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Purpose Bone morphogenetic protein (BMP)-2 is a potent growth factor that is widely used in the orthopedic and dental fields for bone regeneration.However, recombinant human BMP-2 (rhBMP-2) products have not been legally approved in Japan. Recently, our research group succeeded in producing GMP-grade rhBMP-2 using the E. coli system (E-rhBMP-2) at the industrial level and developed E-rhBMP-2 adsorbed onto β-TCP (E-rhBMP-2/β-TCP) as an alternative material to autogenous bone grafts. Previous studies on the toxicity, pharmacokinetics, and optimal doses of E-rhBMP-2 have confirmed its safety and efficiency. However, comparative studies with standard treatment therapies are still necessary before clinical application in humans. Therefore, in this preclinical study, we compared the bone regeneration ability of E-rhBMP-2/β-TCP and autogenous bone grafts in a canine guided-bone regeneration model. Methods Following extraction of the maxillary third premolar, box-type bone defects (10 mmL × 4 mmW × 9 mmH) were created in the extraction socket area and transplanted with E-rhBMP-2/β-TCP or autogenous bone graft in a canine. After 8 weeks, micro-CT and histological analyses were performed. Results Transplantation of both E-rhBMP-2/β-TCP and autogenous bone graft significantly promoted bone formation compared to the non-transplantation control group. The bone formation ability of E-rhBMP-2/β-TCP was equal to that of the autogenous bone graft. Histological analysis showed that excessive infiltration of inflammatory cells and residual β-TCP particles mostly were not observed in the E-rhBMP-2/β-TCP transplantation group. Conclusions This preclinical study demonstrated that E-rhBMP-2/β-TCP and autogenous bone have equal potential to promote bone regeneration.

Introduction Chromophobe renal cell carcinoma presents in early pathological stages with a lower risk of metastasis. However, aggressive features and metastasis can occur. A rare case of rapidly progressive disease with histological changes is presented. Case presentation A 56-year-old woman had a right renal tumor with multiple lymph node metastases, and the pathological diagnosis of the biopsy specimens from the primary tumor was chromophobe renal cell carcinoma. After sunitinib treatment, the metastatic lymph node had decreased in size and the numbers of circulating tumor cells were decreased, consequently, cytoreductive nephrectomy was performed. However, rapid progression of lymph node metastases was observed. Histopathological examination showed that the renal tumor was diagnosed as spindle cell renal carcinoma. Conclusion It appears that the primary tumor underwent epithelial-mesenchymal transition; further tissue specimen collection and analysis might be needed.

Background: Male breast cancer is rare, accounting for approximately 0.5% - 1.0% of all breast cancer cases; hormone-dependent luminal type male breast cancer is the most common. The proportion of hormone receptor-negative and human epithelial growth factor Receptor type 2-positive breast cancer is extremely low among male breast cancer. A patient with advanced HER2 type breast cancer, a rare male breast cancer, was successfully treated with pertuzumab, trastuzumab, and eribulin therapy. Case Presentation: A 75- year-old man presented to our hospital with induration of the right anterior chest and lymphoedema of the right upper limb. Based on the results of core needle biopsy, he was diagnosed with HER2 type invasive ductal carcinoma associated with bone metastasis (stage IV). Chemotherapy with pertuzumab, trastuzumab, and eribulin was started. The drugs were remarkably effective, and his lymphoedema tended to improve. Conclusion: We reported a successful case of chemotherapy and targeted therapy for a rare male breast cancer of HER2 positive and hormone negative type.

We experienced a surgical case of a rare primary tracheal tumor. A 77-year-old woman visited a local clinic with chief complaints of coughing, wheezing, and discomfort in the throat. Computed tomography revealed a mass measuring approximately 1.5 cm in the mediastinal trachea, extending from the membranous portion of the trachea to the esophagus. Bronchofibroscopy showed a flat, smooth-surfaced, round mass arising from the membranous portion. Surgery was performed because of the possibility of airway obstruction and suffocation. Sleeve resection of five tracheal rings was performed via median sternotomy and interrupted suture was performed using 3-0 absorbable suture material. The postoperative course was favorable and there has been no evidence of recurrence. The pathological diagnosis was solitary fibrous tumor. A primary solitary fibrous tumor of the trachea is extremely rare. Here, we report this disease with a literature review.

The current study was conducted to clarify the frequency of systemic circulating tumor cells (CTCs) appearing after surgery for renal cell carcinoma and to evaluate the differences in postoperative CTCs between different surgical procedures. This prospective, cohort study included 60 consecutive patients who underwent laparoscopic radical nephrectomy (RN) (n = 22), laparoscopic partial nephrectomy (PN) (n = 19), open RN (n = 8), or open PN (n = 11). In this study CTCs were measured by the FISHMAN-R system, and CTCs drawn from a peripheral artery were collected just before and immediately after surgery. The number of pre- and postoperative CTCs and the perioperative changes in CTCs were measured for each surgical method. Six patients were excluded from the current analyses. Preoperative CTCs did not differ significantly by surgical approach (laparoscopic RN: 3.4 ± 4.2; laparoscopic PN: 3.4 ± 4.1; open RN: 7.7 ± 6.8; open PN: 6.0 ± 7.6; P = 0.19). Open RN resulted in a significantly greater number of postoperative CTCs (laparoscopic RN: 4.8 ± 3.7; laparoscopic PN: 7.9 ± 9.1; open RN: 22.5 ± 26.3; open PN: 6.4 ± 6.3; P

