Nagoya City University Graduate School Research Articles

Girdin regulates both migration and angiogenesis in pancreatic cancer cell lines.

Girdin, an actin‑binding protein, is reportedly involved in the invasion and angiogenesis of various cancers. It has been suggested that the flavonoid Scutellarin (SCU) inhibits Girdin signaling. In the present study, the function and therapeutic applications of Girdin in pancreatic cancer (PaCa) were investigated. Immunohistochemical staining of Girdin in resected PaCa specimens from the Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science showed that high Girdin expression was associated with poor overall survival and relapse‑free survival, as well as with T factor, indicating invasion into the surrounding tissues. On the other hand, Girdin was highly expressed in almost all PaCa cell lines, and the migration ability of Girdin‑knockdown cell lines was decreased even under epidermal growth factor (EGF) stimulation. In addition, SCU suppressed PaCa cell migration by inhibiting the phosphorylation of Girdin. The expression and production of vascular endothelial growth factor A (VEGF‑A) was significantly decreased in Girdin‑knockdown cell lines. Furthermore, in Matrigel tube formation assays performed using culture supernatant, the lumen‑forming ability of vascular endothelial cells was also decreased in Girdin‑knockdown cell lines. However, SCU treatment did not significantly alter the expression or production of VEGF‑A. These results suggested that Girdin is involved in EGF signaling‑mediated migration of PaCa cells, that SCU inhibits PaCa invasion by suppressing Girdin activity, and that Girdin is also involved in angiogenesis via an activation pathway different from the action site of SCU. Girdin may be a prognostic biomarker, and the development of a novel molecular‑targeted drugs for Girdin may improve the prognosis of PaCa in the future.

Serum IgG level is a predicting factor for the response to neoadjuvant chemotherapy in patients with esophageal squamous cell carcinoma

BackgroundDespite the established oncological benefits of neoadjuvant chemotherapy for esophageal squamous cell cancer, not all cases demonstrate benefit. Hence, predicting the response to chemotherapy before treatment is desirable. Some reports have shown that immune factors are related to the chemotherapy response. This study aimed to investigate the utility of serum IgG levels for predicting chemotherapy response.MethodsAmong the patients who underwent esophagectomy after neoadjuvant chemotherapy at Nagoya City University Hospital between December 2012 and June 2019, 130 cases were included in this study. Response to chemotherapy and pretreatment serum IgG levels were examined in 77 cases. FP (5-fluorouracil and cisplatin) therapy or DCF (docetaxel, cisplatin, and 5-FU) therapy was performed as neoadjuvant chemotherapy. DCF therapy was selected for patients aged <75 years, who could be safely administered chemotherapy based on their medical history.ResultsThis study divided cases into two groups: the effective response group (PR) and ineffective response group (SD and PD). We classified 1, 37, and 39 cases as PD, PR, and SD, respectively. None of the cases were classified as CR. The effective response group had significantly lower serum IgG levels than the ineffective response group (p < 0.001). The cutoff serum IgG value was determined to be 1087 mg/dL. The low IgG group had significantly more cases who had effective response to chemotherapy compared with the high IgG group (odds ratio [OR] = 9.009; 95% confidence interval [CI] = 2.974–30.157; p < 0.001). Univariate and multivariate analyses revealed serum IgG level to be an independent predictor for response to chemotherapy (p = 0.001). Furthermore, cases with effective pathological response had significantly lower pretreatment serum IgG levels than those who did not (p = 0.006).ConclusionsOur finding showed that serum IgG levels can be an independent predictor of the response to neoadjuvant chemotherapy for esophageal squamous cell carcinoma.Trial registrationThis retrospective study was approved by the review board of Nagoya City University Graduate School of Medical Sciences (reception number: 60-18-0008).

Suicide, other externally caused injuries and cardiovascular death following a cancer diagnosis: study protocol for a nationwide population-based study in Japan (J-SUPPORT 1902)

IntroductionA growing body of literature has demonstrated that cancer patients have a higher risk of suicide and cardiovascular mortality compared with the general population, especially immediately after a cancer diagnosis....

