Advances in Modern Medicine

A concurrent superselective intra-arterial chemoradiotherapy (SIACRT) is a new therapeutic strategy for advanced squamous cell carcinomas of the maxillary sinus and upper gingiva that might enable patients to keep the shape and function as well as improve curability. We have been applying SIACRT since 2008. We will present the results of SIACRT compared to conventional combined therapy at our hospital. SIACRT is promising to preserve patient’s quality of life (QOL) both under and after the treatment without sacrificing a cure rate.

To examine long-term outcomes of a single institution’s cases of partial breast irradiation.

Between January 1990 and March 2001, a total of 104 patients with T1 or T2 breast cancer were treated with partial breast irradiation using external beam after breastconserving surgery. Ipsilateral breast tumor recurrence (IBTR) and contralateral breast tumor occurrence (CBTO) were examined. Median follow-up time was 10.2 years.

IBTR rates at 5, 10 and 15 years were 2%, 6.5% and 13.2%, respectively. CBTO rates at 5, 10 and 15 years were 0%, 1% and 5%, respectively. Failure within radiation field occurred in 1 patient and failure outside radiation field occurred in 7 patients. Of 7 recurrences outside radiation field, 1 recurred diffusely in the skin of the breast, 3 recurred in another portion of the breast and 3 recurred in the breast near the radiation field. The incidence of failure outside radiation field was high compared to that of CBTO, but this difference was not statistically significant (p=0.059).

This study speculates that PBI is a feasible alternative to WBI.

We examined the expression of ER, HER2, Ki-67, CK5/6 and EGFR by immunohistochemistry in breast tumors from patients who underwent neoadjuvant chemotherapy (NAC).

88 breast cancer patients who received NAC and surgery at our institute between January 2008 and March 2013 were enrolled. Staining results of ER, HER2, CK5/6, EGFR and Ki-67 were quantitated by automated immunostaining analysis. Patients were stratified into four grades (0, 1+, 2+, 3+) by ER status. Ki-67 index and nuclear grade were compared between a CK5/6- and/or EGFR-positive cohort and a CK5/6- and EGFR-negative cohort for each ER status grade. We also assessed response to chemotherapy according to ER, CK5/6 and EGFR status in a HER2 negative cohort.

The percentage of CK5/6- and/or EGFR-positive tumors decreased inversely with increasing degree of ER expression. In the ER0 cohort, the CK5/6- and/or EGFRpositive cohort had a higher Ki-67 index (p=.0875) and nuclear Grade 3 (p=.0036) than a CK5/6- and EGFR-negative cohort. A CK5/6- and/or EGFR-positive cohort showed a higher tumor reduction rate of clinical effect than a CK5/6- and EGFR-negative cohort (mean=57.3% and 24.6%, respectively, p=.2053) in an ER0 cohort. In the CK5/6- and/or EGFR-positive cohort, two of nine showed Grade 3 and seven showed Grade 2a or more of pathological effect. In cohorts of ER2+ or ER3+, there was no correlation between CK5/6 and EGFR status and response to chemotherapy.

In triple negative breast cancer (TNBC), CK5/6 and EGFR expression can be utilized as markers that differentiate the effect of NAC.

Immunohistochemical (IHC) and molecular findings with their histopathological diagnosis are critical in the current therapeutic strategy for a breast cancer patient. These findings require considerable manual human involvement and interpretations can be subjective. In this study, we examined the usefulness of an autoanalysis computer system for analysis of IHC findings.

Forty breast-cancer specimens were examined for IHC expressions of estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki-67 and Topoisomerase II alpha (TopoIIa). One-hundred-fifty-six cancer specimens were examined for HER2. Histopathological images of IHC specimens were stored digitally thru virtual microscopy (Hamamatsu Photonics). A Genie/Aperio software package on a desktop computer auto-analyzed these images.

For ER and PgR, concordant results were obtained between ocular observation and auto-analysis (p < 0.001). The Ki-67 index (r = 0.96) and TopoIIa index (r = 0.95) also showed a significant correlation (p < 0.001). Concordant ratios were 92.9%, 82.2%,

59.5% and 100% for HER2 score 0, 1, 2 and 3, respectively. 24 cases (28.6%) of 84 cases with a HER2 score of 2 by ocular observation were re-analyzed as a score of 3 by auto-analysis. 19 cases (79.2%) of these re-scored cases showed HER2 gene amplification by FISH analysis.

In sum, well-organized auto-analysis is able to provide objective results. Thus, autoanalysis might be a means by which to standardize methods for immunohistochemical detection of breast cancer.

We conducted a paper-based questionnaire and interview targeting patients with breast cancer who had undergone radical surgery, before and after they attended the Pathology Clinic, to investigate the short-term impact on the psychological state and attitude of the patients from attending the Pathology Clinic. There may be increased motivation for treatment and a sense of reassurance, as well as reduction in anxiety in patients as a status indicated by HADS in the group that attended the Pathology Clinic, so this suggests that attending the Pathology Clinic may reduce anxiety in a short term. On the other hand, the MAC Anxious Preoccupation score was significantly higher in the group that attended the Pathology Clinic, both before and after attendance, than the group that did not attend. Therefore, the group that attended may have had characteristics of eliminating anxiety by proactive actions including collecting medical data on the cause of anxiety and adopting healthy behaviors. The result suggests that appropriate support in terms of medical information and emotion is necessary.

To provide a less invasive procedure in video-assisted thoracic surgery (VATS), it is necessary to evaluate two types of VATS approaches in terms of clinical outcome, especially cancer recurrence.

We conducted a prospective feasibility study of two strictly defined types of VATS lobectomy by prospective cohort. Based on a patients’ decision after a similar preoperative explanation, cancer recurrence and long-term-prognosis were evaluated by comparing among assisted VATS and complete VATS groups.

One-hundred-four consecutive patients with clinical T1N0M0 non-small cell lung cancer (NSCLC) were analyzed. Twenty-six cases (ASSIST group) chose lobectomy performed through an anterolateral small thoracotomy with the use of a rib spreader in combination with a thoracoscopic view and direct view. Seventy-eight cases (PURE group) chose complete VATS in which only a monitor was used during smaller access thoracotomy without a rib spreader. Patients in the PURE group exhibited early recovery from surgery. The recurrence rate was equivalent (both 19.2%). At 2,039 days of a median follow-up period, the recurrence pattern was also similar between the two groups; however, two cases (2.6%) of pleural dissemination appeared only in the PURE group. Specific clinicopathological characteristics were not confirmed in the recurrent cases. Recurrence-free and overall 5-year survival rates were equivalent between the two groups.