PurposeThis study investigated the relationship between the pharmacokinetics and pharmacodynamics of everolimus in patients with metastatic breast cancer (mBC) in real-world practice.MethodsTwenty-two patients with mBC treated with everolimus plus exemestane were enrolled. Blood everolimus concentrations were measured at outpatient visits. The inhibition of the mammalian target of rapamycin (mTOR) activity in peripheral blood mononuclear cells (PBMCs) was examined. The efficacy and safety endpoints were progression-free survival (PFS) and the cumulative incidence of dose-limiting toxicities (DLTs), respectively.ResultsBlood samples were obtained from 19 consenting patients. Everolimus did not completely inhibit mTOR activity in PBMCs at therapeutic concentrations (~56% maximal inhibition). The most common adverse event was stomatitis (any grade 77%). The trough concentration (Ctrough) was significantly higher in patients experiencing DLTs than in those without any DLTs (P = 0.030). The optimal Ctrough cutoff predicting DLT development was 17.3 ng/mL. The cumulative incidence of DLTs was significantly higher in patients with Ctrough ≥17.3 ng/mL than in other patients (sub-hazard ratio 4.87, 95% confidence interval [CI] 1.53–15.5; P = 0.007). Furthermore, the median PFS was numerically longer in patients who maintained a steady-state Ctrough below the threshold than in those who did not (327 days [95% CI 103–355 days] vs 194 days [95% CI 45 days–not estimable]; P = 0.35). ConclusionThe suggested upper threshold for the therapeutic window of everolimus Ctrough was 17.3 ng/mL. Pharmacokinetically guided dosing may improve the efficacy and safety of everolimus for mBC, warranting further investigation in a larger study.

Triple-negative breast cancer (TNBC) has a poorer prognosis than other breast cancer subtypes; therefore, identifying markers of early recurrence is important. The present study aimed to establish a liquid biopsy protocol for droplet digital PCR-based detection of frequently mutated genes in patients with TNBC. Tumor DNA from 36 patients with TNBC who relapsed within 2 years after surgical resection was retrospectively analyzed. Somatic mutational profiles were evaluated using targeted sequencing to identify frequently mutated genes and genes associated with molecularly targeted therapies. The association between genetic alterations and associated protein phosphorylation was investigated using immunohistochemical analysis. Recurrent hot spot mutations in the plasma were monitored over time. Mutation-specific probes were used to successfully detect mutations in the blood samples of patients who were positive for PIK3CA H1047R and AKT1 E17K mutations. Somatic mutations in AKT1 (14.9%) and PIK3CA (25.5%) were frequently identified in the data. Robust phosphorylation of AKT and S6RP was more common in tumors with PIK3CA H1047R and AKT1 E17K mutational background than in tumors with wild-type PIK3CA and AKT1. In conclusion, the present study evaluated a high-sensitivity detection system for frequently mutated genes that was also applicable for cell-free DNA. The PI3K/AKT pathway was revealed to be activated in patients harboring PIK3CA H1047R and AKT1 E17K mutations; therefore, the PI3K/AKT pathway may be a promising candidate for targeted therapy in these patients.

Activation of STING signaling plays an important role in anti-tumor immunity, and we previously reported the anti-tumor effects of STING through accumulation of M1-like macrophages in tumor tissue treated with a STING agonist. However, myeloid cells express SIRPα, an inhibitory receptor for phagocytosis, and its receptor, CD47, is overexpressed in various cancer types. Based on our findings that breast cancer patients with highly expressed CD47 have poor survival, we evaluated the therapeutic efficacy and underlying mechanisms of combination therapy with the STING ligand cGAMP and an antagonistic anti-CD47 mAb using E0771 mouse breast cancer cells. Anti-CD47 mAb monotherapy did not suppress tumor growth in our setting, whereas cGAMP and anti-CD47 mAb combination therapy inhibited tumor growth. The combination therapy enhanced phagocytosis of tumor cells and induced systemic anti-tumor immune responses, which rely on STING and type I IFN signaling. Taken together, our findings indicate that coadministration of cGAMP and an antagonistic anti-CD47 mAb may be promising for effective cancer immunotherapy.

Medication-related osteonecrosis of the jaw (MRONJ) is related to impaired bone healing conditions in the maxillomandibular bone region as a complication of bisphosphonate intake. Although there are several hypotheses for the onset of MRONJ symptoms, one of the possible causes is the inhibition of bone turnover and blood supply leading to bone necrosis. The optimal treatment strategy for MRONJ has not been established either. BMP-2, a member of the TGF-β superfamily, is well known for regulating bone remodeling and homeostasis prenatally and postnatally. Therefore, the objectives of this study were to evaluate whether cyclophosphamide/zoledronate (CY/ZA) induces necrosis of the bone surrounding the tooth extraction socket, and to examine the therapeutic potential of BMP-2 in combination with the hard osteoinductive biomaterial, β-tricalcium phosphate (β-TCP), in the prevention and treatment of alveolar bone loss around the tooth extraction socket in MRONJ-like mice models. First, CY/ZA was intraperitoneally administered for three weeks, and alveolar bone necrosis was evaluated before and after tooth extraction. Next, the effect of BMP-2/β-TCP was investigated in both MRONJ-like prevention and treatment models. In the prevention model, CY/ZA was continuously administered for four weeks after BMP-2/β-TCP transplantation. In the treatment model, CY/ZA administration was suspended after transplantation of BMP-2/β-TCP. The results showed that CY/ZA induced a significant decrease in the number of empty lacunae, a sign of bone necrosis, in the alveolar bone around the tooth extraction socket after tooth extraction. Histological analysis showed a significant decrease in the necrotic alveolar bone around tooth extraction sockets in the BMP-2/β-TCP transplantation group compared to the non-transplanted control group in both MRONJ-like prevention and treatment models. However, bone mineral density, determined by micro-CT analysis, was significantly higher in the BMP-2/β-TCP transplanted group than in the control group in the prevention model only. These results clarified that alveolar bone necrosis around tooth extraction sockets can be induced after surgical intervention under CY/ZA administration. In addition, transplantation of BMP-2/β-TCP reduced the necrotic alveolar bone around the tooth extraction socket. Therefore, a combination of BMP-2/β-TCP could be an alternative approach for both prevention and treatment of MRONJ-like symptoms.