Anti-Myeloma Activity of a Syringolin Analog: A Dual 20S Proteasome Inhibitor of Beta 2 and 5 Subunits

Background: Bortezomib (BTZ), a proteasome inhibitor (PI), mainly targets the beta 5 subunit of the 20S proteasome, and is widely used in the treatment of multiple myeloma (MM). However, inhibitory effects on other subunits of the proteasome are not well understood. Therefore, we examined the anti-MM activity of novel syringolin analogs that inhibit the activity of both beta 5 and 2 subunits. After examination, we investigated the activity of compound 19a, developed as a syrbactin-class PI to improve cytotoxic activity and membrane permeability (Chiba T et al. Angew Chem Int Ed. 2014).Materials and method: First, the cytotoxic and inhibitory effects of compound 19a on 20S proteasomes of MM cells, including BTZ-resistant MM cells and primary samples derived from MM patients, were examined. The primary MM specimens were collected after obtaining written informed consent at Nagoya City University Hospital, and the mechanism of antitumor activity of compound 19a on MM cells was evaluated by focusing on the unfolded protein response and endoplasmic reticulum (ER) stress. Finally, to evaluate the toxicity of compound 19a, BALB/c mice were intraperitoneally injected with either 19a or BTZ and body weight change was analyzed. These in vivo experiments were performed in accordance with the United Kingdom Coordinating Committee on Cancer Research Guidelines for the Welfare of Animals in Experimental Neoplasia, Second Edition, and were approved by the Ethics Committee of the Center for Experimental Animal Science, Nagoya City University Graduate School of Medical Sciences.Results: The cytotoxic activity of compound 19a, observed in various MM cell lines at nanomolar concentrations, was found to be similar to the activity observed when BTZ-resistant MM and T-cell lymphoma cell lines were tested. More precisely, the two BTZ-resistant cell lines KMS-11/BTZ and OPM-2/BTZ showed 44.4-fold and 52.1-fold higher resistance, respectively, to BTZ than that shown by their parental cell lines KMS-11 and OPM-2. However, the two BTZ-resistant cells showed only 3.2-fold (IC50: 18.0 nM) and 4.3-fold (IC50: 5.1 nM) higher resistance to compound 19a than that shown by their parental cell lines KMS-11 (IC50: 5.7 nM) and OPM-2 (IC50: 1.2 nM), suggesting that compound 19a exhibits less cross-resistance to BTZ. Evaluation of 20S proteasome activity showed time-dependent inhibition of both beta 5 and 2 subunits in MM cells on treatment with compound 19a. Treatment with 10 nM 19a induced remarkable apoptosis of the MM cells, accompanied by elevated CHOP and NOXA expression, indicating excessive ER stress. A similar activity was also observed in primary MM samples derived from the patients. Furthermore, to clarify the effect of beta 2 inhibition on anti-MM activity, two MM cell lines, U266 and AMO1, and one T-cell lymphoma cell line, Hut78, were transfected with either siRNA-targeting PSMB7 encoding beta 2 subunit or control siRNA and were subjected to the analysis of cell growth and viability. Specific knocking down of PSMB7 was observed, which resulted in the progression of apoptosis of the two MM cell lines and Hut78 when compared with the control. In addition, knocking down of both PSMB7 and PSMB5 encoding beta 5 subunits triggered more potent apoptosis of U266 and Hut78 cells when compared with the knocking down of either PSMB7 or PSMB5 alone. This result suggests that dual-inhibitory activities of beta 5 and 2 subunits have an additive or a synergistic effect on cytotoxicity when compared with single inhibitory activity. Finally, to examine the toxicity of compound 19a, BALB/c mice were administrated with it in a dose-escalation manner and subjected to the analysis of alteration of body weight. No significant difference in loss of body weight was observed between 19a-treated and BTZ-treated mice when administered with the same dose. Study of in vivo cytotoxic activity of 19a on xenografted MM cells is currently underway.Conclusion: We demonstrated the cytotoxic activity of a syringolin analog on various MM cells at nanomolar levels, which was attributed to the dual inhibition of beta 5 and 2 subunits of the 20S proteasome. Compound 19a, as a dual inhibitor of beta 2 and 5, was observed to be a more potent PI than BTZ, and could overcome the acquired BTZ resistance. The findings provide new insight into the treatment of relapse and/or refractory MM. [Display omitted] DisclosuresIshida:Celgene KK: Research Funding; Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Bayer Pharma AG: Research Funding. Iida:Janssen Pharmaceuticals: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Clinical significance of NOTCH1 intracellular cytoplasmic domain translocation into the nucleus in gastric cancer.