Both PURE and ASSIST are feasible in terms of cancer recurrence and long-term prognosis.

DNA methylation is the main mechanism of epigenetic gene silencing that regulates gene expression without altering the DNA sequence, and the promoter methylation of various genes has been demonstrated to be involved in the development and/or progression of lung cancer. The growing body of evidence shows that DNA methylation of several specific genes has been identified as molecular biomarkers that accurately predict the outcome of disease. Additionally, in an effort for early detection of lung cancer, the effect of analyzing DNA methylation in several remote media has also been investigated. Here, recent achievements regarding the role of DNA methylation as a biomarker for prognostic prediction and early detection in lung cancer are reviewed.

To reduce the risk of adverse events related to colorectal endoscopic submucosal dissection (ESD) using a conventional knife, we used a scissors-type knife (SB Knife Jr.) that allowed us to prevented unexpected muscular-layer injury.

The aims of our study were to evaluate the efficacy and safety of ESD using a SB Knife Jr. for early colorectal neoplasms. 121 lesions in 115 patients (M: F=63: 52; median age=68) were resected with ESD using a SB Knife Jr. from October 2010 to March 2014. We evaluated en bloc resection rate, complete resection rate, size of tumor, adverse events and local recurrence rate.

The sites of the neoplasms included the following: 39 lesions were located in the right colon; 38 in the left colon; and 44 in the rectum. By histological examination, 57 lesions were intramucosal cancers, 14 slightly submucosal cancers (<1,000 μm), 15 massively submucosal invasive cancers (>1,000 μm), and 35 tubular adenomas. All lesions were treated safely without unexpected incision. The en bloc resection rate was 96.7% (117/121), and the complete resection rate was 95.0% (115/121). The mean size of the resected tumors was 32.1 mm (range, 7-120 mm), respectively. With regard to adverse events, there were no perforations, and postoperative bleeding occurred in 5 cases (4.1%). All cases were controlled by endoscopic hemostasis. During a median follow-up duration of 15.5 months, local recurrence rate was 0% (0/121).

ESD using a SB Knife Jr. can be adequately adopted as a technically efficient method for resecting early colorectal neoplasms.

Objective: Self-expanding metallic stents (SEMS) have been employed as a palliative treatment for patients with obstructive colorectal cancer or as bridge to surgery for potentially resectable colorectal cancer (CRC). However, concerns have been raised about whether shear forces that act on the tumor during expansion of the stent may result in a release of cancer cells into the circulation (i.e., CTCs). This study was conducted to determine whether insertion of colonic stents results in increased levels of CTCs.

Methods: Between October 2013 and November 2013, three patients who underwent colonic stent insertion for obstructing colorectal cancer were studied. To detect viable CTCs of CRC, we employed a TelomeScanF35 detection system, which was constructed with a GFP-expressing attenuated adenovirus, in which the telomerase promoter regulates viral replication. 7.5ml of peripheral blood samples were obtained before and after stent insertion and after operation.

Results: Three patients were inserted SEMS and performed laparoscopic surgery. In one of these 3 patients, CTCs increased after stent insertion and continued in expression after the operation.

Conclusions: This study demonstrated that endoscopic stent insertion results in dissemination of tumor cells into the peripheral circulation. Although oncological consequences were not examined in this small population, viable CTC detected by TelomeScanF35 may represent a suitable prognostic marker to stratify the risk of patients with distant metastasis following stent insertion for obstructing colon cancer.

Minimally invasive surgery for liver resection still remains controversial. The present study was designed to compare open versus laparoscopic liver resection (LLR).

Between January 2012 and December 2013, LLR was performed on 30 patients at our institution. We performed partial hepatectomy through a pure laparoscopic method and anatomical hepatectomy by a laparoscopy-assisted method. We performed a retrospective review of these patients.

The study comprised 25 men and 5 women with a mean age of 70.5 years. All patients had a liver function of Child-Turcott-Pugh classification A. The mean diameter of the tumors was 20.8 mm. Thirteen cases were resected by the pure method and 17 cases underwent the hybrid method. Nineteen patients underwent partial hepatectomy, 8 patients underwent subsegmentectomy, and 3 patients underwent segmentectomy. Mean intra-operative bleeding was 403.7 ml, and mean operating time was 316.4 min. No patients developed severe postoperative complications. We compared 19 laparoscopic partial hepatectomies (LLR-P) with 9 open partial hepatectomies. Although, no significant differences were observed in perioperative factors, both length of hospital stay and the frequency of analgesic administration were significantly reduced in LLR-P. Furthermore, we compared 13 laparoscopic (sub) segmentectomies (LLR-S) with 11 open cases. The operation time of LLR-S were longer than those of open cases, whereas no significant differences were detected in blood loss in these procedures. All length of hospital stay favored the LLR-S group.

In these series comparing laparoscopic and open liver resections, there were no severe complications observed in the LLR group and there was significant rapid recovery in the LLR group, even for resections involving (sub) segmentectomy by the hybrid method.

Transcatheter arterial chemoembolization (TACE) is the interventional technique and mainstay of treatment for unresectable hepatocellular carcinoma (HCC). TACE is indicated mainly for unresectable HCC, cholangiocarcinoma, and hepatic metastases. In this method if used worldwide; however, many regimens, embolic materials, and techniques exist. The clinical results are also controversial. We present the history and the status of TACE for HCC.

