Outcome of maintenance systemic chemotherapy with drug-free interval for metastatic urothelial carcinoma.

OBJECTIVE: Aiming to achieve long-term disease control, maintenance systemic chemotherapy (MSC) with a 1-3-month drug-free interval is continued in selected patients. We report our experience of MSC for metastatic urothelial carcinoma (UC). METHODS: Of 228 metastatic UC patients treated with systemic chemotherapy, 40 (17.5%, 40/228) had continuously undergone MSC. Data on the regimen, cycle number, and reason for the discontinuation of MSC were also collected. We analyzed OS from the initiation of MSC until death or the last follow-up, using the log-rank test to assess the significance of differences. RESULTS: The median number of cycles of chemotherapy was 6, and the responses were CR in 6, PR in 20, SD in 13, and PD in 1 before MSC. Gemcitabine plus CDDP or carboplatin was mainly performed as MSC (70%, 28/40). MSC was repeated quarterly in 30 (75%, 30/40), every two months in 8 (20%, 8/40), and with other intervals in 2 (5%, 2/40). Overall, a median of 3.5 cycles (range: 1-29) of MSC was performed. The reason for the discontinuation of MSC was PD in 24 (60%, 24/40), favorable disease control in 9 (22.5%, 9/40), and myelosuppression in 3 (7.5%, 3/40), and for other reasons in 2 (5%, 2/40). MSC was ongoing in 2 (5%, 2/40). The median OS was 27 months from the initiation of MSC. PS0 (P = 0.0169), the absence of lung metastasis (P = 0.0387), and resection of the primary site (P = 0.0495) were associated with long-term survival after MSC. CONCLUSIONS: In selected patients, long-term systemic chemotherapy could be performed with a drug-free interval. Our maintenance strategy with cytotoxic drugs may become one of the treatment options for long-term disease control.

Diagnosis and treatment of bone metastasis: comprehensive guideline of the Japanese Society of Medical Oncology, Japanese Orthopedic Association, Japanese Urological Association, and Japanese Society for Radiation Oncology.

Diagnosis and treatment of bone metastasis requires various types of measures, specialists and caregivers. To provide better diagnosis and treatment, a multidisciplinary team approach is required. The members of this multidisciplinary team include doctors of primary cancers, radiologists, pathologists, orthopaedists, radiotherapists, clinical oncologists, palliative caregivers, rehabilitation doctors, dentists, nurses, pharmacists, physical therapists, occupational therapists, medical social workers, etc. Medical evidence was extracted from published articles describing meta-analyses or randomised controlled trials concerning patients with bone metastases mainly from 2003 to 2013, and a guideline was developed according to the Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014. Multidisciplinary team meetings are helpful in diagnosis and treatment. Clinical benefits such as physical or psychological palliation obtained using the multidisciplinary team approaches are apparent. We established a guideline describing each specialty field, to improve understanding of the different fields among the specialists, who can further provide appropriate treatment, and to improve patients' outcomes.

Phase I/II study of S-1 in combination with sorafenib for metastatic renal cell carcinoma.

BACKGROUND: The potential of S-1 for the treatment of metastatic renal cell carcinoma (mRCC) has been shown in two phase II studies. We aimed to assess the safety, tolerance, pharmacokinetics and clinical activity of S-1 combined with sorafenib in patients with mRCC. PATIENTS AND METHODS: In this multicenter, single-arm, open-label, phase I/II study of S-1 plus sorafenib, we recruited patients with clear-cell or papillary renal cell carcinoma who had received a maximum of one prior cytokine-based regimen. The phase I primary end points were the maximum tolerated dose (MTD) and recommended dose (RD). S-1 was administered orally at 60, 80, 100 or 120 mg/day on days 1-28 of a 42-day cycle in combination with sorafenib (400 or 800 mg/day), given daily with dose adjustment. In phase II, the primary end point was to assess the overall response rate (ORR) at the RD. RESULTS: Nine patients were enrolled into phase I and 21 (including 6 patients who received the RD in the phase I portion) were enrolled into phase II. In the phase I portion, the MTD could not be determined, and the RD was defined as S-1 80 mg/m(2)/day on days 1-28 + sorafenib 800 mg/day on days 1-42. In the phase II portion, 21 patients were fully assessable for efficacy and safety. The confirmed ORR was 52% [95% confidence interval (CI) 29.8-74.3], including one complete response (5%) and 10 partial responses (48%). The median progression-free survival was 9.9 (95% CI 6.5-17.1) months. The most frequently reported treatment-related adverse event for all grades was hand-foot skin reaction (100%). The major reasons for dose reduction were hand-foot skin reaction (38%) and rash (14%). CONCLUSION: Combination therapy with S-1 plus sorafenib is effective and tolerable for patients with mRCC. However, skin events management is important in S-1 plus sorafenib combination therapy.

