Splenic vein reconstruction is unnecessary in pancreatoduodenectomy combined with resection of the superior mesenteric vein-portal vein confluence according to short-term outcomes.

BACKGROUND: Superior mesenteric vein-portal vein confluence resection combined with pancreatoduodenectomy (SMPVrPD) is occasionally required for resection of pancreatic head tumors. It remains unclear whether such situations require splenic vein (SV) reconstruction for decompression of left-sided portal hypertension (LSPH). METHODS: The data from 93 of 104 patients who underwent pancreatoduodenectomy (PD) for pancreatic head malignancies were reviewed. Surgical outcomes in three groups-standard PD (control group), PD combined with vascular resection and SV preservation (SVp group), and SMPVrPD with SV resection (SVr group)-were compared. The influence of division and preservation of the two natural confluences (left gastric vein-portal vein and/or inferior mesenteric vein-SV confluences) on portal hemodynamics were evaluated using three-dimensional computed tomographic portography. RESULTS: No mortality occurred. The morbidity rates were not significantly different among the three groups (18/43, 8/21, and 7/29, respectively; p = 0.306). In the SVr group, three patients had gastric remnant venous congestion, and three had esophageal varices without hemorrhagic potential. No patients had splenomegaly, or severe or prolonged thrombocytopenia. These LSPH-associated findings were less frequently observed when the two confluences were preserved. CONCLUSIONS: SMPVrPD without SV reconstruction can be safely conducted. Additionally, preservation of these two confluences may reduce the risk of LSPH.

Hyper-expression of PAX2 in human metastatic prostate tumors and its role as a cancer promoter in an in vitro invasion model.

BACKGROUND: Metastasis is a consequence of many biological events, during which cancer stem cells are shifted into a malignant state. Among these events, invasion of prostate cancer cells into host tissues is possible to be assessed by means of an in vitro invasion model, and is thought to be coupled to altered expression of membrane proteins. Dysregulated functions of the factors regulating organogenesis during embryogenesis are known to facilitate metastasis of many types of cancers. PAX2 (paired box 2) is a member of the PAX transcription factor family, which regulates prostatic ductal growth and branching in organogenesis of mammalian prostates. However, the role of PAX2 in prostate cancer development remains to be determined. METHODS: PAX2 expression in human prostate cancers and normal prostate epithelium were examined by quantitative RT-PCR and immunohistochemistry. Matrigel invasion assay and a gene array analysis were performed using prostate cancer cell lines transfected with either control or PAX2 siRNA. RESULTS: In human prostate cancers, PAX2 was hyper-expressed in metastatic cancers, but was expressed at lower levels in non-metastatic cancers. Consistent with this, PAX2 knockdown repressed cell growth and invasion in a Matrigel invasion assay. Gene ontology analysis revealed that many cell membrane proteins were downregulated after PAX2 knockdown. CONCLUSIONS: Our data suggested that PAX2 hyper-expression promotes the development of the metastatic state in prostate cancer cells, presumably through upregulating the expression of cell membrane proteins.

Post-chemotherapy nerve-sparing laparoscopic retroperitoneal lymph node dissection in stage IIB testicular cancer.

We report our experience of extraperitoneal nerve-sparing laparoscopic retroperitoneal lymph node dissection after chemotherapy. Six patients were diagnosed with non-seminomatous germ cell tumor after orchiectomy and clinical stage IIB disease. Nerve-sparing laparoscopic retroperitoneal lymph node dissection was carried out for residual retroperitoneal tumors after cisplatin-based chemotherapy. The median tumor diameter was 2.95 cm before chemotherapy and 1.95 cm after chemotherapy. A modified left (n=1), right (n=1) and bilateral (n=4) template for the dissection area was used. Surgery was successfully completed in all patients and no conversion to open surgery was necessary. Median operative time was 394 min (range 212-526 min). Median blood loss was 75 mL (range 10-238 mL). The overall complication rate was 33.3% (2/6). Two patients had prolonged lymphatic leakage (grade I), which was managed conservatively. Antegrade ejaculation was preserved in all six patients. The histopathological findings showed that two patients had mature teratoma and four patients had necrotic tissue. After a median follow up of 30 months (range 24-36), no recurrence of disease was observed. We can conclude that extraperitoneal nerve-sparing laparoscopic retroperitoneal lymph node dissection for residual tumors after chemotherapy is a feasible operation. The oncological outcomes need to be confirmed in a certain number of patients with longer follow up.

Optimal duration of androgen deprivation in combination with radiation therapy for Japanese men with high-risk prostate cancer.