Pancreatic cancer remains lethal and most are resistant to traditional therapies. New therapeutic approaches, such as immunotherapy are in urgent demand. Anti-Gal antibody (Ab) is known as the most abundant natural Ab in humans, and the anti-Gal ligand called “α-gal epitopes” with the structure Galα1-3Galβ1-4GlcNAc-R is expressed as a major carbohydrate antigen. Pancreatic cancer cells or their lysate may express α-gal epitopes. Subsequent vaccination with such processed cell membranes result in in vivo opsonization by anti-Gal IgG in cancer patients. The interaction of the Fc portion of the vaccine-bound anti-Gal Ab with Fc cγ receptors of APC induces an effective uptake of the vaccinating tumor cell membranes by the APC, followed by the effective transport of the vaccinating cancer membranes to the regional lymph nodes, and processing and presentation of the cancer-associated antigens. Activation of cancer-specific lymphocytes elicits an immune response to eradicate the residual cancer cells that remain after completion of standard therapy in some patients. This review focuses on this unique antigen/antibody system (α-gal epitope/natural anti-Gal Ab) and shows advances in immunotherapy for pancreatic cancer.

Liquid-based cytology (LBC) has been adopted widely throughout the world. However, diagnosis for glandular abnormalities still remains difficult.

LBC and conventional Papanicolaou smear (CS) were compared for cytological diagnosis by a split- sample method. The results showed that LBC reliability is near to that of CS for screening of glandular malignant lesions.

Herein, we detail the results of 69 cases analyses that were diagnosed as a glandular abnormality by the TP method among a total of 11,092 cases. The TP method resulted in the same diagnosis of CS as either AGC or adenocarcinoma in 54 cases (78.3%), upgrading in four cases (5.8%), and down-grading in seven cases (10.1%). From detailed analysis of individual cases, it is thought that one cause of discrepancy was the characteristic morphology of the cells and clusters that appeared in TP samples.

These results suggest that adequate knowledge of the characteristic features of glandular lesions in LBC could contribute to a more accurate diagnosis and to shifting to LBC for cervical cancer screening.

Telomere dynamics have been reported extensively as a critical component of cancer, and established evidence exists an important relationship between telomere biology and cancer. Although more than 85% of all carcinomas rely on telomerase activity to maintain stable telomere length, most normal somatic cells are telomerase negative. Therefore, effective methods for specific diagnostic and prognostic utility by telomerase detection have been described, and, to date, ideal targeting telomerase therapy with minimal adverse effects on normal somatic cells have been attempted. In this mini review, we summarize the role of telomeres and telomerase in cancer, clinical use, and targeted telomerase cancer therapies.

In Japan, the Cancer Control Act was passed in 2006. Consequently, our center has been proactively conducting palliative care promotions. Concerning health insurance coverage, the “Cancer Counseling Fee” became payable for health insurance remuneration as of April 2010. The cancer counseling fee covers the service provided to patients diagnosed with malignant tumors in an environment with sufficient consideration of their psychological states. Physicians with experience in cancer treatment and full-time nurses with experience with cancer patients collaborate to explain and consult with patients to allow them to select a line of treatment upon full understanding of and consent to diagnoses and treatment methods. At our center, cancer patients are offered cancer counseling in all clinical departments, and an explanation by a pathologist in a pathology clinic plays an important role in performing well-organized cancer counseling.

When explaining the diagnosis to patients in the pathology clinic, the pathologist also attends to the patients’ emotions while listening to their anxieties and empathizing with their pain. Patients that accurately understand the conditions of their illness and the treatment’s policies and effects are more likely to consent to the explanation by the attending physician and proactively accept the standard therapy by the attending physician, which increases medical compliance. The combination of the explanation by a pathologist in the pathology clinic and cancer counseling by a nurse can improve the mental disposition of these patients.

In recent years, the treatment and diagnosis of childhood cancer has led to dramatic improvements in survival rates. Approximately, 75-80% of affected children survived a malignant disease. However, the improvement in prognosis has been achieved at the expense of serious late effects from cancer and cancer treatment. Endocrinological late effects are the most common problem and were found in approximately 20-30% of child cancer survivors (CCSs). Endocrinologists should participate in the follow-up of CCSs in collaboration with pediatric oncologists. Further, long-term follow up is necessary for CCSs because treatment-related complications may occur during childhood and many years after therapy.

An esophagectomy with three-field lymph node dissection has been performed widely in Japan, but multidisciplinary therapy that uses a combination of radiation therapy and chemotherapy is necessary to improve the prognosis in patients with advanced esophageal cancer. Several new techniques have contributed to reducing post-operative complications and we have introduced some techniques into the treatment of esophageal cancer at our hospital.

The recent increase in obesity is a worldwide social problem. Because obesity leads to the enormous increases in the patients with diabetes mellitus (DM) and coronary artery disease (CAD), it has become a growing health threat. Many researchers have found that various bioactive molecules released from adipose tissues, which are conceptualized as adipocytokines/adipokines, are involved in the pathogenesis of obesity-associated diseases. Adiponectin is an adipocytokine that exerts insulin-sensitizing effects in the liver and skeletal muscle and suppresses atherosclerosis in vascular walls via various anti-inflammatory effects. Clinically, circulating adiponectin levels inversely correlate with body mass index (BMI), which may explain the molecular basis that underlies obesity-associated development of DM and CAD. Many clinical studies have demonstrated that low circulating adiponectin levels are associated with the incidence of DM and CAD.

Recently, we showed that reduced adiponectin levels were associated with multi-vessel coronary artery atherosclerosis as detected on computed tomography coronary angiography (CTCA), and adiponectin may be a useful biomarker to predict multivessel coronary atherosclerosis when detected using CTCA in combination with common risk factors including age, sex, DM, and hypertension. Moreover, in another study, we showed that reduced adiponectin levels were associated with elevated serum oxidized low-density lipoprotein levels in which dyslipidemic components of metabolic syndrome were strongly involved. Thus, adiponectin levels are associated directly and indirectly with the development of atherosclerosis.

Measuring adiponectin concentration should provide beneficial information for the selection of high-risk patients and contribute to the reduction of fatal CAD by applying aggressive preventive therapy.

Type 2 diabetes (T2D) is a global health issue and developing new therapies continues to be urgent. Inflammation is thought to participate in the pathogenesis of obesity-induced insulin resistance and T2D, and is a potential target to treat this disease. Circulating white blood cell (WBC) number or C-reactive protein (CRP) concentration, which is a representative blood marker of the inflammation, can predict the incidence of T2D. Recent studies have shown that obesity is accompanied by chronic local inflammation in adipose tissue and increments of adipose tissue macrophage (ATM) number. ATMs are involved in the deterioration of systemic insulin sensitivity, and monocyte chemoattractant protein-1 (MCP-1) contributes to the migration of macrophages into fat and development of insulin resistance. Salicylate and thiazolidinedione (TZD) affect immune cells in circulating blood or adipose tissue, which leads to improved insulin sensitivity systemically. Pharmacological intervention for chronic inflammation may provide a new approach to the treatment of T2D in the future.