This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial License 4.0 (CCBY-NC), BACKGROUND: Visceral pleural invasion (PL) is a prognostic factor in lung cancer. In the lung, lymph flows along the pleura, in addition to the flow toward the pulmonary hilum just as the pulmonary arteries and veins run toward it. Even with the same tumor diameter, a PL1 or higher level of pleural invasion is indicative of a more advanced disease stage. Final diagnosis based on the PL level is made by pathological examination of excised specimens. However, if an intraoperative diagnosis can be established, proper selection of the surgical procedure can be made, and unnecessary surgeries for disseminated lesions can be avoided. We investigated optical diagnostic techniques for identifying the presence or absence of visceral pleural invasion in lung cancer by capitalizing on the phenomenon of 5-amino-levulinic acid (5-ALA) being metabolized to a photosensitizing substance or protoporphyrin IX within malignant tumors, generating red luminescence in response to excitation light. METHOD: This study included 38 patients with primary lung cancer who underwent surgery. They received 5-ALA (20mg/kg) orally 4h before surgery and then we assessed the presence or absence of pleural invasion using an autofluorescence observation system. At visceral pleural invasion sites, we were able to confirm tumor sites visualized in red with a clear border in contrast to the green autofluorescence generated in normal tissues. RESULT: Red luminescence could be confirmed in 100% of PL1-PL3 patients (14/14) and 41.6% of PL0 patients (10/24) with primary lung cancer. PL0 patients in whom visualization was possible were preoperatively diagnosed as having PL1 and many of them showed vascular channel invasion. The sensitivity, specificity, positive predictive value, and negative predictive value of this diagnostic technique were 100%, 58.0%, 63.1%, and 100%, respectively. Red fluorescence emission was observed significantly more often in pleural invasion cases. CONCLUSION: Accurate intraoperative diagnosis for visceral pleural invasion in lung cancer may contribute to determining the indications for limited operations such as segmental resection. In addition, accurate local diagnosis has the possibility of being applicable to photodynamic therapy.

金沢大学附属病院泌尿器科, Background: Both enzalutamide and abiraterone have demonstrated improved radiographic progression-free and overall survival for castration-resistant prostate cancer (CRPC) compared with placebo controls before docetaxel treatment in phase III studies. These oral agents target androgen and androgen receptor signaling and are thought to be less toxic than chemotherapy. Cross-resistance to these agents was recently reported because of their similar mechanism of action, and it is important to assess which agent is more effective to use initially for CRPC. Methods/design: The present study is a phase III, investigator-initiated, multicenter, head-to-head, randomized controlled trial investigating enzalutamide vs. abiraterone as a first-line treatment for CRPC patients. Patients will be randomly assigned to an enzalutamide or an abiraterone treatment group. The primary endpoint is the time to prostate-specific antigen progression. The target sample size is set at 100 patients per group (total, 200 patients). The study duration is 5 years, and the duration for recruitment is 2 years and 6 months. Discussion: Thus far, there have been no prospective head-to-head studies comparing enzalutamide and abiraterone. This ENABLE study will clarify which agent should be prioritized for CRPC patients and enable clinicians to decide the appropriate treatment before chemotherapy. Trial registration: University hospital Medical Information Network (UMIN) Center identifier UMIN000015529. Registrated 11/1/2014. © 2017 The Author(s).

Multiple system atrophy is a neurodegenerative disease that affects autonomic and motor systems. Patients with multiple system atrophy usually experience lower urinary tract symptoms, which sometimes appear as an initial symptom before the emergence of the generalized symptoms. An open bladder neck during the filling phase on video urodynamic study is one characteristic imaging finding after the diagnosis of multiple system atrophy, but has not previously been reported at an early phase of the disease. We report a case in which an open bladder neck was observed on several imaging modalities before generalized symptoms emerged. Because occult neurogenic bladder might exist in patients whose lower urinary tract symptoms are resistant to pharmacotherapy, we report this case to raise awareness of the importance of sufficient imaging evaluations. An open bladder neck might be an important imaging finding for diagnosing multiple system atrophy, irrespective of the presence of generalized symptoms. This finding could help avoid false diagnosis and unnecessary treatment.

// Kei Ishibashi 1, 2 , Tobias Haber 2 , Ines Breuksch 3 , Susanne Gebhard 3 , Takashi Sugino 4 , Hitoshi Kubo 5 , Junya Hata 1 , Tomoyuki Koguchi 1 , Michihiro Yabe 1 , Masao Kataoka 1 , Soichiro Ogawa 1 , Hiroyuki Hiraki 1 , Tomohiko Yanagida 1 , Nobuhiro Haga 1 , Joachim W. Thuroff 2 , Dirk Prawitt 6, * , Walburgis Brenner 2, 3, * and Yoshiyuki Kojima 1, * 1 Department of Urology, Fukushima Medical University, Fukushima, Japan 2 Department of Urology, Johannes Gutenberg University Medical Center, Mainz, Germany 3 Department of Gynecology and Obstetrics, Johannes Gutenberg University Medical Center, Mainz, Germany 4 Department of Pathology, Shizuoka Cancer Center, Shizuoka, Japan 5 Advanced Clinical Research Center, Fukushima Medical University, Fukushima, Japan 6 Center for Pediatrics and Adolescent Medicine, Johannes Gutenberg University Medical Center, Mainz, Germany * These authors contributed equally to this work Correspondence to: Walburgis Brenner, email: brenner@uni-mainz.de Kei Ishibashi, email: keikun@fmu.ac.jp Keywords: renal cell carcinoma, tyrosine kinase inhibitor, resistance, IL-6, tocilizumab Received: March 01, 2017 Accepted: July 12, 2017 Published: July 21, 2017 ABSTRACT Metastatic renal cell carcinoma (RCC) is a tumor entity with poor prognosis due to limited therapy options. Tyrosine kinase inhibitors (TKI) represent the standard of care for RCCs, however a significant proportion of RCC patients develop resistance to this therapy. Interleukin-6 (IL-6) is considered to be associated with poor prognosis in RCCs. We therefore hypothesized that TKI resistance and IL-6 secretion are causally connected. We first analyzed IL-6 expression after TKI treatment in RCC cells and RCC tumor specimens. Cell proliferation and signal transduction activity were then quantified after co-treatment with tocilizumab, an IL-6R inhibitor, in vitro and in vivo . 786-O RCC cells secrete high IL-6 levels after low dose stimulation with the TKIs sorafenib, sunitinib and pazopanib, inducing activation of AKT-mTOR pathway, NFκB, HIF-2α and VEGF expression. Tocilizumab neutralizes the AKT-mTOR pathway activation and results in reduced proliferation. Using a mouse xenograft model we can show that a combination therapy with tocilizumab and low dosage of sorafenib suppresses 786-O tumor growth, reduces AKT-mTOR pathway and inhibits angiogenesis in vivo more efficient than sorafenib alone. Furthermore FDG-PET imaging detected early decrease of maximum standardized uptake values prior to extended central necrosis. Our findings suggest that a combination therapy of IL-6R inhibitors and TKIs may represent a novel therapeutic approach for RCC treatment.