OBJECTIVES: To evaluate the efficacy and toxicity of external beam radiation therapy (EBRT) combined with androgen deprivation therapy (ADT) for Japanese high-risk prostate cancer (PCa) patients in a single institution. METHODS: Seventy-five high-risk PCa patients were treated by three-dimensional conformal radiotherapy of 70 Gy combined with neoadjuvant, concurrent and adjuvant ADT. RESULTS: Median age was 72 (59-82) years. Median initial serum prostate-specific antigen (PSA) was 19.0 (4.7-200) ng/ml. Median duration of the entire ADT was 27 (8-63) months. Median follow-up after initiating ADT and after completing EBRT was 66 (41-105) and 59 (36-94) months, respectively. Five-year overall, clinical progression-free, and biochemical progression-free survival rates were 98.3, 97.2, and 87.4%; 2 (2.7%) cancer deaths, 3 (4.0%) clinical progressions, and 11 (14.7%) biochemical progressions. Multivariate analysis suggested a total duration of ADT shorter than 24 months as an independent risk factor of biochemical progression (p = 0.01). Grade 3 toxicities related to EBRT were observed: 1 patient with proctitis and rectal bleeding and 1 patient with rectal bleeding. CONCLUSIONS: It is suggested that 70 Gy EBRT combined with ADT confers disease-free survival benefit with tolerable adverse events for Japanese high-risk PCa patients. ADT of 24 months or longer might be recommended to minimize biochemical progression.

[Prostatic neuroendocrine carcinoma with priapism : a case report].

An 84-year-old man presented with priapism in May, 2009. At 79 years old, he was diagnosed with stage C prostate cancer and then, was treated with hormonal therapy. The serum level of prostate-specific antigen (PSA) was within the normal range (0.02 ng/ml). Penile caverno-dorsal vein shunt (Barry shunt) and caverno-spongiosum shunt (Quackels shunt) were performed for the purpose of managing local symptoms. Following operation, the penile pain was mitigated. Postoperative computed tomography (CT) revealed the enlarged prostate and multiple metastases to lungs and multiple bone metastases. Histological examination of the prostatic needle biopsy revealed poorly differentiated neuroendocrine carcinoma of the prostate.

[Localized amyloidosis of the urinary bladder: a case report].

Amyloidosis is characterized by extracellular deposition of abnormal insoluble fibrils, which cause structural and functional disorders. Amyloidosis is classified into systemic and localized amyloidosis. Localized amyloidosis in individual organs is uncommon. We report a rare case of localized form of primary amyloidosis of the urinary bladder. A 76-year-old male visited our hospital with a complaint of macroscopic hematuria. Cystoscopy showed submucosal hematoma in the anterior wall and broad-based mass occupying the trigone without normal mucosa covered by calcification. Transurethral biopsy and resection were performed. Histopathological diagnosis was AL type amyloidosis occupying submucosal extracellular space. We gave the patient occlusive dressing with dimethyl sulfoxide. In 12 months, cystoscopy and magnetic resonance imaging revealed improvement of the mass-like lesion in the bladder wall.

Early ligation of the dorsal pancreatic artery with a mesenteric approach reduces intraoperative blood loss during pancreatoduodenectomy.

BACKGROUND: Early ligation of the inferior pancreatoduodenal artery has been advocated to reduce blood loss during pancreatoduodenectomy. However, the impact of early ligation of the dorsal pancreatic artery (DPA) remains unclear. This study was performed to investigate the clinical implications of early ligation of the DPA. METHODS: From October 2014 to April 2017, 34 consecutive patients underwent pancreatoduodenectomy using a mesenteric approach. The patients were divided into the early DPA ligation group (n = 15) and late DPA ligation group (n = 19). The clinical features were retrospectively compared between the two groups (H29-044). RESULTS: Preoperative multidetector row computed tomography and intraoperative findings revealed that the right branch of the DPA supplied the pancreatic head region in all cases. Intraoperative blood loss was significantly lower in the early than late ligation group (median 609 ml [range 94-1,013 ml] vs. 764 ml [range 367-1,828 ml], respectively; P = 0.008). Multivariable analysis revealed that early DPA ligation was independently associated with blood loss (P = 0.023). The DPAs arising from the superior mesenteric artery underwent early ligation at a significantly higher rate. CONCLUSIONS: Early ligation of the DPA during pancreaticoduodenectomy with a mesenteric approach could reduce intraoperative blood loss.

Gastric venous congestion and bleeding in association with total pancreatectomy.