We evaluated renal function before and after laparoscopic partial nephrectomy by calculating differential renal function thru the use of renal scintigraphy with 99mtecnetium-mercaptoacetyltriglysine (99mTc-MAG3).

Differential renal function was assessed for 62 patients undergoing laparoscopic partial nephrectomy for renal tumors with renal scintigraphy before operation and six months post operation.

Mean operating time, ischemic time, blood loss and tumor diameter were 142 min, 27 min, 75 ml and 2.0 cm, respectively. The mean reduced rates of calculating glomerular filtration rate (cGFR) of a bilateral and the diseased-side kidney were 7.96% and 23.3%, respectively, and was statistical significant (p<0.001).

Meanwhile, the mean rate of increase of cGFR on the non-diseased-side kidney was 6.8%, which was significantly decreased (p=0.005). By univariate analysis, patients with a tumor of more than 2 cm in size and with clamping of the renal artery for over 30 minutes had decreased 6-month postoperative cGFR by more than 20%.

In multivariate analysis, tumor size was the most significant factor related to a decrease in cGFR. Patients with a tumor larger than 2 cm in size had a longer operation time (p=0.0005) and a higher amount of bleeding (p=0.0012).

In comparison, the six-month postoperative cGFR of patients less than 55 years-old had significantly increased cGFR over 20%.

Lower cGFR of the diseased-side kidney after partial nephrectomy was predicted by longer ischemic interval and tumor size. Age predicted increasing cGFR of the nondiseased side after partial nephrectomy. Currently, we are endeavoring to shorten ischemic time. Younger patients with renal tumors should adapt to laparoscopic partial nephrectomy.

Beginning 2014, all newborns living in Japan will have newborn screening (NBS) using tandem mass spectrometry (MS/MS). We participated in a pilot study for this new NBS initiative and provided diagnoses in cooperation with Hiroshima University and other facilities. Here, we introduce the information that we obtained. Medium-chain acyl-CoA dehydrogenase deficiency (MCADD), ACADM mutations found among Japanese patients are quite different from those of Caucasian patients. We estimated MCAD activities of 11 mutants found among Japanese patients and positively screened babies using molecular genetics methods. Some mutations were destructive, but others found by NBS maintained activities to a certain degree. Regarding methylmalonic academia (MMA), we found the first Japanese patient with isolated methylmalonic acidemia caused by a cblD defect. Unfortunately, he was negative in the NBS and developed acute metabolic decompensation during an acute illness. We found MMADHC mutation heterozygously in this patient. Through our study, we offered reliable data for most of the positively screened newborns and their family members through our original enzymatic assay using peripheral blood mononuclear cells. We also obtained beneficial information from these investigations. In order to raise the quality of the newly introducing MS/MS-NBS system in Japan, it is essential to achieve accurate diagnosis through a combination of enzymatic and genetic evaluation.

Recent advancements in medical technology have led to development of various medical equipment and have improved clinical outcomes. Management of medical equipment requires expertise and knowledge of technical know-how, and there is a growing need for professional engineers in clinical practice. In Japan, a clinical engineer (CE) operates life-sustaining devices and provides maintenance management of life-sustaining device; the term CE was officially established in 1987. CEs have contributed to the development of a medical procedure by becoming technical experts.

In our hospital, the hyperbaric oxygen chamber operated by a CE was used to treat patients diagnosed with sudden sensorineural hearing loss or decompression illness. This job requires expertise of target illnesses. The oxygenator for cardiopulmonary bypass surgery is also operated by a CE, and handling of this instrument needs an inventive approach, as it directly affects the surgical outcome. For implantable cardiac devices, the CE helps to merge knowledge from the fields of electrophysiology and engineering. Configuring accurate device programming improves patients’ prognoses. Furthermore, not just life-sustaining devices but also various medical equipment are centrally managed by the CE. Such management allows efficient use of the medical equipment.

In Japan, the CE contributes tremendously to clinical practice. CEs make the efficient use medical procedures using inventive approach or by active participation or management of these devices.

Postmortem studies of patients with depression show a reduction of glial cells and altered expression of glia-related genes in restricted areas of the brain, suggesting that glia are part of a neural network affected in the pathophysiology and treatment of the disorder. Glia, especially astrocytes, are major components in the CNS and play a role in the storage of several types of neurotrophic factors that might be systematically associated with the pathophysiology and treatment of depression. The expression of neurotrophic factors caused by antidepressants in glia is regulated by not only a monoamine-dependent, but also a monoamine-independent mechanism. Our data demonstrated that astrocytes stimulated by an antidepressant may be important mediators that produce several neurotrophic/growth factors, especially GDNF and FGF-2, through a de novo protein synthesis-dependent and a monoamine-independent mechanism. Antidepressants act directly on astrocytes to increase GDNF production after the activation of the FGFR/FRS2alpha/ERK/CREB signaling cascade via a MMPdependent shedding of FGFR ligands. Clarifying monoamine-independent novel targets of antidepressants in astrocytes may contribute to the development of more effective treatments for depression.

We reviewed the history of electroconvulsive therapy (ECT) around the world and in Japan. Although the practice of ECT began in Japan at around the same time as the discovery of ECT in the world, improvements in anesthetics and ECT devices in Japan have not progressed at a similar pace in comparison with that of the world. Recently, a brief pulse device was approved for use in Japan and ECT practice guidelines were established. ECT has been recently reevaluated and an ECT network has been extended in Japan.

Specifically, we offer here a history of ECT and clinical and biological research findings for ECT from the Kure Medical Center. In 2013, our center conducted nearly 500 ECT sessions with approximately 40 individuals who had mood disorders, schizophrenia or Parkinson disease. Research on ECT has shown that several factors are important in recovery. For example, a strategy that includes a dosage of stimulation energy or reduction of anesthetic might be effective for ECT treatment. Mood stabilizers such as lithium may be effective in preventing relapse after ECT, not only in mood disorders, but also for schizophrenia. In addition, cerebral blood flow evaluation using near-infrared spectroscopy and blood markers such as matrix metalloproteinases may be related to diagnosis and the course of ECT treatment.

