenously injected and lung metastasis was estimated by counting colonies in the lungs. Mice treated with a selective COX-2 inhibitor, celocoxib, were suppressed lung metastasis compared to vehicle mice. This lung metastasis formation was also reduced in mPGES-1 knockout (mPGES-1 KO) mice, compared with wild type (WT) mice. This was accompanied with reduced angiogenesis around the metastasized colonies of RM9. Plasma protein levels and metastasized lung tissue mRNA levels of vascular endothelial growth factor (VEGF) and stromal cell derived factor-1 (SDF-1) were significantly suppressed in mPGES-1 KO mice in comparison with WT mice. In addition, the expressions of matrix metalloproteinases (MMP)-9, and metalloproteinases (MMP)-2 were down-regulated in metastatic lungs in mPGES-1 KO mice. These results suggested that host mPGES-1 was essential for MMP-2 and MMP-9 up-regulation that enhances tumor metastasis. mPGES-1 appears to be critical for tumor metastasis in prostate cancers. mPGES-1 inhibitors may be useful to protect against prostate cancer metastasis.

Evaluation of nutritional status and skin condition among elderly residents in a long-term care hospital.

OBJECTIVE: The availability of nutritional screening tools for older adults is limited, depending on their physical characteristics or the setting. We investigated the relationships between various nutritional indicators and skin conditions as possible screening indicators. DESIGN: Cross-sectional study. SETTING: A long-term care hospital in Japan. PARTICIPANTS: 90 elderly residents who were aged ≥65 years old. MEASUREMENTS: The nutritional status of the residents was assessed by body mass index (BMI), involuntary weight loss, arm muscle area, and serum albumin and prealbumin levels. Leg skin condition was evaluated by: 1) functional factors including pH, hydration and transepidermal water loss; 2) skin color including L*, a*, b* and individual typology angle (ITA°) using a tristimulus colorimetric instrument; and 3) skin morphology. Repeated measures analysis of variance was employed, adjusted for demographic characteristics and room temperature, with measurement site as the repeated variable. RESULTS: Among the skin indicators, b* was significantly correlated with BMI (p=0.018), and weight loss over the previous month (p=0.042) and 6 months (p=0.002). Additionally, ITA° was associated with weight loss over 1 month (p=0.013). Both b* and ITA° showed the area under the receiver operating characteristic curve of 0.64 to 0.80 for weight loss >2% over 1 month. CONCLUSIONS: Residents with poorer nutritional status had yellower and darker skin color.

[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.

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.

Therapeutic effects of gelatin matrix-embedded IL-12 gene-modified macrophages in a mouse model of residual prostate cancer.

We evaluated the potential use of intraoperative gelatin matrix hemostatic sealant (GMHS; FloSeal; Baxter Healthcare) embedded with macrophages (Mphi) transduced with murine interleukin (IL)-12 recombinant adenoviral vector (G/Mphi/AdmIL-12) for prevention of recurrence of prostate cancer following radical prostatectomy. Application of G/Mphi/AdmIL-12 resulted in significant suppression of tumor growth and spontaneous lung metastases, a statistically significant survival advantage of the G/Mphi/AdmIL-12-treated animals, more efficient trafficking of Mphi to lymph nodes draining from the prostate and generation of systemic natural killer cell activity and tumor-specific cytolytic T lymphocyte responses compared to the controls in a preclinical mouse model of residual prostate cancer. Our data recommend this treatment as a novel adjuvant for prevention of local recurrence of prostate cancer following radical prostatectomy.

Cooperative effects of adenoviral vector-mediated interleukin 12 gene therapy with radiotherapy in a preclinical model of metastatic prostate cancer.

We investigated the potential benefits of combining adenoviral vector mediated in situ interleukin-12 (AdmIL-12) gene therapy with radiation therapy (XRT) to enhance therapeutic efficacy. In a metastatic mouse prostate cancer cell line, 178-2 BMA, AdmIL-12+XRT demonstrated enhanced therapeutic activities in vitro as determined by clonogenic survival, apoptosis, and mIL-12 levels. At the molecular level, increased expression of tumor necrosis factor-alpha mRNA was specific for the combined therapy. In a subcutaneous 178-2 BMA in vivo model, the combination of AdmIL-12+XRT produced statistically significant tumor growth suppression compared to control vector Adbetagal, Adbetagal XRT, or AdmIL-12 as monotherapy. In addition, significant prolongation of survival was demonstrated for the combination of AdmIL-12+XRT. The combination of AdmIL-12+XRT significantly suppressed both spontaneous and pre-established lung metastases, and led to a prolonged elevation of serum IL-12 and significantly increased natural killer (NK) activities. Importantly, in vivo depletion of NK cells resulted in significant attenuation of the antimetastatic activities of AdmIL-12 alone or AdmIL-12+XRT. These combined effects suggest that AdIL-12 gene therapy together with radiotherapy may achieve maximal tumor control (both local and systemic) in selected prostate cancer patients via radio-gene therapy induced local cytotoxicity and local and systemic antitumor immunity.