Recent studies have shown constitutive activation of the Notch signaling pathway in various types of malignancies. However, it remains unclear whether this signaling pathway is activated in gastric cancer. In the present study, the aim was to investigate the role of Notch signaling in gastric cancer by investigating the subcellular localization of Notch-associated proteins in tissue samples from gastric cancer patients. Samples were obtained from 115 gastric cancer patients who had undergone surgery at the Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science without pre-operative chemotherapy or radiation. Subsequently the correlation between translocation of NOTCH1 intracellular cytoplasmic domain (NICD) into the nucleus (as measured by immunostaining) and survival in gastric cancer patients after surgery was investigated. The results were analyzed in reference to the patients' clinicopathological characteristics and the effects of these results on patient prognosis were determined. Significant correlations were observed between NICD nuclear localization and clinicopathological characteristics, such as tumor status (T factor), lymph node status (N factor), pathological stage and differentiation status. No significant correlations were observed between NICD nuclear localization and age, gender, tumor location, vein invasion or lymphatic invasion. Patients with >30% of cancer cell nuclei positively stained for NICD (as revealed by immunostaining) were associated with a significantly shorter survival following surgery than patients with <30% NICD-positive cancer cell nuclei (log-rank test, P=0.0194). Univariate analysis revealed that among the clinicopathological factors examined, T factor [risk rate (RR)=10.870; P=0.0016], N factor (RR=41.667; P=0.0003), lymphatic invasion (RR=13.158; P=0.0125), vein invasion (RR=25.000; P= 0.0019) and translocation of NICD to the nucleus (RR=3.937; P=0.0312) were all identified to be statistically significant prognostic factors. However, multivariate analysis revealed that translocation of NICD to the nucleus was not independently associated with an unfavourable prognosis in patients with gastric cancer. The present results suggest that NOTCH1 acts as an oncogene in gastric cancer. It is hypothesized that translocation of NICD into the nucleus may be used as a therapeutic target in gastric cancer.

Prevention of increased abnormal fundus autofluorescence with blue light–filtering intraocular lenses

To observe changes in fundus autofluorescence 2 years after implantation of blue light-filtering (yellow-tinted) and ultraviolet light-filtering (colorless) intraocular lenses (IOLs). Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, and the Department of Ophthalmology, University of Bern, Bern, Switzerland. Prospective comparative observational study. Patients were enrolled who had cataract surgery with implantation of a yellow-tinted or colorless IOL and for whom images were obtained on which the fundus autofluorescence was measurable using the Heidelberg Retina Angiogram 2 postoperatively. The fundus autofluorescence in the images was classified into 8 abnormal patterns based on the classification of the International Fundus Autofluorescence Classification Group, The presence of normal fundus autofluorescence, geographic atrophy, and wet age-related macular degeneration (AMD) also was recorded. The fundus findings at baseline and 2 years postoperatively were compared. Fifty-two eyes with a yellow-tinted IOL and 79 eyes with a colorless IOL were included. Abnormal fundus autofluorescence did not develop or increase in the yellow-tinted IOL group; however, progressive abnormal fundus autofluorescence developed or increased in 12 eyes (15.2%) in the colorless IOL group (P = .0016). New drusen, geographic atrophy, and choroidal neovascularization were observed mainly in the colorless IOL group. The incidence of AMD was statistically significantly higher in the colorless IOL group (P = .042). Two years after cataract surgery, significant differences were seen in the progression of abnormal fundus autofluorescence between the 2 groups. The incidence of AMD was lower in eyes with a yellow-tinted IOL. No author has a financial or proprietary interest in any material or method mentioned.