Antidepressants and electroconvulsive therapy (ECT) are major therapeutic strategies for mood disorders. ECT is the most potent treatment for antidepressantresistant mood disorders; however, the underlying mechanisms of action remain largely unclear. Therefore, the identification of the molecular and cellular mechanisms affected by ECT may provide further insight into the pathophysiology of depression and the development of more effective therapeutic strategies.

Herein, a variety of hypotheses on the pathophysiology of mood disorders and the mechanism of antidepressive treatments are reviewed, with an emphasis on synaptogenesis. Our findings suggest that synaptogenesis is involved in the mechanism of action of ECT, possibly via thrombospondin (TSP)-1, a member of TSP family that was reported to be secreted by astrocytes to regulate synaptogenesis in the brain.

Japan's National Hospital Organization (NHO), a Designated Public Corporation specified in the Disaster Countermeasure Basic Act, promptly responded to the 2011 Great East Japan Earthquake by mobilizing medical teams from NHO hospitals nationwide. This report describes the activities conducted by NHO and lessons learnt for better preparedness and response in the future.

Various factors, including platelets, endothelial cells, and coagulation factors, regulate the mechanisms of thrombosis and hemostasis. Von Willebrand factor (VWF) is one of the key molecules to initiate platelets adhesion and aggregation. Quantitative and qualitative VWF abnormalities cause both hemorrhagic and thrombotic disorders. The role of VWF has emerged from molecular mechanisms of von Willebrand disease (VWD) and thrombotic thrombocytopenic purpura (TTP). This review summarizes the current knowledge of these diseases and the importance of VWF in thrombosis and hemostasis.

Over the last decade there have been many advances in neurology. This article reviews topics in neurology, specifically for stroke and neurodegenerative diseases. Advances in magnetic resonance imaging provide a powerful tool for diagnosing stroke and thrombolysis by alteplase and have facilitated a paradigm shift in the approach to super-acute phase ischemic stroke. Secondary prevention of ischemic stroke has changed in terms of both anti-platelet therapy and anti-coagulation therapy. Over the last decade, understanding about the etiology and pathogenesis of many neurodegenerative diseases has progressed. Recent reports are reviewed here regarding Alzheimer’s disease, Parkinson disease, dementia with Lewy bodies, motor neuron disease and frontotemoral dementia as they share many common mechanisms involving aggregation and accumulation of proteins.

To examine the impact of dose reduction on the efficacy of pegylated interferon (PEG-IFN) plus ribavirin (RBV) plus telaprevir (TVR) triple therapy for patients infected with genotype 1b and high viral loads.

A total of 51 patients were recruited for this study. Patients were divided into groups receiving either 2,250 mg of TVR for 12 weeks and 600 – 1,200 mg of RBV for 24 weeks according to body weight (Group 1, N = 39) or 1,500 mg of TVR for 12 weeks and 400 mg of RBV for 24 weeks (Group 2, N = 13) plus 1.5 μg/Kg (range: 1.3 - 2.0 μg/Kg) of peg-IFN alpha-2b for 24 weeks. Patients of Group 1 were less than 65 years old or IL28 non T/T and over 65 to less than 70 years old. Patients of Group 2 were IL28B T/T and over 65 to less than 70 years old or over 70 years old.

Rapid virological response (RVR) rates were 66.7% in Group 1 and 84.2% in Group 2 (NS). Early virological response (RVR) rates were 79.5% in Group 1 and 91.7% in Group 2 (NS). End of treatment response (ETR) rates were 71.8% in Group 1 and 69.2% in Group 2 (NS). Sustained virological response (SVR) rates were 60.5% in Group 1 and 69.2% in Group 2 (NS). In multivariate analysis, significant contribution factors for SVR were IL28B (genotype TT; OR 1.83, P = 0.0032) and platelet counts (< 120,000; OR 2.14, P = 0.0140).

It was concluded that the treatment strategy of dose reduction based on patient background (age and IL28B SNP polymorphism) was proper in Japanese patients.

The clinical presentation of acute cholangitis, etiology and complications from endoscopic early biliary drainage in elderly patients was evaluated.

205 patients with acute cholangitis treated at the Kure Medical Center and Chugoku Cancer Center were enrolled. Of these, 108 patients were 75 years old or older (elderly) and 97 patients were younger than 75 years old. Patients’ clinical characteristics, etiology and severity of cholangitis, and complications of endoscopic early biliary drainage were compared between the elderly and younger cohorts.

There was a significant difference in severe cholangitis between elderly and younger patients, at 17.6% and 0%, respectively. There was no significant difference in complications between elderly and younger patients, and between patients with and without early biliary drainage. One 91-year old woman with early biliary drainage had post-ERCP (endoscopic retrograde cholangiopancreatography) aspiration pneumonia and died.

Acute cholangitis in elderly patients may become severe in degree with a high incidence. Early ERCP for elderly persons is relatively safe, but it should be done carefully, not induce a consequent death due to complications such as aspiration pneumonia.

In plastic surgery, hyperbaric oxygen therapy is used to promote healing of intractable ulcers caused by severe diabetes mellitus, peripheral circulatory disorders, and severe scald burns. We performed hyperbaric oxygen therapy to improve blood flow disorders of transferred flaps and reported the utility of and problems with this method.

We performed hyperbaric oxygen therapy for 10 patients with postoperative blood flow disorder after flap transfer. All cases were reconstruction using pedicled flaps. Subject disorders were intractable ulcers with myelitis in three cases, decubitus ulcers in three cases, gas gangrene in one case, injury in one case, hair loss in one case, and defect after tumor resection in one case. Among the 10 patients for whom we performed hyperbaric oxygen therapy, eight experienced local chronic inflammation or systemic wound healing protraction factors.

The transferred flaps in 4 of 10 patients treated with hyperbaric oxygen therapy were salvaged, and the diseases were cured. In one patient, the flap was saved; however, myelitis symptoms were caused by an intramedullary bone screw. The other five patients showed epidermal or adiposal partial necrosis of the transferred flap and closed wounded area.