Detoxification mechanism of asbestos materials by microwave treatment.

The detoxification mechanism of asbestos materials was investigated through simulations and experiments. The permittivities of pure CaO and Mg3Si4O12, as quasi-asbestos materials, were measured using the cavity perturbation method. The real and imaginary parts of the relative permittivity (ɛr' and ɛr″) of CaO are functions of temperature, and numerical simulations revealed the thermal distributions in an electromagnetic field with respect to both asbestos shape and material configuration based on permittivity. Optical microscopic observation revealed that the thickness of chrysotile fibers decreased as a result of CaO heating. The heating mechanism of asbestos materials has been determined using CaO phase, and the detoxification mechanism of asbestos materials was discussed based on the heating mechanism.

A randomized multicenter phase II trial on the efficacy of a hydrocolloid dressing containing ceramide with a low-friction external surface for hand-foot skin reaction caused by sorafenib in patients with renal cell carcinoma.

BACKGROUND: The purpose of this study was to investigate the usefulness of a hydrocolloid dressing containing ceramide for hand-foot skin reaction (HFSR) on the soles of the feet in metastatic renal cell carcinoma (RCC) patients treated with sorafenib. PATIENTS AND METHODS: Patients with grade 1 HFSR on the soles of the feet were randomly assigned in to two groups. One group received a hydrocolloid dressing containing ceramide (arm A) and the other received 10% urea cream (arm B). Patients in both groups applied treatment to the affected sites on the soles of the feet, but not to the hands. The primary end point was the incidence of grade 2 or 3 HFSR on the soles of the feet in the first 4 weeks. RESULTS: Thirty-three patients were assessed (17 in arm A and 16 in arm B), and there were no significant differences in baseline characteristics between the two groups. During the observation period of this study, grade 2 or 3 HFSR on the soles of the feet was found in 29% of patients in arm A and was significantly less than the 69% in arm B (P=0.03). The incidence of HFSR on the hands, however, was similar in both arms. The median time to grade 2 or 3 HFSR on the soles of the feet was also significantly longer in arm A than in arm B (P=0.03). CONCLUSIONS: These results indicate that a hydrocolloid dressing containing ceramide prevented the worsening of HFSR caused by sorafenib in metastatic RCC patients. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000002016.

Indoor air quality and thermal comfort in temporary houses occupied after the Great East Japan Earthquake.

UNLABELLED: Thermal conditions and indoor concentrations of aldehydes, volatile organic compounds (VOCs), and NO2 were investigated in 19 occupied temporary houses in 15 temporary housing estates constructed in Minamisoma City, Fukushima, Japan. The data were collected in winter, spring, and summer in January to July 2012. Thermal conditions in temporary log houses in the summer were more comfortable than those in pre-fabricated houses. In the winter, the indoor temperature was uncomfortably low in all of the houses, particularly the temporary log houses. Indoor air concentrations for most aldehydes and VOCs were much lower than the indoor guidelines, except for those of p-dichlorobenzene, acetaldehyde, and total VOCs. The indoor p-dichlorobenzene concentrations exceeded the guideline (240 µg/m(3)) in 18% of the temporary houses, and the 10(-3) cancer risk level (91 µg/m(3)) was exceeded in winter in 21% due to use of moth repellents by the occupants. Indoor acetaldehyde concentrations exceeded the guideline (48 µg/m(3) ) in about half of the temporary houses, likely originating from the wooden building materials. Indoor NO2 concentrations in the temporary houses were significantly higher in houses where combustion heating appliances were used (0.17 ± 0.11 ppm) than in those where they were not used (0.0094 ± 0.0065 ppm). PRACTICAL IMPLICATIONS: In the winter, log-house-type temporary houses are comfortable in terms of humidity, dew condensation, and fungi based on the results of questionnaires and measurements, whereas pre-fabricated temporary houses are more comfortable in terms of temperature. In the summer, log-house-type temporary houses are comfortable in terms of temperature and humidity. More comfortable temporary housing in terms of temperature and humidity year-round is needed. Indoor air concentrations of p-dichlorobenzene and NO2 were quite high in some temporary houses due to occupants' activities, such as use of moth repellents and combustion heating appliances. The government should provide recommendations for safe use of temporary houses by occupants.