Training for Microvascular Surgery in Nagoya City University Graduate School of Medical Science

Training for Microvascular Surgery in Nagoya City University Graduate School of Medical Science

Efficacy of combined corticosteroid and pirfenidone for acute exacerbation of idiopathic pulmonary fibrosis after surgery for lung cancer: A case report

Hirotsugu Ohkubo, MD, PhD, Eiji Kunii, MD, Satoru Moriyama, MD, PhD, Akio Niimi, MD, PhD Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan Department of Oncology, Immunology, and Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan

Prof. Akio Niimi: the clinical identification of cough variant asthma.

Dr. Akio Niimi is the Professor of Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan (Figure 1). He trained in Chest Disease Research Institute, Kyoto University in 1985-1987, and then he worked in Respiratory Medicine, Wakayama Red Cross Hospital in the next two years. From 1989 through 2012 Dr. Niimi worked in Kyoto University Hospital and promoted to Associate Professor in 2008, and to Head of Respiratory Medicine in 2011. During 2002-2003, Dr. Niimi conducted his post-doctoral research under the supervision of Prof. Kian Fan Chung, in National Heart & Lung Institute, Imperial College London, UK.

Postsurgical propriospinal myoclonus emerging at wake to sleep transition

1389-9457/$ see front matter 2013 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2013.07.020 ⇑ Corresponding author. Address: Department of Neurology and Neuroscience, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuhoku, Nagoya, Aichi 467-8601, Japan. Tel.: +81 (0) 52 853 8094; fax: +81 (0) 52 852 3590. E-mail address: toguri@mac.com (T. Oguri). sleep/) Guide for Authors for instructions. We hope this section will be enriched by the contributions of our colleagues who wish to offer stimulating opportunities for discussion and new insights into the field of sleep.

Group cognitive behavioral therapy for patients with generalized social anxiety disorder in Japan: outcomes at 1-year follow up and outcome predictors

BackgroundSocial anxiety disorder (SAD) is one of the most common psychiatric disorders worldwide. Cognitive behavioral therapy (CBT) is an effective treatment option for patients with SAD. In the present study, we examined the efficacy of group CBT for patients with generalized SAD in Japan at 1-year follow-up and investigated predictors with regard to outcomes.MethodsThis study was conducted as a single-arm, naturalistic, follow-up study in a routine Japanese clinical setting. A total of 113 outpatients with generalized SAD participated in group CBT from July 2003 to August 2010 and were assessed at follow-ups for up to 1 year. Primary outcome was the total score on the Social Phobia Scale/Social Interaction Anxiety Scale (SPS/SIAS) at 1 year. Possible baseline predictors were investigated using mixed-model analyses.ResultsAmong the 113 patients, 70 completed the assessment at the 1-year follow-up. The SPS/SIAS scores showed significant improvement throughout the follow-ups for up to 1 year. The effect sizes of SPS/SIAS at the 1-year follow-up were 0.68 (95% confidence interval 0.41–0.95)/0.76 (0.49–1.03) in the intention-to-treat group and 0.77 (0.42–1.10)/0.84 (0.49–1.18) in completers. Older age at baseline, late onset, and lower severity of SAD were significantly associated with good outcomes as a result of mixed-model analyses.ConclusionsCBT for patients with generalized SAD in Japan is effective for up to 1 year after treatment. The effect sizes were as large as those in previous studies conducted in Western countries. Older age at baseline, late onset, and lower severity of SAD were predictors for a good outcome from group CBT.

Safety profiles of topical vitamin D3 in psoriasis patients: a retrospective large-scale study