We performed hyperbaric oxygen therapy for 10 patients with unstable flap blood flow.

A therapy effect was apparent in all cases, and supplemental surgical procedures were not required in five cases. Hyperbaric oxygen therapy is a useful flap salvation method for institutions that have access to hyperbaric oxygen devices.

New surgical wound closure methods have been developed, and octyl-2- cyanoacrylate has been used for wound closure after surgery. In this study, we compared clinical outcomes for total knee arthroplasty with a new wound closure using cyanoacrylate glue without drain and conventional skin suture procedure with drain. Complications in the group of cyanoacrylate included one case of delayed skin healing. No case of blood transfusion, pulmonary embolism, deep-venous thrombosis, or deep infection existed. Concerning estimated blood loss, the group of cyanoacrylate decreased significantly at the time of post-op; 1 day and post-op, 3 days. This procedure had some benefits for patients and clinical staff.

Febuxostat, a new xanthine oxidase (XO) inhibitor, could become the standard for managing uric acid levels in patients with chronic kidney disease (CKD). However, little has been reported regarding patients with severe renal impairment. Further, the conversion rate for switching patients from allopurinol to febuxostat remains unknown.

We studied 65 CKD patients being administered allopurinol for hyperuricemia and then switched them to febuxostat at a conversion ratio of 100 mg allopurinol: 10 mg febuxostat. Serum uric acid and creatinine levels were measured before and 4–8 weeks after the switch.

Sixty-three patients remained after excluding those who had discontinued treatment. There was no significant difference in serum uric acid and creatinine levels before and after the switch. Further, no significant differences were observed in serum uric acid levels before and after the switch when patients were stratified into diabetic and nondiabetic groups or when classified per gender. We divided patients into G1–G3b and G4–G5 groups depending on the stage of CKD; there were no significant differences in the G1–G3b group after the switch, but there was a significant decrease in serum uric acid levels in the G4–G5 group (p < 0.05).

We demonstrated that 100 mg allopurinol and 10 mg febuxostat had equivalent hypouricemic effects in CKD patients and that these drugs did not affect serum creatinine levels. Thus, 10 mg febuxostat may have greater hypouricemic effects in patients with advanced CKD.

Methicillin-resistant Staphylococcus aureus (MRSA) infection is causing increased morbidity and mortality in intensive care units (ICUs). Its presence causes several challenges in implementing infection control measures. This study determined the incidence of MRSA acquisition in the ICUs and evaluated interventions to reduce the rate of MRSA acquisition.

A prospective study was conducted from April 2004 to March 2013 in the ICUs of our hospital that is a district teaching hospital in Japan. Patients were screened for MRSA with their sputa, nose or throat swabs on admission. MRSA acquisition was defined when negative on admission screening and positive after admission in hospital. The MRSA control program consisted of four practices: 1) frequent oral care with brushing from April 2006, 2) the use of a closed suction system for all patients receiving mechanical ventilation from December 2006, 3) reinforcement of standard precautions for patient contact, with emphasis on hand hygiene, by the supervisory nurse from August 2007, and 4) cleaning equipment and environment with alcohol swab from September 2007.

Of the 9,401 patients examined, 570 (6.06%; 2.9%-9.65%/year) had MRSA on admission. MRSA acquisition rates in the ICU per 1,000 MRSA-negative patients decreased significantly from 28.56 in the three years before the interventions to 14.01 in the 6 years after the interventions (p<0.05).

Although MRSA infection in ICUs has continued, we succeeded in decreasing MRSA acquisition in the ICUs by routine long-term MRSA screening on admission and a MRSA control program.

Recent studies have indicated a high prevalence of persistent postoperative pain (PPP) in patients who undergo various surgical procedures. Patient suffering from PPP and the cost to manage this pain are substantial socioeconomic burdens. Although recent studies have revealed various underlying mechanisms of PPP, prevention and management remains unsatisfactory. In this review, we briefly summarize the current understanding of etiology and pathophysiology, which include neuropathic, nociceptive, inflammatory, and myofascial pains as well as psychological or psychiatric factors, and advances in the prevention and management of PPP over the last decade. In addition to the literature review, we present findings from our observation studies of patients with post-thoracotomy pain syndrome, which indicate myofascial pain as a major pathophysiological cause of PPP. Based on the literature review and our recent clinical studies, we propose a comprehensive practical strategy for the prevention and management of PPP.

To assess the adoptability of a new measuring method when true values are unknown, it is necessary to compare the proposed with the conventional method. Although Bland-Altman correlation analysis is widely accepted, it is occasionally misused or applied where it is inappropriate. We provide an overview of Bland-Altman analysis and teach its application and the interpretation of its results. We also comment briefly on regression analysis, another comparison method.

Gefitinib and erlotinib, which are epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), have been used for the treatment of inoperable and recurrent non-small cell lung cancer patients. A major side effect of these drugs is skin rash, which occurs at a high frequency. Biotin is a water-soluble vitamin that belongs to the vitamin B family; biotin deficiency increases the risk of skin dermatitis. We recently reported that biotin was administered to four patients with skin rash, all of whom were treated with either gefitinib or erlotinib and were unable to be treated by a steroid ointment alone. Biotin may be considered useful in the treatment of skin rash caused by EGFR-TKIs. The aim of this paper is to discuss the usefulness of biotin in patients with erythema because of gefitinib and erlotinib.

When making decisions about palliative chemotherapy, patients require information on how the cancer and its treatment will affect their life expectancy. To properly communicate this information, truthful and honest conversations about a patients’ prognosis and the goals of treatment are essential, because any misunderstanding about the intent of treatment may lead to requests for ineffective or futile treatment. However, these conversations are inherently difficult due to a low confidence in an oncologist’s ability to prognosticate accurately and fear of destroying hope or provoking emotional distress. There are few studies or guidelines for oncologists in estimating and explaining life expectancy in a way that conveys meaning without destroying hope. A recent study has demonstrated that providing estimates for worst-case, typical and best-case scenarios for survival are a helpful way of communicating life expectancy while conveying hope, and that the percentiles from an overall survival curve in first-line chemotherapy trials for advanced non-small cell lung cancer (NSCLC) can provide accurate estimates of the three scenarios. Furthermore, the initiation of establishment of illness understanding and discussing patients’ goals for treatments of metastatic NSCLC earlier in the course provides a more accurate assessment of their prognosis, depression and survival. Additionally, decision aids (DAs) in the setting of advanced colorectal cancer and palliative chemotherapy has shown that the use of DAs improved patient understanding of prognosis, treatment options, risks, and benefits without increasing anxiety. This review explores communication issues when talking about life expectancy with our cancer patients participating in palliative chemotherapy.