BACKGROUND: Gastric venous congestion and bleeding in association with total pancreatectomy (TP) were evaluated. METHODS: Thirty-eight patients of TP were retrospectively analyzed. TP was classified as TP with distal gastrectomy (TPDG), pylorus-preserving TP (PPTP), subtotal stomach-preserving TP (SSPTP), and TP with segmental duodenectomy (TPSD). RESULTS: Portal vein or superior mesenteric vein resection and reconstruction was performed in 24 patients (62.2%). Gastric bleeding occurred immediately after tumor resection in one of eight patients who underwent SSPTP, and urgent anastomosis between the right gastroepiploic and left ovarian vein stopped the bleeding. Another case of gastric bleeding was observed a few hours after TP in one of nine patients who underwent PPTP, and hemostasis was achieved after conservative therapy. Gastric bleeding was not observed in 16 patients who underwent TPDG and five who underwent TPSD. Some patients underwent preservation of gastric drainage veins (left gastric vein, right gastric vein, or right gastroepiploic vein). Neither patient with bleeding underwent preservation of a gastric drainage vein. CONCLUSIONS: To preserve the subtotal or whole stomach when performing TP, one of the gastric drainage veins should undergo preservation or reconstruction, and anastomosis between the right gastroepiploic vein and left ovarian vein may be beneficial.

Gene therapy with TRAIL against renal cell carcinoma.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells. However, TRAIL is not toxic against most normal cells. We have accordingly examined by in vivo electroporation whether TRAIL induces apoptosis in renal cell carcinoma. In addition, combination treatment with TRAIL and 5-fluorouracil (5-FU) against renal cell carcinoma was also investigated. The NC65 renal cell carcinoma line was used as a target. pCAGGS TRAIL was injected into the NC65 tumors in the right flanks of severe combined immunodeficient mice. Tumors were pulsed with the CUY21 electroporator. Electroporation was done once on day 0 or thrice on days 0, 2, and 4. Apoptosis was determined by terminal deoxyribonucleotide transferase-mediated nick-end labeling assay. When TRAIL gene therapy using in vivo i.t. electroporation was done once only, the growth of NC65 tumors was not inhibited. However, when TRAIL gene therapy was done thrice, growth suppression of the NC65 tumors was observed. Transfection of the TRAIL gene by in vivo electroporation induced apoptosis in NC65 tumors. When NC65 cells were treated with TRAIL gene therapy in combination with 5-FU, stronger growth suppression was obtained. TRAIL gene therapy did not induce liver dysfunction in severe combined immunodeficient mice. This study shows that TRAIL gene therapy induced growth suppression and apoptosis in NC65 tumors without severe side effects, and that combination treatment of NC65 cells with TRAIL gene therapy and 5-FU resulted in higher antitumor activity. These findings suggest that TRAIL gene therapy and/or 5-FU may be effective against renal cell carcinoma without harmful toxic effects.

Cat-eye syndrome with isolated idiopathic hypogonadotropic hypogonadism.

A 34-year-old Japanese man diagnosed as having cat-eye syndrome (CES) with isolated idiopathic hypogonadotropic hypogonadism (IHH) was treated at our university. He showed preauricular pits/tags, downward slanting palpebral fissures, ocular hypertelorism, and strabismus. However, ocular coloboma and anal atresia, major characteristic features of CES, were negative. Chromosomal analysis revealed malformation in chromosome 22 and eunuchoid features and a low grade development of secondary sexual characteristics were also evident. Endocrinological examinations revealed that this patient was in a state of isolated IHH. Although CES with IHH is extremely rare, endocrine disorders should be given due attention.

Present and future perspectives on immunotherapy for advanced renal cell carcinoma: Going to the core or beating around the bush?

Metastatic lesions of renal cell carcinoma (RCC) occasionally regress spontaneously after surgical removal of the primary tumor. Although this is an exceptionally rare occurrence, RCC has thus been postulated to be immunogenic. Immunotherapies, including cytokine therapy, peptide-based vaccines, and immune checkpoint inhibitors have therefore been used to treat patients with advanced, metastatic RCC. We review the history, trends, and recent progress in immunotherapy for advanced RCC and discuss future perspectives, with consideration of our experimental work on galectin 9 and PINCH as promising specific immunotherapy targets.

Androgen-Regulated SPARCL1 in the Tumor Microenvironment Inhibits Metastatic Progression.