Correspondence: Akimichi Morita Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, I-Kawashmi Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan Tel +81 52 853 8261 Fax +81 52 852 5449 Email amorita@med.nagoya-cu.ac.jp Abstract: Topical vitamin D 3 ointments are widely used to treat psoriasis, sometimes in combination with cyclosporine, phototherapy, and biologic agents. However, the risk factors for hypercalcemia resulting from these ointments, and interactions with underlying disorders and age are unclear. We performed a retrospective study of psoriasis patients at Nagoya City University Hospital between January 1, 2004, and December 31, 2009, treated with a vitamin D 3 -containing topical drug, either calcipotriol, maxacalcitol, or tacalcitol. Data from blood samples and clinical scores collected during routine visits throughout the study period were analyzed. We assessed changes in the serum calcium levels over time in association with age, liver dysfunction, renal dysfunction, concomitant medication, and concomitant therapy. Serum calcium levels were significantly lower in the calcipotriol group than in the maxacalcitol group (P , 0.05), regardless of other factors, at the observation period. Calcipotriol was associated with lower serum calcium levels than maxacalcitol in patients $ 65 years (P , 0.05), those with renal disease (P = 0.0362), and those with liver disease (P = 0.0255). Only three patients using calcipotriol developed hypercalcemia that did not seem to be related to the treatment. Hypercalcemia was observed in 10 patients using maxacalcitol, although serum calcium levels rapidly recovered when use was discontinued. Only one patient using tacalcitol developed hypercalcemia. Hypercalcemia tended to occur in patients with conditions in which the skin is more vulnerable, even at standard doses; patients taking oral etretinate; patients requiring concomitant systemic therapy, even if the Psoriasis Area and Severity Index score was not severe; and patients with renal or liver dysfunction. These findings highlight the importance of the awareness of the risk factors for hypercalcemia in patients treated with topical vitamin D 3 ointment, and point to calcipotriol as the first-choice treatment for those over 65 years old, or those with renal or liver disease.

Stereotactic Body Radiation Therapy (SBRT) for Stage I Non-small Cell Lung Cancer (NSCLC): Analysis Based on the New TNM Classification and Difference Due to Histology

Stereotactic Body Radiation Therapy (SBRT) for Stage I Non-small Cell Lung Cancer (NSCLC): Analysis Based on the New TNM Classification and Difference Due to Histology C. Hashizume, Y. Shibamoto, Y. Mori, T. Tsugawa, S. Otsuka, A. Hayashi, and H. Nakazawa; Nagoya Kyoritsu Hospital-Radiosurgery Center, Nagoya, Japan, Department of Radiology and Radiation Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

Clinical Experience With Respiratory-Gated Stereotactic Body Radiation Therapy (SBRT) for Lung Tumors Using Audio Coaching

Stereotactic Body Radiation Therapy (SBRT) for Stage I Non-small Cell Lung Cancer (NSCLC): Analysis Based on the New TNM Classification and Difference Due to Histology C. Hashizume, Y. Shibamoto, Y. Mori, T. Tsugawa, S. Otsuka, A. Hayashi, and H. Nakazawa; Nagoya Kyoritsu Hospital-Radiosurgery Center, Nagoya, Japan, Department of Radiology and Radiation Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

Ureteral Advancement in Patients Undergoing Laparoscopic Extravesical Ureteral Reimplantation for Treatment of Vesicoureteral Reflux

Laparoscopic extravesical ureteral reimplantation for vesicoureteral reflux has gained acceptance as a feasible treatment associated with minimal morbidity. However, ureteral advancement with this technique has not been attempted. We examined the usefulness of ureteral advancement via laparoscopy. A total of 30 patients with 51 refluxing ureters underwent laparoscopic extravesical ureteral reimplantation for treatment of vesicoureteral reflux between August 2009 and September 2011. Mean ± SD patient age was 60.8 ± 48.6 months. During the procedure 15 patients underwent ureteral advancement (advancement group), while 15 did not (nonadvancement group). We compared operative times and postoperative rates of urinary tract infections and persistent reflux between the groups. There was no significant difference in operative times in unilateral (mean ± SD 110 ± 25 vs 125 ± 42 minutes) and bilateral cases (mean ± SD 214 ± 52 vs 203 ± 40 minutes) between the nonadvancement vs advancement groups. All patients underwent voiding cystourethrography 3 to 4 months postoperatively. Reflux resolution rate for ureters was significantly higher in the advancement group (100%) than in the nonadvancement group (85%, p <0.05). No patient in the advancement group had postoperative urinary tract infection. Fixation of the ureter with the bladder muscularis at the proximal limit of the detrusor defect and/or a percutaneous hitch stitch placed in the ventral side of the proximal limit of the detrusor defect facilitated ureteral advancement. Ureteral advancement is a simple and feasible procedure in laparoscopic ureteral extravesical reimplantation and may improve the resolution rate of vesicoureteral reflux.