Lysyl oxidase secreted by tumour endothelial cells promotes angiogenesis and metastasis.

BACKGROUND: Molecules that are highly expressed in tumour endothelial cells (TECs) may be candidates for specifically targeting TECs. Using DNA microarray analysis, we found that the lysyl oxidase (LOX) gene was upregulated in TECs compared with its expression in normal endothelial cells (NECs). LOX is an enzyme that enhances invasion and metastasis of tumour cells. However, there are no reports on the function of LOX in isolated TECs. METHODS: TECs and NECs were isolated to investigate LOX function in TECs. LOX inhibition of in vivo tumour growth was also assessed using ß-aminopropionitrile (BAPN). RESULTS: LOX expression was higher in TECs than in NECs. LOX knockdown inhibited cell migration and tube formation by TECs, which was associated with decreased phosphorylation of focal adhesion kinase (Tyr 397). Immunostaining showed high LOX expression in human tumour vessels in vivo. Tumour angiogenesis and micrometastasis were inhibited by BAPN in an in vivo tumour model. CONCLUSION: LOX may be a TEC marker and a possible therapeutic target for novel antiangiogenic therapy.

Biglycan is a specific marker and an autocrine angiogenic factor of tumour endothelial cells.

BACKGROUND: We isolated tumour endothelial cells (TECs), demonstrated their abnormalities, compared gene expression profiles of TECs and normal endothelial cells (NECs) by microarray analysis and identified several genes upregulated in TECs. We focused on the gene encoding biglycan, a small leucine-rich repeat proteoglycan. No report is available on biglycan expression or function in TECs. METHODS: The NEC and TEC were isolated. We investigated the biglycan expression and function in TECs. Western blotting analysis of biglycan was performed on sera from cancer patients. RESULTS: Biglycan expression levels were higher in TECs than in NECs. Biglycan knockdown inhibited cell migration and caused morphological changes in TECs. Furthermore, immunostaining revealed strong biglycan expression in vivo in human tumour vessels, as in mouse TECs. Biglycan was detected in the sera of cancer patients but was hardly detected in those of healthy volunteers. CONCLUSION: These findings suggested that biglycan is a novel TEC marker and a target for anti-angiogenic therapy.

The incidence and mechanism of sunitinib-induced thyroid atrophy in patients with metastatic renal cell carcinoma.

BACKGROUND: To elucidate the incidence and mechanisms of sunitinib-induced thyroid atrophy, we investigated serial volumetric and functional changes, and evaluated histological changes of the thyroid gland in metastatic renal cell carcinoma patients who received sunitinib. METHODS: Thyroid volume (by computed tomography volumetry) and thyroid function were measured at baseline, during the treatment, and at post-treatment periods. Histological evaluation of the thyroid gland was performed in four autopsied patients. RESULTS: The median reduction rate in thyroid volume at last evaluation during sunitinib treatment was 30% in all 17 patients. The incidence of hypothyroidism during sunitinib treatment was significantly higher in the high reduction rate group (n=8; more than 50% reduction in volume) than in the low reduction rate group (n=9; less than 50% reduction in volume). Half of the patients in the high reduction rate group exhibited a transient thyroid-stimulating hormone suppression, suggesting thyrotoxicosis during sunitinib treatment. Histological evaluation demonstrated atrophy of thyroid follicles and degeneration of follicular epithelial cells without critical diminution of vascular volume in the thyroid gland. CONCLUSION: Thyroid atrophy is frequently observed following sunitinib treatment and may be brought about by sunitinib-induced thyrotoxicosis or the direct effects of sunitinib that lead to degeneration of thyroid follicular cells.