To compare the postoperative tissue damage and longitudinal changes in functional and patient-reported outcomes after vesicourethral anastomosis with barbed suture and nonbarbed suture in robot-assisted laparoscopic radical prostatectomy (RARP). This was a prospective cohort study involving 88 consecutive patients who underwent RARP. These patients were categorized into the barbed suture group (n = 50) and the nonbarbed suture group (n = 38). Urethral and periurethral damages determined by magnetic resonance imaging at nine months after RARP were compared using generalized linear models. The International Prostate Symptom Score (IPSS), quality of life (QOL) index, uroflowmetry, and the 1-h pad test were measured at baseline and at 1, 3, 6, 9, and 12 months after RARP. The findings were analyzed using mixed-effects models. Confounding was adjusted for using propensity score covariate adjustment. The likelihood of having Grade 2/3 urethral and periurethral damages was greater in the barbed suture group than in the nonbarbed suture group (adjusted risk ratios: 2.98 and 3.85, respectively). IPSS, QOL index, and urinary leakage transiently increased at one month after RARP in both groups. QOL index was higher in the barbed suture group than in the nonbarbed suture group at 1, 9, and 12 months (P = 0.023, P = 0.025, and P = 0.011, respectively). The barbed suture group had significantly more cases of urinary incontinence than the nonbarbed suture group at 3 months (P = 0.041). Other outcomes were comparable between the two groups at all time points. This cohort study showed that, after RARP, barbed sutures during VUA induced more severe tissue damage as determined by MRI and greater transient aggravation of QOL and continence function than nonbarbed sutures. The present findings suggest that using nonbarbed sutures during VUA may facilitate earlier acquisition of urinary QOL and urinary continence.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0)., Pulmonary arteriovenous malformation (PAVM), which is asymptomatic in most cases, is often identified in patients with central nervous system disorders such as brain abscesses and/or cerebral infarctions. We have reported a patient with idiopathic multiple PAVM identified at the onset of cerebral infarction. A 69-year-old woman visited the Department of Neuropathic Internal Medicine at our hospital with chief complaints of numbness in her left hand and a feeling of weakness. The patient was given a diagnosis of subacute cerebral infarction. Multiple old lacunar infarctions were also observed in the deep white matter of the left frontal lobe. Chest computed tomography showed multiple nodular structures, mainly in the right lower lung field (S8), as well as continuous arteries and veins at the site; thus, the patient was finally diagnosed with multiple PAVM. Right lower thoracoscopic lobectomy was performed, as is typical surgical practice in such cases. The patient had a favorable postoperative course, and had no recurrence of cerebral infarction. Although the patient’s lesions were mainly restricted to S8, the fact that there were multiple lesions deemed a lobectomy as the appropriate course of treatment. This case emphasizes that attention should be paid to cases of multiple PAVM since cerebral infarction may arise from the disease.

Aims To elucidate the effects of a nerve-sparing (NS) procedure on lower urinary tract symptoms (LUTS) and urinary function after robot-assisted radical prostatectomy (RARP), the associations between the NS procedure and LUTS and urinary function were investigated. Methods The participants in this study were 200 consecutive patients who underwent RARP. These patients were categorized into unilateral and bilateral NS groups and the non-NS group. The International Prostate Symptom Score (IPSS), quality of life (QOL) index, frequency-volume chart, uroflowmetry, 1-h pad test, and the 5-item International Index of Erectile Function (IIEF-5) questionnaire were evaluated before and after RARP. Results The total IPSS score was significantly lower in the unilateral (P = 0.03) and bilateral NS groups (P = 0.03) than in the non-NS group after RARP. Diurnal maximum voided volume (MVV) values were significantly greater in the bilateral NS group than in the non-NS group after RARP (P = 0.002). Nocturnal frequency was significantly decreased in the unilateral NS group than in the non-NS group after RARP (3 months P = 0.01, 12 months P = 0.01). Erectile function was significantly better in both the unilateral NS group (P

Introduction Intraperitoneal urinary bladder perforation due to blunt trauma in intoxicated patients requires quick and accurate diagnosis. However, this is difficult to correctly diagnose in intoxicated patients because their symptoms can be masked. We describe a rare case of intraperitoneal urinary bladder perforation that occurred after blunt trauma. Case presentation A 66-year-old intoxicated man stumbled, tripped on a stone step and landed on his lower abdomen, but felt no pain at the time. Two days later, he was diagnosed with intraperitoneal urinary bladder perforation, which was repaired by open surgery. Conclusion Urinary bladder perforation should be considered when patients present with abdominal pain and decrease in urine volume following trauma.

Purpose We developed a diagnostic method for pleural disseminated lesions of lung cancer using a combination of 5-aminolevulinic acid (5ALA) and autofluorescence observation system. We utilized a phenomenon in which externally ingested 5ALA is metabolized to protoporphyrin IX, a precursor of heme, which remains inside malignant cells and emits red fluorescence of approximately 630 nm. The diagnosis was made employing an observation system based on autofluorescence emitted from normal tissues that we have investigated. Methods Between January 2017 and April 2019, we examined 82 lung cancer patients with suspected pleural invasion. We orally administered 5ALA (20 mg/m2) to the patients 4 hours before surgery, and malignant pleural lesions were thoracoscopically visualized using the autofluorescence observation system. Results (1) Pleural disseminated lesions were observed in six patients. Of these lesions, two were not detected by usual white light inspection, and the use of this method enabled the diagnosis of disseminated lesions. (2) Regarding the diagnosis of lung cancer pleural invasion to estimate the risk of pleural dissemination, if limited to adenocarcinoma, the sensitivity was 93.9%; specificity, 74.3%; positive predictive value, 60.8%; and negative predictive value, 96.2%. Conclusion This method may facilitate the detection of minute disseminated lesions that are difficult to detect by usual inspection. In addition, the degree of pleural invasion may be diagnosed to evaluate the need for limited resection such as segmentectomy.