We describe the significance of the end-of-life care for cancer patients based on our experience. During the terminal phase of cancer, particularly within the final two months, physical function rapidly declines and various symptoms appear; therefore, a prompt response is required to alleviate symptoms. Treatment must be selected in accordance with the patient’s wishes to reduce their symptoms. Advance care planning (ACP) is primarily done by the patient and their family, and is sustained collaboratively by the supporting medical team, and not the unilateral “elicitation of a commitment” from the patient by the medical staff. ACP increases patient and family satisfaction during the end-of-life stage, and alleviates anxiety and depression among survivors after the death of a patient. Performing symptom control during the end-oflife stage of the patient is important with no demand for explanations. The use of morphine is recommended as drug therapy for dyspnea. Treatment of death rattle involves administering anticholinergic drugs and reducing intravenous (IV) infusions. It is important to provide families with explanations and make considerations for their inquiries. Routine assessments and corrections must be conducted using a guideline for intravenous infusions of 1,000 ml or less per day. Unbearable pain can remain in the end-of-life stage, even after palliative treatment has been performed. In these cases, sedation is performed after sufficient assessment of pain and after obtaining agreement from the medical team and consent from the patient and family following an explanation.

Many studies of human immunology have been limited to ex vivo analysis due to ethical considerations. Detailed study, however, requires in vivo analysis, as ex vivo analysis of human immune cells does not always represent in vivo status. Therefore, small animal models have been used to overcome this limitation and several humanized mouse models that reproduce the human immune system have been developed. This review summarizes humanized mouse model characteristics and progress in their use for research of human diseases immunology.

A clinical study, clinical trial, and clinical protocol are all concerned with a similar question. How does a new treatment affect patients?

Thru clinical studies, clinical researchers find new and better methods to address illnesses. A clinical trial protocol is used to manage a trial that is prepared by specialists. All clinical researchers are expected to strictly follow the protocol.

The aim of this review is to describe the Phase I, II, and III studies, and translational research for cancer tumors.

To achieve both security and convenience of hospital information systems, we introduced two virtual servers; one with an Internet connection and the other using electronic medical records not connected to the Internet. Electronic medical records and other applications, such as mailer, Microsoft office products, and Internet browser, were ran by Citrix XenApp™, a product of an application virtualization. The virtual servers connected to the Internet and the virtual servers for the electronic medical records were isolated, and the interface between the two was strictly cutting off. Clients were based on the thin and thick client principles, and ordinary personal computers were allowed for applications not installed in the virtual servers. We set up personal data and unit data repositories in the virtual server that was connected to the Internet. Therefore, when users logged in using the contact type IC card to authenticate the active directory, they were able to operate both the electronic medical records and the shared data repositories anywhere in the hospital. Users could search the Internet even while writing electronic medical records, and the number of PCs connected to the electric medical records was increase significantly, which resulted in additional expansion of the blade servers. To develop the virtualization system of the HIS, stabilization of virtualization technology, virtual license fee of applications, and improvement of management capacity will be required.

Dermoscopy is a useful tool to examine pigmented skin lesions. We use this method as a routine tool and have experienced many pigmented lesions. Here, we present four pigmented skin lesions (three are pigmented nevi and one is malignant melanoma) to demonstrate the usefulness of dermoscopy when making a clinical diagnosis of pigmented skin lesions.

This is a case report of superior sagittal sinus thrombosis (SSST), with bilateral papilledema as the initial manifestation.

A 65-year-old male was referred to us with bilateral decreased vision and recurrent blackouts associated with postural change. Although his intracranial pressure was increased, an intracranial space-occupying lesion was not detected by computed tomography (CT). Magnetic resonance imaging (MRI) with a fluid-attenuated inversion recovery (FLAIR) technique and magnetic resonance venography (MRV) findings revealed a thrombosed superior sagittal sinus. Anticoagulation therapy with heparin was started and recurrent blackouts disappeared one month thereafter. Thoracoabdominal CT examination revealed an infiltrative shadow in the right inferior lobe of the lungand was diagnosed as squamous cell carcinoma from biopsy by bronchoscopy. Bilateral papilledema gradually decreased over an 18-month observation period after anticoagulation therapy.

MRV was useful in the diagnosis of SSST in this case of bilateral papilledema with increased intracranial pressure.

Guidelines for the valuation of valvular heart disease by echocardiography recommend the quantification of severity. For accurate quantification, it is necessary to assume the mitral annulus (MA) area to calculate mitral stroke volume (SV). We applied and preliminarily verified a new method to calculate the MA area.

A Japanese man in his 60s without any abnormal cardiac findings including regurgitation in the aortic or mitral valve was simultaneously evaluated by a conventional and new method. The MA area was calculated by using a conventional method with an apical 4 chamber view (4CV) and apical 2 chamber view (2CV), and a new method with an apical commissure-commissure view (CCV) and apical 3 chamber view (3CV). Mitral SV was calculated from the MA area values by both methods and compared with left ventricular SV (LVSV) by using a modified Simpson method.

MA areas estimated by the new method were smaller than that those estimated by the conventional method. Mitral SV estimated by the new method was closer to LVSV than that estimated by the conventional method.

The new echocardiographic method to calculate an MA area with apical CCV and 3CV may be more exact and useful than the conventional method. The results in this case report suggest that further evaluation at a larger scale may yield promising results.

Eosinophilic pancreatitis (EP) is a rare disease characterized by eosinophilic infiltration of pancreatic parenchyma. Although the etiology of EP is not fully understood, there may be some allergic mechanisms related to the disease. Here we report on an EP patient with psoriasis vulgaris.