Role of lymph node dissection in the treatment of urothelial carcinoma of the upper urinary tract: multi-institutional relapse analysis and immunohistochemical re-evaluation of negative lymph nodes.

AIM: To determine the role of lymph node dissection (LND) in the treatment of urothelial carcinoma (UC) of the upper urinary tract (UUT). PATIENTS AND METHODS: [Study-1] A retrospective multi-institutional study evaluated 293 patients undergoing predominantly nephroureterectomy for UC of the UUT. Of 293 patients, 267 patients had pure UC and 26 demonstrated other histological components. Regarding the pathological node status, 130 patients had pN0 disease, 141 patients had pNx disease and 22 patients had pN+ disease. The sites of initial recurrence and time to first recurrence were reviewed. The sites of recurrence were classified as locoregional or distant recurrence. The relationship between node status and future recurrence was analyzed. [Study-2] Fifty-one patients treated by nephroureterectomy at Hokkaido University Hospital were included. All had LND and all LNs were negative on hematoxylin and eosin staining. We re-evaluated the presence of micrometastasis in LND specimens by anti-cytokeratin immunohistochemistory. RESULTS: [Study-1] Of 293 patients, 76 developed disease relapse. Regional lymph node recurrence was the most common site (34 patients). On multivariate analyses that adjusted for the effect of tumor stage and tumor grade, pNx (skipping LND) was an adverse factor not only for locoregional recurrence, but also for distant relapse. [Study-2] Immunohistochemistry identified micrometastases in 7 (14%) of 51 patients. Regarding survival, 5 of these 7 patients with micrometastases were alive at last follow-up. CONCLUSIONS: On relapse analysis, skipping LND was an adverse factor not only for locoregional recurrence, but also for distant relapse. Immunohistochemistry detected micrometastases in about 14% of patients previously diagnosed as pN0. These findings further support a potential therapeutic benefit of LND by eliminating micrometastases.

Controle bacteriológico de carne caprina para elaboração de hambúrguer caprino defumado / Bacteriological control of goat meat to elaboration of smoked goat hamburger

Realizaram-se avaliações bacteriológicas da matéria-prima utilizada na elaboração de um produto cárneo caprino tipo hambúrguer defumado, antes e após sanitização. A carne foi tratada por aspersão, com uma solução de ácidos orgânicos contendo 2 por cento de ácido acético, 1 por cento de ácido lático, 0,25 por cento de ácido cítrico e 0,1 por cento de ácido ascórbico, e armazenada sob refrigeração. As análises bacteriológicas foram realizadas no dia 0 e aos 7 e 14 dias após defumação. Na carne, no dia 0, a contagem de coliformes fecais estava acima do limite permitido pela legislação vigente, mas sete dias após a sanitização, esse parâmetro estava dentro dos limites permitidos. No produto final todos os parâmetros bacteriológicos encontraram-se dentro dos padrões higiênico-sanitários.

In order to obtain a safe goat smoked hamburger, bacteriological analysis of the raw material was performed before and after sanitation. Meat was sprayed with a solution of organic acids containing 2 percent acetic acid, 1 percent lactic acid, 0.25 percent citric acid and 0.1 percent ascorbic acid and, after that, stored under refrigeration. Bacteriological analysis was carried out on days 0, 7 and 14 after goat smoked hamburger processing. In meat, on day 0, the fecal coliform count was above legal limits, but on day 7 after sanitation this parameter was these limits. In the final product, all the results of the bacteriological parameters were according to the sanitary-hygienic standards.