Prostate cancer is a leading cause of cancer death in men due to the subset of cancers that progress to metastasis. Prostate cancers are thought to be hardwired to androgen receptor (AR) signaling, but AR-regulated changes in the prostate that facilitate metastasis remain poorly understood. We previously noted a marked reduction in secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) expression during invasive phases of androgen-induced prostate growth, suggesting that this may be a novel invasive program governed by AR. Herein, we show that SPARCL1 loss occurs concurrently with AR amplification or overexpression in patient-based data. Mechanistically, we demonstrate that SPARCL1 expression is directly suppressed by androgen-induced AR activation and binding at the SPARCL1 locus via an epigenetic mechanism, and these events can be pharmacologically attenuated with either AR antagonists or HDAC inhibitors. We establish using the Hi-Myc model of prostate cancer that in Hi-Myc/Sparcl1(-/-) mice, SPARCL1 functions to suppress cancer formation. Moreover, metastatic progression of Myc-CaP orthotopic allografts is restricted by SPARCL1 in the tumor microenvironment. Specifically, we show that SPARCL1 both tethers to collagen in the extracellular matrix (ECM) and binds to the cell's cytoskeleton. SPARCL1 directly inhibits the assembly of focal adhesions, thereby constraining the transmission of cell traction forces. Our findings establish a new insight into AR-regulated prostate epithelial movement and provide a novel framework whereby SPARCL1 in the ECM microenvironment restricts tumor progression by regulating the initiation of the network of physical forces that may be required for metastatic invasion of prostate cancer.

Elevated expression of tyrosine kinase DDR2 in primary biliary cirrhosis.

BACKGROUND: Primary biliary cirrhosis (PBC) is characterized by chronic progressive destruction of small intrahepatic bile ducts with portal inflammation and cholestasis, leading to fibrosis. METHODS: We utilized a novel restriction analysis system to profile the expression of tyrosine kinases (TKs). This methodology targets a conserved sequence present in the majority of human TKs, and exploits the known restriction map of the TK cDNA sequences. We isolated mRNA from biliary epithelial cell (BEC)-enriched cell fractions, amplified the TK transcripts using degenerative primers, and identified specific TKs by restriction enzyme digest analysis and then performed in situ hybridization. RESULTS: BEC-enriched samples from PBC livers displayed marked expression of discoidin domain receptor-2 (DDR2), whereas, non-diseased livers showed no detectable DDR2. Furthermore, in situ hybridization of PBC livers revealed that DDR2 is expressed in the small bile duct epithelial regions as well as in fibroblasts/stromal cells of fibrotic regions. A similar pattern was observed in livers of primary sclerosing cholangitis (PSC), although the amount of small ducts that were positively stained was lower than in PBC. Furthermore, cirrhotic livers of patients with other diseases, including alcoholic liver disease and chronic hepatitis C, DDR2 transcripts were noted only within fibrotic lesions and the degree of intensity was much lower than in PBC and PSC. CONCLUSIONS: DDR2, a TK that is stimulated by fibrillar collagens that accumulate in cirrhotic livers, is present at elevated levels in the small bile ducts of PBC patients. DDR2 is part of a positive feedback loop in which its enhanced expression leads to enhanced deposition of fibrillar collagens (types I andIII). These fibrillar collagens can also provide binding sites for immune mediators, such as cytokines and chemokines. Therefore, unusually high DDR2 expression in the bile ducts of PBC patients could contribute to duct injury by altering local cytokine levels and thereby increasing immune-mediated damage.

[Sarcomatoid carcinoma of the urinary bladder with a spontaneous perforation: a case report].

A 65-year-old woman was referred to our clinic with gross hematuria. Cystoscopy revealed a non-papillary and non-pedunculated tumor on the left lateral wall of the bladder. A piece of necrotic tissue obtained from the bladder irrigation was histologically squamous cell carcinoma. A perforation at the left lateral wall of the bladder was found on the cystogram. Bone scintigraphy showed multiple metastases and computed tomography scans showed multiple lymph node metastases in the pelvic cavity. The clinical diagnosis was bladder carcinoma of T4N2M1 stage with an abscess due to a spontaneous perforation. Total cystectomy with bilateral ureterocutaneostomy was performed. She died due to sepsis 13 days after the operation. Histologically, the tumor was composed of carcinomatous and sarcomatous elements. The carcinomatous element was compatible with squamous cell carcinoma and the sarcomatous element was composed of undifferentiated malignant spindle cells. Immunohistochemical examination showed that the carcinomatous component was positive for keratin and human chorionic gonadotropin (HCG) and the spindle cell component positive for vimentin, desmin and HCG. Therefore, we diagnosed the tumor as sarcomatoid carcinoma. We reviewed 56 cases of carcinosarcoma of the bladder in Japan and discussed the clinicopathology of the disease.