Neurological deficits in a patient with selenium deficiency due to long-term total parenteral nutrition

The neurological symptoms of selenium deficiency are unclear. We report a patient with neurological deficits associated with selenium deficiency following long-term total parenteral nutrition (TPN). A 40-year-old man was referred complaining of visual loss followed by slurred speech and staggering gait that had developed over the preceding 2 months. He had suffered from Crohn’s disease for 22 years and had received home TPN management for 3 years following extensive surgical resection of the gastrointestinal tract. As a result of shortbowel syndrome, he received only a little water and gastric coating agents. Neurological examination showed visual loss, bradyarthria, truncal and limb ataxia, and loss of limb proprioception. Physical examination showed curly hair and whitened nail beds on the fingers and toes, which had developed 3 months before the neurological manifestations (Fig. 1a, b). Brain magnetic resonance (MR) imaging and MR spectroscopy appeared normal. Ophthalmological examination showed large optic disc cupping, concentric visual field constriction and diminished flicker sensitivity without elevation of intraocular pressure, suggesting optic nerve disorder. Blood examination revealed an elevated mean corpuscular volume (MCV) of 109.1 fl. Blood concentrations of vitamins A, B1, B2, B6, B12, C and E, folic acid and trace metals (Fe, Cu, Zn, Pb and Al) were all normal. Serum inflammatory and autoimmunological markers, including antineuronal antibodies, and cerebrospinal fluid findings showed no abnormalities. Clinical history, nail and hair abnormalities, and macrocytosis were suspicious for selenium deficiency. The serum selenium level was below the detection limit of 2.0 lg/dl. He was diagnosed with systemic dysfunctions caused by selenium deficiency, and 100 mg/day sodium selenite was administered intravenously. By continuous administration, his curly hair and whitened nail beds gradually disappeared (Fig. 1c, d), and the MCV returned to normal over several months. Although deterioration of his neurological symptoms stopped shortly after initiation of replacement, improvements were insufficient to allow resumption of daily activities. Visual, speech and gait disturbances were unchanged by 3 years of selenium replacement. Selenium is an essential trace element that acts as an antioxidant in tissues [1, 2]. Selenium deficiency may occur as a result of long-term unphysiological nutrition, and is known to present macrocytosis [3], nail bed or hair abnormalities [3–5], skeletal muscle disorders [6, 7] and cardiomyopathy [8], between 1 month and 6 years [6, 8, 9]. The scarcity of cases, however, means that the neural symptoms of selenium deficiency remain unknown. To the best of our knowledge, only seven cases with neurological symptoms have been reported, including the present and three in Japanese abstracts (not available via MEDLINE) [10, 11]. Visual disturbance was the major symptom in six of these, and other neurological symptoms included consciousness disturbance, dysarthria, spasticity of the extremities, ataxia and sensory disturbances. These were manifested over 1–12 years after initiating TPN or T. Oguri M. Hattori T. Yamawaki N. Matsukawa (&) K. Ojika Department of Neurology and Neuroscience, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-ku, Nagoya 467-8601, Japan e-mail: norim@med.nagoya-cu.ac.jp

Factors influencing distant recurrence of hepatocellular carcinoma following combined radiofrequency ablation and transarterial chemoembolization therapy in patients with hepatitis C

Background:The purpose of this study was to clarify important risk factors for distant recurrence of hepatocellular carcinoma in patients positive for hepatitis C and without local recurrence.Methods:A total of 212 patients (145 males and 67 females) underwent radiofrequency ablation and transcatheter arterial embolization or transcatheter arterial chemoembolization at initial development of hepatocellular carcinoma. All patients were positive for hepatitis C. Child–Pugh classification was A in 115 and B in 97. The indication for radiofrequency ablation was the presence of up to three tumors ≤ 3 cm. The distant recurrence rate was analyzed using the Kaplan–Meier method and tested by Wilcoxon’s method.Results:Cumulative distant recurrence rates at years 1, 3, and 5 were 19%, 62%, and 79%, respectively. On univariate analysis, a ≥ 3 cm tumor, ≥ 50 ng/mL α-fetoprotein level, and < 3.6 g/dL serum albumin level were significant risk factors for distant recurrence, but only a serum albumin level < 3.6 g/dL (P = 0.004) was identified as significant on multivariate analysis. In the group with a pretreatment albumin level ≥ 3.6 g/dL, the distant recurrence rate was compared between patients in whom the albumin level rose, remained unchanged, or decreased by < 0.3 g/dL, and those in whom the level decreased by ≥ 0.3 g/dL. The rate was significantly higher in the latter, with a one-year recurrence rate of 7% versus 15% (P = 0.04).Conclusion:Distant recurrence was significantly decreased in patients with a high serum albumin level. Distant recurrence was more likely to occur in patients with a decreased albumin level, although the pretreatment level was high. Thus, strict follow-up after treatment for hepatocellular carcinoma is necessary in patients with low serum albumin levels.