Effectiveness of Cryptosporidium spp. oocysts detection and enumeration methods in water and milk samples

Cryptosporidium spp. oocyst recovery in water and milk samples was evaluated. Samples were inoculated with a suspension of 1.2×10(7) Cryptosporidium spp. oocysts and submitted to centrifugal flotation, using different solutions (sucrose, NaCl, MgSO4, ZnSO4, AlSO4, NH4SO4 40 percent and NH4SO4 80 percent). Centrifugation of the samples was carried out in two stages for concentration using two methods that differed in the order in which the saturated solutions were used, namely only in the first stage of method I and only in the second stage of method II. Oocyst identification was performed using the Kinyoun and Koster histochemical staining techniques. Samples analyzed by method I showed different degree of oocyst recovery, namely 10.9 percent with NaCl and 42.5 percent with MgSO4 in water and milk samples, while those samples analyzed by method II showed 10.6 percent with NaCl and 5.3 percent with sucrose in water and milk, respectively. Histochemical staining methods have no influence on the degree of oocysts recovery. The efficiency of Cryptosporidium spp. oocysts recovery methods depends on the nature and composition of the sample and on the methodology used for oocyst concentration.

Avaliou-se a recuperação de oocistos de Cryptosporidium spp. em amostras de água e leite. As amostras foram contaminadas experimentalmente com uma suspensão de 1,2×10(7) oocistos de Cryptosporidium spp. e concentradas por centrífugo-flutuação para comparação entre diferentes substâncias (sacarose, NaCl, MgSO4, ZnSO4, AlSO4, NH4SO4 40 por cento e NH4SO4 80 por cento). A centrifugação das amostras foi realizada em duas etapas para concentração utilizando-se dois métodos, diferentes pela ordem do uso das soluções saturadas no procedimento, na primeira etapa de concentração do método I, e na segunda etapa, do método II. A identificação do oocisto foi realizada mediante as técnicas de coloração histoquímica Kinyoun e Koster modificado. O grau de recuperação de oocistos foi 10,9 por cento com NaCl e 42,5 por cento com MgSO4 nas amostras de água e leite, respectivamente (método I), e de 10,6 por cento com NaCl e 5,3 por cento com sacarose nas amostras de água e leite, respectivamente (método II). Os métodos de coloração histoquímica não influenciaram nos resultados. A eficácia dos métodos de recuperação de oocistos de Cryptosporidium spp. depende da natureza e composição da amostra e da metodologia usada para a concentração dos oocistos na amostra.

Contribution of CD4+ and CD8+ T cells and interferon-gamma to the progress of chronic rejection of kidney allografts: the Th1 response mediates both acute and chronic rejection.

T cells mediating chronic rejection (CR) of human kidney allografts were characterized by comparing them with those mediating acute rejection (AR). Two lines of analysis were performed using biopsy specimens (23 CR and 8 AR). First, the extent of infiltration of CD4+ and CD8+ T cells into allografts was assessed from mRNA expression of CD4 and CD8. The group of CR specimens was not significantly different from the group of AR specimens in terms of the extent of CD4+ and CD8+ T cell infiltration, underlining the importance of the immunological contribution to the progress of CR. Second, Th1/Th2 polarization in infiltrating T cells was investigated by measuring mRNA expression of interferon gamma (IFN-gamma; a Th1 cytokine) and interleukin 4 (IL-4; a Th2 cytokine). IFN-gamma expression was detected in most CR specimens, and was not significantly different between the group of CR specimens and the group of AR specimens. On the other hand, IL-4 expression was detected in only two CR specimens and one AR specimen; from its pathological features, the AR in this last case was concomitant with CR. These results suggest that most cases of CR and of AR are mediated by Th1 mechanisms, although some cases of CR show features of both Th1 and Th2.

Clonality analysis of T cells mediating acute and chronic rejection in kidney allografts.

The clonality of T-cell populations mediating acute and chronic rejection (AR and CR, respectively) of kidney allografts was ascertained by investigating the diversity of TCRBV genes expressed by allograft-infiltrating T cells. Both oligoclonality and polyclonality cases were found in biopsy specimens of AR as well as CR. These results indicated that the T-cell clonality in each specimen did not correlate directly with the mode of rejection. When AR and CR specimens were compared, however, the CR specimen group was significantly more polyclonal (or less oligoclonal) than the AR group. This result may reflect the higher chance of epitope spreading in the more slowly progressing CR than in AR.

Immunohistochemical analysis of E-cadherin, alpha-catenin, beta-catenin, gamma-catenin, and neural cell adhesion molecule (NCAM) in chordoma.