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.

Effect of additives on photodegradation of 1,3,5-trichlorobenzene in aqueous surfactant solutions.

Photolysis of 1,3,5-trichlorobenzene (TCB) in moderate concentration (0.5 mM) in the presence of several additives was examined in 10 mM of cationic and nonionic surfactant solutions. Additions of small amounts of hydrophobic additives, n-dodecanethiol (1 mM), n-dodecyldimethylamine (<2.5 mM), and N-(n-dodecyl)-N-methylaniline (C12An: <0.5 mM), were effective for photodechlorination of TCB, while the formation of by-products could not be inhibited perfectly. In contrast, exclusive and efficient dechlorination of TCB in cetyltrimethylammonium chloride solution was achieved in the presence of sodium borohydride (<5 mM), which was due to the enhanced local concentration of borohydride anions in cationic micelle surfaces.

Premature apoptosis of keratinocytes and the dysregulation of keratinization in porokeratosis.

BACKGROUND: Porokeratosis is a dyskeratotic disorder of the skin characterized by cornoid lamella with parakeratosis, hyperkeratosis and loss of granular layers. The pathogenesis of porokeratosis and the mechanism(s) of its abnormal keratinization are still unknown. OBJECTIVE: To elucidate the mechanism(s) of abnormal keratinization that leads to the formation of cornoid lamellae in porokeratosis. METHODS: Apoptosis of keratinocytes was assessed in the skin of seven patients by an in situ apoptosis assay based on the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling (TUNEL) reaction. Patterns of loricrin and involucrin expression were examined by immunohistochemistry. RESULTS: TUNEL-positive keratinocytes were observed in the epidermis underlying the cornoid lamella in all cases examined. Furthermore, loricrin expression was interrupted there, in contrast to involucrin, which was expressed diffusely in the lesional epidermis. CONCLUSIONS: These results suggest that an abnormal early keratinocyte apoptosis accompanied by dysregulation of terminal differentiation of those cells may be involved in the pathogenesis of porokeratosis.

Acute and chronic intracerebroventricular morphine infusions affect long-term potentiation differently in the lateral perforant path.

Experiments were performed to investigate the effects of acute and chronic intracerebroventricular (icv) morphine infusions via osmotic minipumps on long-term potentiation (LTP) in the lateral perforant path (LPP)-granule cell synapse of the rat dentate gyrus. Although significant antinociceptive activity was observed when morphine was infused (25 nmol/microl/h) for 30 min or 1 h, the activity was not observed in rats receiving morphine chronically for 72 h, and the tail-flick latency of this group was comparable to that of rats receiving saline. LTP induction was significantly attenuated after acute morphine infusion (1 h) in LPP-granule cell synapses of the dentate gyrus. In contrast, LTP induction was augmented after chronic morphine infusion for 72 h. Bath-perfused morphine augmented the baseline population spike (PS) amplitude in rats treated with saline, whereas it attenuated the LTP induced by chronic morphine infusion. Returning the LTP to the level of saline infusion after in vitro morphine perfusion suggests that enhancement of the LTP is a withdrawal-like phenomenon. These results suggest a difference between the effects of acute and chronic intracerebroventricular morphine infusions on synaptic plasticity in the LPP-granule cell synapses of the dentate gyrus.

Myb-binding site regulates the expression of glucosamine-6-phosphate isomerase in Dictyostelium discoideum.

A homolog of the glucosamine-6-phosphate isomerase in the cellular slime mold Dictyostelium discoideum has been analyzed. The gene disruption mutant was arrested at the mound stage, demonstrating that the gene is important for development. The gene was expressed in vegetatively growing cells, silenced on starvation and expressed again in prestalk cells during the multicellular stages. The upstream region of the gene (1376 bp relative to ATG) was cloned and sequenced to study the transcription control mechanisms. Analysis of deletion mutants and a site-directed mutant indicated that the Myb-binding sequence (5'-AACTG-3') localized in the upstream region is important for gene expression. The results of gel-shift assays showed the presence of an Myb-related protein binding to the sequence at the growing phase and another protein binding to the sequence at developmental stages.

Generation and properties of ascorbic acid-deficient transgenic tobacco cells expressing antisense RNA for L-galactono-1,4-lactone dehydrogenase.