Factors influencing distant recurrence of hepatocellular carcinoma following combined radiofrequency ablation and transarterial chemoembolization therapy in patients with hepatitis C

Factors influencing distant recurrence of hepatocellular carcinoma following combined radiofrequency ablation and transarterial chemoembolization therapy in patients with hepatitis C Shunsuke Nojiri, Atsunori Kusakabe, Noboru Shinkai, Kentaro Matsuura, Etsuko Iio, Tomokatsu Miyaki, Takashi JohDepartment of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, JapanBackground: The purpose of this study was to clarify important risk factors for distant recurrence of hepatocellular carcinoma in patients positive for hepatitis C and without local recurrence.Methods: A total of 212 patients (145 males and 67 females) underwent radiofrequency ablation and transcatheter arterial embolization or transcatheter arterial chemoembolization at initial development of hepatocellular carcinoma. All patients were positive for hepatitis C. Child&ndash;Pugh classification was A in 115 and B in 97. The indication for radiofrequency ablation was the presence of up to three tumors &le; 3 cm. The distant recurrence rate was analyzed using the Kaplan&ndash;Meier method and tested by Wilcoxon&rsquo;s method.Results: Cumulative distant recurrence rates at years 1, 3, and 5 were 19%, 62%, and 79%, respectively. On univariate analysis, a &ge; 3 cm tumor, &ge; 50 ng/mL &alpha;-fetoprotein level, and &lt; 3.6 g/dL serum albumin level were significant risk factors for distant recurrence, but only a serum albumin level &lt; 3.6 g/dL (P = 0.004) was identified as significant on multivariate analysis. In the group with a pretreatment albumin level &ge; 3.6 g/dL, the distant recurrence rate was compared between patients in whom the albumin level rose, remained unchanged, or decreased by &lt; 0.3 g/dL, and those in whom the level decreased by &ge; 0.3 g/dL. The rate was significantly higher in the latter, with a one-year recurrence rate of 7% versus 15% (P = 0.04).Conclusion: Distant recurrence was significantly decreased in patients with a high serum albumin level. Distant recurrence was more likely to occur in patients with a decreased albumin level, although the pretreatment level was high. Thus, strict follow-up after treatment for hepatocellular carcinoma is necessary in patients with low serum albumin levels.Keywords: distant recurrence, hepatocellular carcinoma, radiofrequency ablation

Newly developed back pain after subthalamic nucleus stimulation in Parkinson’s disease