Significance of serum tumor necrosis factor-related apoptosis-inducing ligand as a prognostic biomarker for renal cell carcinoma.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is endogenously expressed in immune cells and contributes to immunosurveillance for cancer. TRAIL induces apoptosis preferentially in various cancer cells, including renal cell carcinoma (RCC) cells. In this study, the serum TRAIL level was examined using an enzyme-linked immunosorbent assay in 52 healthy controls and in 84 RCC patients prior to surgery and its significance as a biomarker was evaluated. The median serum TRAIL level was lower in RCC patients compared to the healthy controls (55.9 vs. 103.1 pg/ml; P=0.019). RCC with lymph node metastasis (N1-2), distant metastasis (M1), stage III-IV, or microscopic venous invasion was associated with decreased serum TRAIL levels (P=0.032, 0.067, 0.020 and 0.011). When comparing serum TRAIL levels in the same RCC patients prior and subsequent to surgery (n=11), the levels were significantly higher after surgery (P=0.031). The cause-specific survival rate was significantly higher in RCC patients with high serum TRAIL levels compared to those with low serum TRAIL levels (P=0.0451). TRAIL was estimated to contribute 64 and 13% of the lymphocyte-mediated cytotoxicity against human RCC ACHN and Caki-1 cells, respectively. These data suggest that the serum TRAIL level may be useful as a prognostic biomarker in RCC patients.

Significant induction of apoptosis in renal cell carcinoma cells transfected with cationic multilamellar liposomes containing the human interferon-ß gene through activation of the intracellular type 1 interferon signal pathway.

We previously reported that cationic multilamellar liposome containing the human interferon-ß (huIFN-ß) gene (IAB-1) demonstrated significant cytotoxic effect in the NC65 human renal cell carcinoma (RCC) cell line. In this study, we investigated the molecular mechanisms of IAB-1-induced apoptosis and cytotoxicity in RCC cells. Remarkable in vitro cytotoxic and apoptosis-inducing effects of IAB-1 against NC65 cells were observed by a colorimetric method and TUNEL staining, respectively. In contrast, treatment of NC65 cells with exogenously added huIFN-ß protein induced low-level cytotoxicity without apoptosis. Neutralizing antibodies against huIFN-ß significantly suppressed the cytotoxic effect of huIFN-ß protein, but they were unable to block the effect of IAB-1. Cytotoxicity assays using transwell plates revealed that NC65 cells treated with IAB-1 did not secrete cytotoxic soluble factors other than IFN-ß. Substantial enhancement of interferon-stimulated response element (ISRE) activity of NC65 cells by IAB-1 was demonstrated by promoter reporter assays. In addition, immunofluorescence using confocal microscopy revealed the intracellular expression of IFN-ß and its receptor induced by IAB-1. The induction of c-Myc by IAB-1 was suggested by a cDNA macroarray and was confirmed by western blot analysis. These findings indicate that IAB-1 induces significant cytotoxicity and apoptosis in NC65 cells, possibly through enhanced ISRE activity, that is associated with increased intracellular localization of huIFN-ß and IFN-receptor. Our data support the potential clinical application of IAB-1 gene therapy for RCC resistant to IFN.

Myocardin functions as an effective inducer of growth arrest and differentiation in human uterine leiomyosarcoma cells.

Myocardin is an important transcriptional regulator in smooth and cardiac muscle development. We noticed that the expression of myocardin was markedly downregulated in human uterine leiomyosarcoma cells. Restoration of myocardin expression induced the reexpression of smooth muscle marker proteins and the formation of well-developed actin fibers. A concomitant increase in the expression of a cyclin-dependent kinase inhibitor, p21, led to significantly reduced cell proliferation, via p21's inhibition of the G(1)-S transition. A p21 promoter-reporter assay showed that myocardin markedly increased p21's promoter activity. Furthermore, a serum response factor (SRF)-binding cis-element CArG box in the p21 promoter region was required for this myocardin effect. Chromatin immunoprecipitation and DNA-protein binding assays showed that myocardin indirectly bound to the CArG box in the p21 promoter through the interaction with SRF. Furthermore, immunohistochemistry revealed that the levels of myocardin and p21 were both lower in leiomyosarcoma samples than in normal smooth muscle tissue. Taken together, our results indicate that the downregulation of myocardin expression facilitates cell cycle progression via the reduction of p21 expression in human leimyosarcomas and suggest that myocardin could be a useful therapeutic target for this disease.