In the area of neurosurgical tumor diagnosis, clinical research on photodynamic diagnosis using 5-aminolevulinic acid (5-ALA) has already been undertaken, and the safety of 5-ALA has also been demonstrated. 5-ALA is approved in the diagnosis of brain tumor and bladder tumor by the Ministry of Health, Labour and Welfare. 5-ALA is a natural amino acid contained in a living body and is a precursor of hemoglobin. When absorbed into the body by oral ingestion, porphyrin synthesis by heme synthesis is specifically performed in a tumor-specific manner, and accumulation of fluorescent protoporphyrin IX (pp IX) is observed. However, pp IX is metabolized and disappeared in normal tissues. When tumor tissue is irradiated with excitation light, at the site where pp IX accumulates, it exhibits red fluorescence. We applied 5-ALA for photodynamic diagnostic in thoracic malignancies.

To assess whether the preoperative 1-h pad test could predict postoperative urinary incontinence and quality of life after robot-assisted radical prostatectomy. A total of 329 patients who underwent robot-assisted radical prostatectomy between 2013 and 2016 were prospectively enrolled in this study. These patients were divided into the preoperative urinary continence group and the preoperative urinary incontinence group according to the 1-h pad test. The time to achieve urinary continence, lower urinary tract function evaluated by uroflowmetry and post-voided residual urine volume, and quality of life evaluated by King’s Health Questionnaire and International Consultation on Incontinence Questionnaire-Short Form were compared between these two groups. There were 190 patients (58%) in the preoperative urinary continence group (1-h pad test ≤ 2 g) and 139 patients (42%) in the preoperative urinary incontinence group (1-h pad test > 2 g). In the preoperative urinary continence/incontinence groups, 83%/76% of patients achieved continence within 12 months, respectively, and urinary incontinence remained significantly longer in the preoperative incontinence group than in the preoperative continence group (P = 0.042). Although there were no significant differences in all quality of life items between the two groups before surgery, several items were significantly higher in the preoperative urinary continence group. Achievement of urinary continence and improvement of urinary quality of life are delayed in patients with preoperative urinary incontinence assessed by the 1-h pad test. The preoperative 1-h pad test could be a useful predictor of prolonged urinary incontinence and poor quality of life after robot-assisted radical prostatectomy.

Background Head and neck squamous cell carcinoma (HNSCC) originates from squamous epithelium of the upper aerodigestive tract and is the most common malignancy in the head and neck region. Among HNSCCs, oropharynx squamous cell carcinoma (OSCC) has a unique profile and is associated with human papillomavirus infection. Recently, anti-programmed cell death-1 monoclonal antibody has yielded good clinical responses in recurrent and/or metastatic HNSCC patients. Therefore, programmed death-ligand 1 (PD-L1) may be a favorable target molecule for cancer immunotherapy. Although PD-L1-expressing malignant cells could be targeted by PD-L1-specific CD8+ cytotoxic T lymphocytes, it remains unclear whether CD4+ helper T lymphocytes (HTLs) recognize and kill tumor cells in a PD-L1-specific manner. Methods The expression levels of PD-L1 and HLA-DR were evaluated using immunohistochemical analyses. MHC class II-binding peptides for PD-L1 were designed based on computer algorithm analyses and added into in vitro culture of HTLs with antigen-presenting cells to evaluate their stimulatory activity. Results We found that seven of 24 cases of OSCC showed positive for both PD-L1 and HLA-DR and that PD-L1241-265 peptide efficiently activates HTLs, which showed not only cytokine production but also cytotoxicity against tumor cells in a PD-L1-dependent manner. Also, an adoptive transfer of the PD-L1-specific HTLs significantly inhibited growth of PD-L1-expressing human tumor cell lines in an immunodeficient mouse model. Importantly, T cell responses specific for the PD-L1241-265 peptide were detected in the HNSCC patients. Conclusions The cancer immunotherapy targeting PD-L1 as a helper T-cell antigen would be a rational strategy for HNSCC patients.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0), Introduction: Neuroendocrine carcinoma (NEC) occurs mostly in the digestive organs, such as the pancreas and gastrointestinal tract, and the lungs. Primary NEC of the breast is a rare entity. There are not many studies on this disease, and this study was carried out in order to know the clinical pathology of this disease. Methods: Of 2354 patients who underwent surgery for breast cancer in our hospital during the period from January 2000 to July 2015, 8 (0.34%) were pathologically diagnosed with NEC of the breast. This study is retrospectively registered. Result: The histological types were small cell carcinoma in one patient and invasive ductal carcinoma (IDC) with neuroendocrine differentiation in the remaining 7. The mean patient age was slightly higher than that of patients with usual IDC. On pathological examination, the NEC tumors were more hormone dependent and often HER2 negative, as compared to usual IDC, though there was no significant difference in nuclear grade. The patients with NEC of the breast showed positivity for neuroendocrine markers on immunohistological staining, and had favorable outcomes. Conclusion: NEC of the breast is rare, and there is no established consensus regarding the pathological significance, prognosis, and treatment method. Further accumulation of cases is necessary.

Robot-assisted radical prostatectomy (RARP) has enabled steady and stable surgical procedures due to both meticulous maneuvers and magnified, clear, 3-dimensional vision. Therefore, better surgical outcomes have been expected with RARP than with other surgical modalities. However, even in the RARP era, post-prostatectomy incontinence has a relatively high incidence as a bothersome complication. To overcome post-prostatectomy incontinence, it goes without saying that meticulous surgical procedures and creative surgical procedures, i.e., "Preservation", "Reconstruction", and "Reinforcement" of the anatomical structures of the pelvis, are most important. In addition, medication and appropriate pad usage might sometimes be helpful for patients with post-prostatectomy incontinence. However, patients who have 1) BMI > 26 kg/m(2), 2) prostate volume > 70 mL, 3) eGFR < 60 mL/min, or a 4) Charlson comorbidity index > 2 have a tendency to develop post-prostatectomy incontinence despite undergoing the same surgical procedures. It is important for patients who have a high risk for post-prostatectomy incontinence to be given information about delayed recovery of post-prostatectomy incontinence. Thus, not only the surgical procedures, but also a comprehensive approach, as mentioned above, are important for post-prostatectomy incontinence.