AIMS: The epithelioid features seen in chordoma are unique among mesenchymal tumours. However, no detailed analysis regarding cell-cell communication has been conducted in this epithelioid tumour. The aims of this study were to investigate cell-cell communication in chordoma. METHODS: By means of immunohistochemical techniques that incorporated a panel of monoclonal antibodies against cell adhesion molecules (CAMs), including E-cadherin, alpha-catenin, beta-catenin, gamma-catenin, and neural cell adhesion molecule (NCAM), the expression of CAMs was studied in 15 specimens of chordoma and eight specimens of chondrosarcoma. RESULTS: Most chordoma specimens showed some positive immunoreactivity for all the CAMs examined. For the various CAMs investigated, between two and five cases showed diffuse immunoreactions, indicating well preserved expression. Well preserved expression of all the CAMs examined was limited to only one case, thus indicating that the expression of CAMs was decreased in most of the chordoma specimens; however, no significant correlation was found between the decreased expression of CAMs and the histological grade of malignancy, cellular growth pattern, or clinical parameters in chordoma. In chondrosarcoma, only a few specimens showed positive immunoreactivity for CAMs and the expression of E-cadherin, beta-catenin, gamma-catenin, and NCAM was seen more frequently in the chordoma specimens than in the chondrosarcoma specimens. CONCLUSIONS: These results suggest that the expression of CAMs is associated with the formation and maintenance of chordoma tissue architecture, just as it is in other epithelial tumours or normal tissue. Immunohistochemistry for CAMs was found to be of diagnostic value for discriminating chordoma from chondrosarcoma, and these markers could be used along with the cytokeratins, which are already used for this purpose.

[Contrivance for frozen section diagnosis of early minute lung cancer during operation].

We reported the technique of pathological diagnosis for minute lung cancer lesion of early stage during operation. Target lesion for our technique may be less than 1 cm in size and not be detected by palpation. Our technique may superior to usual method of frozen section of tissue specimen without fixation. At first, resected lung specimen was fixed by injection of 20% formalin solution subsequent warming by microwave oven for 40 seconds. Almost all lesions may be detected in proper thickness of specimen. Specimen was washed out and steeped in the 20% of sucrose solution for 30 to 60 seconds in order to avoid crystallization of water that was contained within lung specimen. Then thin sliced section of specimen was made by Cryostat in usual method. The minute cancer lesion was able to detect more easy than usual method of making frozen section of specimen. Formalin fixed and sucrose steeped frozen section may be able to evaluate the surgical margin from cancer exactly than the section made by non-fixed specimen.

Adenovirus-mediated gene therapy for bladder cancer in an orthotopic model using a dominant negative H-ras mutant.

It has been suggested that abnormal Ras function is important in the carcinogenesis and progression of bladder cancer. Our aim was to investigate the efficacy of transurethral inoculation of an adenovirus expressing the dominant negative H-ras mutant N116Y against orthotopically implanted human bladder-cancer cells in nude mice. We used a replication-defective adenovirus vector containing the beta-galactosidase gene (AdCMV-LacZ) as a control and the N116Y gene (AdCMV-N116Y) as the therapeutic vector under the transcriptional control of the cytomegalovirus promoter. We initially investigated the in vitro growth-suppressive effects of AdCMV-N116Y on 2 human bladder-cancer cell lines, KU-7 and UMUC-2. Thereafter, we examined the inhibitory effects of AdCMV-N116Y on the 2 orthotopically implanted cell lines in nude mice. Intravesically created, orthotopic human bladder cancers were established in female KSN athymic nude mice with 1x 10(7) cancer cells. Then, 2, 3 and 4 days following implantation, 1 x 10(9) pfu of AdCMV-LacZ or AdCMV-N116Y were administered transurethrally. In vitro growth assays revealed significant growth suppression (>95%) with apoptosis of target cells treated with AdCMV-N116Y compared to AdCMV-LacZ. Transurethral inoculation of AdCMV-N116Y into the bladder brought about a significant reduction in size (73% to 90%) and number (47% to 78%) of orthotopically implanted human bladder tumors compared to AdCMV-LacZ or PBS. Normal mucosa in nude mice had minor inflammation with the infiltration of mononuclear cells. Our results suggest that gene therapy via transurethral inoculation of AdCMV-N116Y holds promise for the treatment of human bladder cancer.