Dear editor, Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been widely performed for medically refractory Parkinson’s disease (PD). We have encountered patients with newly developed back pain after successful STNDBS surgery. In this report, we review these cases and discuss the pathogenesis of newly developed back pain after STN-DBS. Between November 2003 and December 2008, 148 patients with medically refractory PD underwent implantation of bilateral STN-DBS electrodes in Nagoya City University Hospital, Nagoya, Japan. STN-DBS was indicated in most patients for significant motor complications from levodopa such as fluctuation and dyskinesia. Among these patients, seven complained of newly developed back pain in the early period after STN-DBS despite having had no experience of back pain before STN-DBS. None of the patients showed camptocormia. The demographic details for all patients are shown in Table 1. STN-DBS yielded marked improvement in the UPDRS III motor score and UPDRS IV dyskinesia/fluctuation score, and reduced the need for dopaminergic medication in all patients. The time until they complained of back pain varied from 2 weeks to 5 months after surgery. Imaging study of lumbar X-ray, CT or MRI revealed various lumbar spine pathologies such as lumbar disc herniation, lumbar spinal stenosis, scoliosis, spondylolisthesis, and old compression fracture. Two patients subsequently underwent lumbar surgery for their lumbar pathology. We performed lumbar laminectomy and discectomy for disc herniation, and laminectomy and pedicle screw-rod fixation for spondylolisthesis. One patient was treated with epidural injections, and the other four patients were treated conservatively with analgesic medication. Consequently, the back pain was controlled well in all of the patients. Several types of pain occur frequently in PD. Ford classified pain in PD into several categories: musculoskeletal pain, radicular or neuropathic pain, dystonia-related pain, central or primary pain, and akathitic discomfort [2]. The most prevalent painful sensations in PD seem to be musculoskeletal pain and dystonia-related pain. Depression in PD may also confound and aggravate pain. Back problems in particular seem to be common in PD. Broetz et al. reported that the prevalence of back pain in PD (74%) was significantly higher than in control patients (27%) [1]. Postural abnormalities or truncal dystonia in PD seem to put stress on the lumbar disc structures and cause lumbar disc herniation. Increased muscle tone and reduced flexibility of the spine may also cause nonradicular back pain originating from the muscle, soft tissues, and skeletal structures. Some previous studies demonstrated that STN-DBS improved fluctuating pain, namely, pain in the "off" period [3, 6]. STN-DBS also improves painful "off" period dystonia [4]. Nevertheless, we showed that a significant incidence (approximately 5%) of newly developed back pain occurs after STN-DBS in spite of the marked improvement of cardinal PD symptoms. Kim et al. also reported that new pain developed in some patients A. Umemura (*) :Y. Oka :A. Okura :K. Yamada Department of Neurosurgery, Nagoya City University Graduate School of Medicine, 1 Kawasumi, Mizuho-ku, Nagoya 467-8601, Japan e-mail: aume@med.nagoya-cu.ac.jp

Increased reactive oxygen metabolites is associated with cardiovascular risk factors and vascular endothelial damage in middle-aged Japanese subjects

BackgroundVascular endothelium, a provider of nitric oxide, is essential for the maintenance of homeostasis in healthy vascular systems. Increased oxidative stress promotes vascular inflammation and is a common pathway involved in endothelial damage. The present study sought to investigate the usefulness of derivative reactive oxygen metabolites (d-ROM) as an oxidative stress marker for detecting endothelial damage in the clinical setting in subjects with early-stage atherosclerosis.MethodsStudy 1 investigated the relationship between serum d-ROM levels and cardiovascular risk factors in apparently healthy middle-aged subjects (n = 1992, 49 ± 8 years) who participated in our health checkup program. Study 2 analyzed the association between d-ROM levels and endothelial function assessed by flow-mediated dilation and that between d-ROM levels and high-sensitivity C reactive protein (hs-CRP) levels in middle-aged outpatients with mild-to-moderate cardiovascular risk (n = 43, 40 ± 5 years).ResultsIn study 1, the d-ROM level was independently correlated with age, systolic blood pressure, fasting plasma glucose, low-density lipoprotein cholesterol, and brain natriuretic peptide in univariate and multivariate regression analysis. In study 2, the d-ROM level was correlated positively with the hs-CRP level and inversely with the flow-mediated dilation value. Patients in the highest tertile of d-ROM had significantly lower flow-mediated dilation values compared with patients in the other tertiles. Moreover, after subdivision of patients into four groups according to d-ROM and hs-CRP levels, patients with high levels of both d-ROM and hs-CRP showed significantly reduced flow-mediated dilation as compared with those with low levels of both indices.ConclusionThe close relationship of d-ROM with cardiovascular risk factors, brain natriuretic peptide, inflammatory markers (hs-CRP), and endothelial function (flow-mediated dilation) suggest that d-ROM is a useful oxidative stress marker for detection of endothelial damage in the clinical setting. Assessment of d-ROM, especially combined with hs-CRP, may be a possible predictor of cardiovascular disease.