Introduction: Metaplastic breast cancer (MBC) is a rare pathological type with an incidence rate of not more than 1%, and has been reported to be often detected after its progression and highly malignant with a high proportion of triple negative type tumors, with poor outcomes as compared to IDC [1] [2] [3]. We analyzed clinicopathological characteristics of patients who underwent surgery for epithelial MBC at our department. Patients and Methods: From January 2000 to March 2014, a total of 2120 patients underwent surgery for breast cancer, and MBC was diagnosed in 15 of these patients. Fourteen of the 15 had epithelial MBC and were included in this study. The present study compared clinopathological characteristics of MBC with those of IDC of triple negative type (TN type group) and IDC of non-triple negative type (IDC group). Results: Breast conserving surgery was performed in 7 patients with MBC (50%), a proportion clearly lower than the 64.3% in the IDC group. The mean tumor size was 3.8 cm, which was greater than the 2.13 cm in the TN type group and the 1.7 cm in the IDC group. About nuclear grade, the proportion of grade III was 57.1%, markedly higher than the 38.6% in the TN type group and the 12.6% in the IDC group. All patients were estrogen receptor (ER) and progesterone receptor (PgR) negative; 11 patients were TN type tumors and 3 were HER2 type. Conclusion: We studied patients who underwent surgery for epithelial MBC. The examined cases showed clinopathological characteristics of the disease, including large tumors with a highly malignant nature at the initial detection, higher Ki-67 levels, ER and PgR negativity (all cases), mostly TN type, and a high recurrence rate.

Metastatic renal cell carcinoma (mRCC) is a tumor entity with poor prognosis due to limited therapy options. Tyrosine kinase inhibitors (TKIs), the novel targeted agents have been used for the treatment of mRCC and have shown efficacy. Interferon (IFN)-α is also one of the most frequently used agents in immunotherapy. However, drug resistance needs to be overcome to achieve a sufficiently positive effect. Interleukin-6 (IL-6), which induce suppressor of cytokine signaling-3 (SOCS3) expression, is one of the factors associated with poor prognosis of patients with renal cell carcinoma (RCC). To analyze the influence of IL-6 in drug resistance of RCC, anti-IL-6 receptor antibody was used in combination with IFN or TKIs. The SOCS3 mRNA expression level was significantly increased by IFN-α stimulation in 786-O RCC cells which were resistant to IFN, but not in ACHN cells that were sensitive to IFN. The overexpression of SOCS3 by gene transfection in ACHN significantly inhibited the growth-inhibitory effect of IFN-α. An in vivo study demonstrated that co-administration of SOCS3-targeted siRNA promoted INF-α-induced cell death and growth suppression in 786-O cell xenograft. SOCS3 could be a key component in the resistance to interferon treatment of renal cell carcinoma. Because SOCS3 is rapidly up-regulated by IL-6 and a negative regulator of cytokine signaling, IL-6 expression on RCC cells was also analyzed and the 786-O cells showed the high level of IL-6 mRNA expression under the condition of interferon stimulation. IL-6R antibody, tocilizumab, significantly suppressed cell proliferation in 786-O cells by interferon stimulation accompanied with phosphorylation of STAT1 and inhibited SOCS3 expression. The in vivo effects of combination therapy with tocilizumab and interferon showed significant suppression of 786-O tumor growth in a xenograft model. We also hypothesized that TKI resistance and IL-6 secretion are causally connected. And we found that 786-O RCC cells secrete high IL-6 levels after low dose stimulation with the TKIs sorafenib, sunitinib and pazopanib, inducing activation of AKT-mTOR pathway, NFκB, HIF-2α and VEGF expression. Tocilizumab neutralizes the AKT-mTOR pathway activation and results in reduced proliferation. A combination therapy with tocilizumab and TKI suppresses 786-O tumor growth and inhibits angiogenesis in vivo more efficient than TKI alone. Our findings suggest that IL-6 could induce drug resistance on RCC, and combination therapy of IL-6R inhibitors and IFN/TKIs may represent a novel therapeutic approach for RCC treatment.

BACKGROUND To elucidate the pathogenesis of benign prostatic enlargement (BPE) in humans due to chronic inflammation caused by arteriosclerosis, the relationships between prostate size and the degree of chronic inflammation induced by local arteriosclerosis were investigated. METHODS The present cohort included 50 subjects who underwent robot-assisted radical prostatectomy (RARP) in a prospective study. The presence or absence of local arteriosclerosis in the prostatic arteries removed during RARP was evaluated by microscopic assessment. Chronic inflammation in the prostate was judged according to both the density and the extent of inflammatory cells. The expression of lectin-like oxidized-low density lipoprotein receptor-1 (LOX-1) and the infiltration of macrophages in the prostate, which are high in arteriosclerosis, were investigated by immunohistochemistry. RESULTS Local arteriosclerosis was observed in 28% (14/50). Prostate size and the inflammation score were significantly increased in the presence of arteriosclerosis (P = 0.006, P

OBJECTIVES To assess whether atherosclerosis is involved in the development of overactive bladder and the function of lower urinary tract after robot-assisted radical prostatectomy. METHODS The present cohort consisted of 80 consecutive participants. The preoperative cardio-ankle vascular index was used to evaluate the presence of atherosclerosis. The present cohort was split into two groups, the atherosclerotic group, whose cardio-ankle vascular index was ≥9.0, and the control group, whose index was