In higher plants, the terminal step of L-ascorbic acid (AsA) biosynthesis is catalyzed by the enzyme L-galactono-1,4-lactone dehydrogenase (EC 1.3.2.3, GalLDH). We generated AsA-deficient transgenic tobacco BY-2 cell lines by antisense expression of the GalLDH cDNA that was amplified from BY-2 cells using PCR. Two transgenic cell-lines, AS1-1 and AS2-2, having a marked expression of antisense RNA were analyzed. Antisense suppression of GalLDH mRNA led to a significant decline in the GalLDH activity. The AsA levels in the transgenic cell lines were found to be 30% lower than the wild-type BY-2 cells. In synchronous cultures, division of AS1-1 and AS2-2 cells was restrained with a concomitant decrease in mitotic index that was probably due to a decline in AsA levels. The rate of cell growth was also found to be less than that of the wild-type cells. Interestingly, there was a significant phenotypic difference between the transgenic and wild-type cells. The calli of AS1-1 and AS2-2 appeared to be sticky and soft. Back extrusion method also showed that AsA-deficient BY-2 callus was rheologically soft. Furthermore, microscopic analysis revealed that AS1-1 and AS2-2 cells were abnormally slender, suggesting a potential for a significant and a uni-axial elongation. Thus, we observed that decline in the AsA levels has an adverse effect on the division, growth and structure of a plant cell.

Medium-chain fatty acids stimulate interleukin-8 production in Caco-2 cells with different mechanisms from long-chain fatty acids.

BACKGROUND AND AIM: It has been suggested that dietary fat exacerbates intestinal inflammation. We investigated the effect of fatty acids on interleukin (IL)-8 production in a human intestinal epithelial cell line (Caco-2). METHODS: The cells were cultured as monolayers on microporous membranes in culture inserts. Oleic acid (OA), capric acid (CA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were applied to the apical compartment of Caco-2 cell monolayers. The concentration of IL-8 in the basolateral medium was measured by using enzyme-linked immunosorbent assay, and the expression of IL-8 mRNA was measured by using competitive reverse transcription--polymerase chain reaction. Protein kinase C inhibitors (GF109203X and calphostin C) and H-7 (a protein kinase inhibitor) were used to study the mechanisms by which IL-8 production is stimulated. RESULTS: Both OA and CA enhanced IL-8 production (approximately fivefold), whereas DHA and EPA did not. Both OA and CA also enhanced IL-1-induced IL-8 production. The onset of OA-induced IL-8 production was delayed compared with that of CA-induced IL-8 production. Both OA and CA enhanced IL-8 mRNA expression (approximately fivefold) after 6 and 3 h, respectively. The protein kinase inhibitor (H-7) reduced both OA- and CA-induced IL-8 production by 88.0 and 85.9%, respectively. The protein kinase C inhibitors (GF109203X and calphostin C) reduced OA-induced IL-8 production by 29.3 and 54.5%, respectively, but showed no effect on CA-induced IL-8 production. CONCLUSIONS: These findings suggest that not only OA but also CA stimulates IL-8 production in intestinal epithelial cells, and the mechanisms of action differ between OA and CA.

Hemiballism with hyperglycemia and striatal T1-MRI hyperintensity: an autopsy report.

We report on an autopsy findings of a 92-year-old male with hemiballism-hemichorea associated with hyperglycemia and striatal hyperintensity on T1-weighed magnetic resonance imaging (MRI), a recently described clinicoradiological syndrome. Histologically, the putamen contralateral to the hemiballism consisted of multiple foci of recent infarcts associated with reactive astrocytic and interneuronal response. Substrate responsible for the MRI signal changes is still inconclusive.

Ameliorative effects of paeoniflorin, a major constituent of peony root, on adenosine A1 receptor-mediated impairment of passive avoidance performance and long-term potentiation in the hippocampus.

We examined the effects of paeoniflorin on adenosine A1 receptor-mediated memory disturbance in the mouse passive avoidance test and inhibition of long-term potentiation (LTP) in the rat hippocampal CA1 region. The pretraining administration of the selective adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) significantly impaired the retention performance determined 24 h after the training test. The intraperitoneal injections of paeoniflorin and the adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) significantly attenuated the deficit in retention performance caused by CPA. The in vitro studies revealed that adenosine (1 and 10 microM) dose dependently reduced both the population spike (PS) amplitudes and the tetanic stimulation-induced LTP in the hippocampus. DPCPX, at the concentration (0.1 microM) that had no effect on PS amplitudes or LTP induction, significantly reversed the suppressive effects of adenosine on both indices. Paeoniflorin also dose dependently reversed 10 microM adenosine-induced suppression of LTP but had no effect on PS reduced by adenosine. These results suggest that paeoniflorin ameliorates memory disruption mediated by adenosine A1 receptor and that modulation of adenosine-mediated inhibition of LTP in the hippocampus is implicated in its beneficial effect on learning and memory impairment in rodents.