A 47-year-old man was admitted with cardiac space pain and a feeling of abdominal compression. He had a history of psoriasis vulgaris treated with steroid ointment for the past 30 years. Laboratory findings revealed elevated serum titers amylase. An abdominopelvic computed tomography scan showed a cystic lesion 45 mm in diameter localized in the pancreatic tail. He was diagnosed with pancreatic pseudocyst and conservative medical treatment was initiated with antimicrobial drugs and gabexate mesilate. Whenever meals were taken, pancreatitis aggravation returned. Eosinophilic leukocytosis occurred during steroid administration. Pseudoaneurysm in the splenic artery solution part occurred and a splenic artery embolism was performed in interventinal radiology. The patient underwent distal pancreatectomy. The operation specimen revealed eosinophilic infiltration.

Despite the unusual occurrence of EP, it should be considered in the differential diagnosis of patients with allergic disease or with an eosinophillia group presenting pancreatitis. In such cases, EUS-FNA or laparoscopic biopsy should be mandatory to avoid unnecessary surgical operation.

Acute renal failure caused by ingestion of ethylene glycol during a suicide attempt is rare. In this case report, a Japanese man ingested ethylene glycol in a suicide attempt and was transported to our hospital. He complained of severe nausea and blood tests revealed metabolic acidosis, and elevated white blood cell count, creatinine and BUN levels. Hemodialysis was implemented four hours after the ethylene glycol was ingested, and urine volume increased to 1,500 mL/day on the ninth day after admission. Creatinine clearance, however, did not improve. A renal biopsy performed on the 45th day revealed numerous collapsed glomerulus, cortical infarction, and swelling of the renal tubular epithelial cells. Hemodialysis has been recommended for the treatment of ethylene glycol poisoning in the presence of severe metabolic acidosis that is unresponsive to therapy.

An infarcted intraductal breast tumor was excised from a woman in her 60s. The tumor was reduced in size from 15 x 8 mm to 6 x 6 mm one month after the fine needle aspiration biopsy. The necrosis was considered to be caused by an infarction and an immunohistohemical analysis revealed positive immunoreactivity of smooth muscle actin of myoepithelial cells that indicated a two-cell layer of tumor cells in the necrosis. Although this necrotic tumor was diagnosed as an infarcted intraductal papilloma by histological examination, its diagnosis was more difficult as it showed partial necrosis by cytological examination alone.

Renal angiomyolipoma (AML) is recognized as a benign renal tumor composed of atypical blood vessels, smooth muscle and fat tissue, and constitutes about 1% of all renal masses. In contrast, extrarenal AMLs are extremely rare tumors of which there have been less than 70 reported cases since they were first described in 1982. We present the case of a 65-year-old female with a retroperitoneal extrarenal mass. Histopathological examination and HMB-45 staining revealed the mass to be an extrarenal AML.

A 65-year-old female presented with a 2cm mass next to the pancreas head during a follow-up CT scan one year after chemotherapy for malignant lymphoma. Diagnosis of the tumor was not possible with EUS-FNA cytology. The tumor was considered to be a solid-pseudopapillary neoplasm (SPN) or endocrine tumor of the pancreas. Subsequently, surgical resection of the tumor was performed.

Gross microscopic examination of the tumor, which was located in the retroperitoneum and was separated from the pancreas, showed histologically tortuous thick blood vessel with bundles of smooth muscle. Mature adipose tissue was also detected. Imprint cytology of the cut surface of the tumor showed atypical cells which had spindle shaped outlines, nuclear enlargement and hyperchromasia. HMB-45 staining performed on the larger lesion was positive, which is characteristic of AMLs.

Extrarenal AMLs are rare and occur most commonly in the liver. Lesions in the retroperitoneum require definitive diagnosis since they can mimic other benign and malignant retropelitoneal tumors, which must be differentiated.

Postoperative medullary infarctions have been reported as a poor prognostic factor after internal coil trapping of a ruptured vertebral artery dissecting aneurysm (VA-DA). We succeeded in treating a ruptured VA-DA involving the origin of the posterior inferior cerebellar artery (PICA) without critical medullary infarctions. We discuss the reasons why we were able to avoid critical medullary infarctions in this case report.

A 42-year-old Japanese man presented with a sudden onset of left sided headache. He also reported a history of neck pain suddenly occurring two days prior while playing the drum. He had a re-ruptured left VA-DA involving PICA. The re-ruptured VA-DA was initially treated by endovascular bleeding point coil embolization. Dejerine syndrome occurred as a complication of the initial treatment. The neurological symptoms were temporary and the patient made a recovery from the syndrome within a week. MRA revealed recanalization on day 16, and re-bleeding from the ruptured VADA was identified on CT scanning on day 20, which was treated by endovascular proximal coil embolization. Postoperative infarction was noted only in the small area of the left cerebellum. The patient showed marked improvement. On one-year follow-up, the patient remains in good clinical condition (Score 1 on modified Rankin scale).

The bleeding point coil embolization and proximal coil embolization were not performed simultaneously in this case. Decreasing the length of the coil embolization could save the perforating branches.

Stool samples from 432 patients with suspected for Clostridium difficile (CD) infection were tested with the novel kit, COMPLETE, which was evaluated for the efficacy in detecting glutamate dehydrogenase (GDH), and cultures were then reevaluated to determine necessity.

CD positive samples by culture and GDH positive samples by COMPLETE were 71 (16.4%) and 80 (18.5%) of 432 samples, respectively. Sensitivity and specificity of COMPLETE for detection of GDH were 100% and 97.5%, respectively. The toxin types of 71 samples were toxin A+B+ in 45, toxin A-B+ in 21, and toxin A-B- in five. In comparison, the toxin types of 44 samples whose toxin was detected by COMPLETE were toxin A+B+ in 31, and toxin A-B+ in 13. The sensitivity and specificity of COMPLETE for detection of toxin were 66.7% and 100%, respectively.

The combined use of COMPLETE and culture of suspicious CDI samples is beneficial for prompt detection of CD.

An auto-stainer (AS), whole-slide imaging system (WSI), and computer software were used as quality assurance tools for breast cancer immunohistochemistry (IHC).

Cell lines, such as MCF-7 for estrogen receptors and progesterone receptors, and SKBR- 3 for Topo2a, were co-stained with samples as IHC control.

Combinatory usage of AS, WSI, computer software and cell lines can reduce deviation in each IHC step and is beneficial for IHC quality assurance.