BACKGROUND To investigate the possible pathogenesis of the benign prostatic enlargement (BPE) induced by local atherosclerosis, the association between local atherosclerosis and prostatic enlargement was investigated, and molecular biological analyses were performed using human prostatectomy specimens. METHODS A total of 69 consecutive patients who underwent robot-assisted radical prostatectomy (RARP) participated in this prospective study. To evaluate actual local atherosclerosis, prostatic arteries were removed during RARP. Microscopic assessment of local atherosclerosis was classified as one of three degrees of narrowing (minimal, moderate, and severe) according to the degree of obstruction of the inner cavity of the prostatic artery. The expressions of several mediators related to chronic ischemia and cell proliferation of the prostate were investigated by immunohistochemistry. RESULTS The median age of the present cohort was 68 (range: 55-75) years. Although there was no relationship between local atherosclerosis and lower urinary symptoms evaluated by questionnaires, local atherosclerosis was significantly more severe in patients who had a history of treatment for benign prostatic hyperplasia (P = 0.02). Prostate size was significantly larger in the severe local atherosclerosis group than in the minimal and moderate local atherosclerosis groups (P

Background: Intramedullary spinal cord metastasis (ISCM) from breast cancer is a relatively rare disease. We present this disease. Case presentation: The patient was a 67-year-old woman with lung metastasis appearing 3 years after breast cancer surgery. Complete remission was achieved for the metastatic lesion with chemotherapy, but multiple cerebellar metastases were found 3 months after the completion of chemotherapy. Whole-brain irradiation was administered, resulting in symptomatic improvement. Approximately 6 months later, the patient experienced weakness in the lower extremities and difficulty walking. Magnetic resonance imaging detected a well-defined intraspinal tumor measuring 13 × 13 × 30 mm at the level of Th12-L1. After 20-Gy irradiation to the tumor, oral steroid administration, and rehabilitation, the patient regained the ability to walk. Eight months have passed, to date, since these interventions and the patient is currently receiving treatment for metastases to bones, including the spine, but is still capable of walking without difficulty. We herein report this case with a review of the relevant literature. Conclusion: ISCM in the breast cancer is relatively rare. But, it is the clinical condition which it should always place in the mind.

Bypass pyeloplasty (BP) is a simple, non-dismembered procedure that is a side-to-side anastomosis without dividing the ureteropelvic junction (UPJ). BP has been considered more suitable especially for novice surgeons than dismembered pyeloplasty via the laparoscopic approach, but not reported. However, the disadvantage of laparoscopic BP is that it is difficult to suture the side of the anastomosis that is far from the camera. To overcome this disadvantage, a modified technique was developed. This procedure and its initial results are reported. Twenty-six consecutive patients underwent laparoscopic modified BP. The patients’ median age at surgery was 10.5 years. Ten patients were adults and 16 were children. The key step of modified BP involves dividing the UPJ after ureteral spatulation and suture of the dependent portion. This provides both better visualization of the anastomosis portion and easy anastomosis. All procedures were completed by laparoscopic modified BP. The median operative time was 246 (range 170–357) min. The median time for ureteropelvic anastomosis was 205 (range 145–311) min. There were no significant differences in mean operative time and ureteropelvic anastomotic time between adults and children (adults/children = 243 ± 49 min:252 ± 58 min, p = 0.66, 192 ± 33 min:214 ± 48 min, p = 0.21, respectively). Successful resolution of UPJO was observed in 96 % of cases. Laparoscopic modified BP combines the advantages of non-dismembered and dismembered pyeloplasty. Because there were no differences in mean operative and anastomotic times between adults and children, laparoscopic modified BP might be an efficient procedure for all ages, especially children.

The aim of the present study is to investigate the effect of pad use for postprostatectomy incontinence on urinary quality of life (QoL) after robot-assisted laparoscopic radical prostatectomy (RARP) in the early postoperative period.Ninety patients underwent RARP simultaneously completed International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) and modified pad use questionnaire that evaluated pad use and urinary QoL and a 24-hour pad test. Pad use was also assessed by pad form, pad size, the number of pad exchanges per day, and the timing of pad exchanges (i.e., to what extent the pad was wet when the patients exchanged it.). The investigation involved patients visiting the outpatient clinic for the first time after RARP. The association between pad use and urinary QoL was investigated.The mean frequency of pad exchanges was 2±2/day. The mean 24-hour pad test was 139±193 g/day. Multivariate analyses revealed the timing of pad exchanges was significantly associated with QoL on the ICIQ-SF and the modified pad use questionnaire (P=0.007 and P0.001, respectively) and the number of pad exchanges per day was significantly associated with QoL on the ICIQ-SF (P=0.01); QoL worsened with pad wetness and increasing frequency of pad exchange. The other factors relating to pad use were not significantly associated with aggravation of QoL.In the early postoperative period after RARP, the timing of pad exchanges was the most important factor affecting QoL. Namely, patients with postprostatectomy incontinence should wear the appropriate size of pad according to the volume of urinary incontinence and exchange pads when the pad is not too wet. On the other hand, pad form, pad size, and volume of urinary incontinence were not associated with decreased QoL.

Aims The aim of the present study was to investigate whether atherosclerosis could be associated with lower urinary tract dysfunction in the early postoperative period after robot-assisted laparoscopic radical prostatectomy (RARP). Methods Eighty consecutive patients undergoing RARP were investigated. The severity of atherosclerosis was evaluated by the cardio-ankle vascular index (CAVI) before RARP. Patients were divided into two groups, the atherosclerotic group (CAVI ≥9.0) and the control group (CAVI

Objectives To determine whether lysophosphatidic acid activates the mitogen-activated protein kinase and increases DNA synthesis in human bladder smooth muscle cells, and to examine the involvement of lysophosphatidic acid and lysophosphatidic acid receptor in mechanical stretch-induced mitogen-activated protein kinase activation in cultured human bladder smooth muscle cells. Methods TaqMan reverse transcription polymerase chain reaction was used to determine the mRNA expression levels of six lysophosphatidic acid receptor subtypes. Mitogen-activated protein kinase activity enhanced by either lysophosphatidic acid or mechanical stretch was measured by western blotting. The effect of lysophosphatidic acid on DNA synthesis was assessed by 5-bromo-2’-deoxy-uridine incorporation assay. Results Lysophosphatidic acid 1 subtype mRNA was predominantly expressed (96%). Lysophosphatidic acid activated the mitogen-activated protein kinase in a concentration-dependent manner. C-jun NH2-terminal kinase showed the highest activity among the three subsets of the mitogen-activated protein kinase family members (c-jun NH2-terminal kinase, extracellular signal-regulated kinases, p38). Lysophosphatidic acid also increased incorporation of 5-bromo-2’-deoxy-uridine. These responses were suppressed by Ki16425 (lysophosphatidic acid receptor antagonist). Mechanical stretch mainly induced c-jun NH2-terminal kinase activation. This activation was partially inhibited by Ki16425. Conclusions Lysophosphatidic acid might activate the c-jun NH2-terminal kinase component of the mitogen-activated protein kinase family and DNA synthesis through lysophosphatidic acid receptors (presumably, through lysophosphatidic acid 1) in human bladder smooth muscle cells. The present study also implicates the involvement of lysophosphatidic acid and lysophosphatidic acid receptors in mechanical stretch-induced c-jun NH2-terminal kinase activation. Lysophosphatidic acid receptor can be partially activated by mechanical stretching through lysophosphatidic acid-dependent or independent mechanism.

Objective To investigate the effect of fasudil, a Rho-kinase inhibitor, on chronic ischemia-related bladder dysfunction. Materials and Methods Male Sprague-Dawley rats (16 weeks old) were divided into control, chronic bladder ischemia (CBI), and CBI with fasudil treatment (CBI-Fa) groups. The CBI and CBI-Fa groups underwent balloon endothelial injury of bilateral iliac arteries and received a 2% cholesterol diet for 8 weeks after the procedure to induce CBI. The CBI-Fa group was given oral fasudil (30 mg/kg/day) using zonde for 8 weeks after the procedure. The control group received a regular diet for 8 weeks. After cystometry in a conscious state, rats from each group were euthanized, and the bladders and common iliac arteries were harvested for pharmacologic and histologic examination. Results Mean wall thickness of the common iliac arteries was significantly greater in the CBI group than in controls. Contractile responses of muscle strips were significantly lower in CBI group rats than in controls. In the CBI group, micturition interval was significantly shorter, and bladder capacity was significantly lower compared with those in controls. In the CBI-Fa group, arterial wall thickening was significantly suppressed compared with the CBI group. Significant improvements in muscle strip contractility and cystometric parameters were seen in the CBI-Fa group compared with the CBI group. Conclusion Our results suggest that chronic treatment with fasudil could prevent neointimal formation in arteries and bladder dysfunction in this rat model. Fasudil may be therapeutically useful in protecting bladder function in chronically ischemic bladders.

Sunitinib, a molecular-targeted therapy, is a potential new treatment strategy for malignant pheochromocytoma. However, because of the rarity of malignant pheochromocytoma and the consequent limited number of patients available for clinical study, there is no good evidence of the efficacy of sunitinib for malignant pheochromocytoma. The present report describes our experience with sunitinib for refractory malignant pheochromocytoma. Two patients were treated with sunitinib at a standard dose (50 mg daily; 4 weeks on, 2 weeks off) after cyclophosphamide/vinblastine/dacarbazine chemotherapy, because vascular endothelial growth factor (VEGF)-positive cells were partly observed by immunohistochemical staining. Both patients were assessed as having stable disease according to the Response Evaluation Criteria in Solid Tumors 1.1. The duration of overall survival from the time sunitinib was initiated was 13 and 8 months, respectively, and the progression-free survival was 5 and 4 months, respectively. Adverse events were evaluated according to the Common Terminology Criteria for adverse events of the US Department of Health and Human Services version 4.0. One patient experienced hypothyroidism (Grade 2) and thrombocytopenia (Grade 2). The other patient experienced anorexia (Grade 3) and general malaise (Grade 3). In conclusion, sunitinib was effective in the treatment of malignant pheochromocytoma when VEGF-positive cells were observed in the tumor specimens.

Appropriate protocol for the sequential treatment of metastatic renal cell carcinoma (mRCC) has not been established yet. Some mRCC cases with favorable risk were reported to achieve complete remission and durable response using interferon alfa (IFNα) + low dose interleukin-2 (IL-2). Cytokine therapies may be suitable for some patients with mRCC as first-line therapy. The present study is a phase III, investigator-initiated, multicenter, prospective randomized controlled trial investigating patients with low and intermediate risk mRCC classified by Memorial Sloan-Kettering Cancer Center risk criteria to evaluate the efficacy and safety of sequential treatment with cytokine (IFNα + IL-2) as first-line and axitinib as second-line therapy versus sequential treatment with sunitinib as first-line and axitinib as second-line therapy, which is the current standard treatment for patients with favorable risk. The target sample size was set at 72 patients per group (total 144 cases). The study duration is 7 years, and the duration for recruitment is 4 years. Our expectation of this trial is to clarify first- and second-line sequential treatment for mRCC better, especially in patients with favorable risk and some with intermediate risk. The results of this trial will certainly contribute to new information for the strategy of first- and second-line sequential treatment for mRCC. Trial registration: University hospital Medical Information Network (UMIN) Center identifier UMIN 000012522. Keywords: Cytokine, Interferon alfa, Interleukin-2, Sunitinib, Axitinib, Metastatic renal cell carcinoma

Background We conducted a study on photodynamic diagnosis (PDD) using autofluorescence in video-assisted thoracic surgery for minute intrathoracic small dissemination or early malignant pleural mesothelioma. Methods Autofluorescence is the spontaneous emission of light that occurs when mitochondria, lysosomes, and other intracellular organelles absorb light. In normal tissues, green autofluorescence of approximately 520 nm is observed in response to 400-450 nm blue excitation rays. However, in cancer lesions, green autofluorescence is reduced due to thickening of the mucosal epithelium, a decrease in autofluorescent substances, etc., and the color spectrum thus shifts to red-violet. This phenomenon is the basis of PDD. Results The color spectrum shift was observed in all tumors located on the pleural surface but not in cases with pleural fibrous disease. Among patients with primary lung cancer, those with pleural infiltration (pl) scores of 1 or greater showed color spectrum shifts due to reduced autofluorescence. Conclusion Localization of pleural lesions by autofluorescence imaging was found to be useful. In primary lung cancer cases, differentiation between pl0 and pl1 lesions appears to be useful for determining therapeutic strategies including surgical procedures.