[Show abstract][Hide abstract] ABSTRACT: Various regimens including molecular targeted agents have been examined in patients with cisplatin (CDDP)-resistant urothelial cancer (UC). However, some studies have been stopped owing to the development of severe adverse events. The main aim of this study was to examine the anticancer effects, changes in the quality of life (QoL), and safety of combined therapy of low-dose gemcitabine, paclitaxel, and sorafenib (LD-GPS) in patients with CDDP-resistant UC. Twenty patients were treated with gemcitabine (700 mg/m(2) on day 1), paclitaxel (70 mg/m(2) on day 1), and sorafenib (400 mg/day on days 8-22). QoL and pain relief were evaluated using the short-form survey (SF)-36 for bodily pain and the visual analog scale (VAS). VAS scores were significantly decreased by both the second- and third-line therapies (P = 0.012 and 0.028, respectively). The bodily pain score from the SF-36 survey was also significantly (P = 0.012) decreased. Complete responses, partial responses, and stable disease were found in 0 (0.0 %), 1 (5.0 %), and 13 patients (65 %), respectively. The median (interquartile range) period of overall survival after starting of this therapy was 7 (5-11) months. Three patients (15.0 %) stopped therapy because of grade 3 fatigue and hand-foot reactions. LD-GPS therapy was well tolerated by patients with CDDP-resistant UC. QoL was maintained, and improvements in their pain levels were found after treatment; pain relief was detected after third-line therapy. We suggest that this treatment regimen is worthy of consideration as second- and third-line therapy for patients with CDDP-resistant UC.
Medical Oncology 10/2015; 32(10):683. DOI:10.1007/s12032-015-0683-y · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clinicopathological features and prognosis of metastatic renal cell carcinoma (mRCC) vary by histopathological type. In this study, we analyzed these relationships with regard to non-clear cell RCC (nccRCC). We also analyzed the therapeutic trends for patients with mRCC. We initially identified 367 patients who were diagnosed with RCC and treated in our hospital between 2001 and 2013 ; 55 patients of whom were diagnosed with nccRCC. We reviewed their backgrounds, histopathological types and outcomes. Median age at diagnosis for patients with nccRCC was significantly younger (58.5 years) than for those with clear-cell RCC (66.3 years ; P=0.008) ; however, these histological types did not significantly differ by sex, affected side or rate of mRCC. Of the 55 nccRCC cases, 19 were mRCC, including 5 of the 8 cases of papillary type-2 RCC, and all patients who had either collecting duct carcinoma, sarcomatoid RCC or Xp11 translocation RCC. The most common metastatic site was lymph nodes. Although patients with papillary type-1 and Xp11 translocation RCC had relatively good prognoses, those with papillary type-2, collecting duct carcinoma and sarcomatoid RCC had poor prognoses. Among the 9 patients with nccRCC who received molecular targeted therapy, median survival was 13.3 months. Although existing therapeutic agents may be effective for some patients with nccRCC, identification of new target molecules and innovative drug development are needed in the future.
[Show abstract][Hide abstract] ABSTRACT: Met is a tyrosine kinase receptor that is considered to be a proto-oncogene. The hepatocyte growth factor (HGF)-Met signaling system plays an important role in tumor growth, invasion, and metastasis in many types of malignancies. Furthermore, Met expression has been reported to be a useful predictive biomarker for disease progression and patient survival in these malignancies. Many studies have focused on the clinical significance and prognostic role of Met in urological cancers, including prostate cancer (PCa), renal cell carcinoma (RCC), and urothelial cancer. Several preclinical studies and clinical trials are in progress. In this review, the current understanding of the pathological role of Met in cancer cell lines, its clinical significance in cancer tissues, and its predictive value in patients with urological cancers are summarized. In particular, Met-related malignant behavior in castration-resistant PCa and the different pathological roles Met plays in papillary RCC and other histological types of RCC are the subjects of focus. In addition, the pathological significance of phosphorylated Met in these cancers is shown. In recent years, Met has been recognized as a potential therapeutic target in various types of cancer; therapeutic strategies used by Met-targeted agents in urological cancers are summarized in this review.
[Show abstract][Hide abstract] ABSTRACT: Introduction
Patients with muscle-invasive bladder cancer (MIBC) often undergo various preoperative treatments to improve survival; however, their efficacy and safety remain unclear.
Materials and methods
The anti-tumour effects and adverse events were evaluated in 163 MIBC patients who received systemic chemotherapy (SC, n = 34), intra-arterial chemotherapy (IAC, n = 50), or combined IAC and radiotherapy (IAC+R, n = 79).
Pathological complete responses were observed in 17.6%, 22.0%, and 43.0% of patients in the SC, IAC, and IAC+R groups, respectively, with respective 5-year overall survival rates of 42.0%, 46.7%, and 50.3%. Multivariate analysis showed that successful IAC+R protocol administration was a significant predictor for survival (hazard ratio = 0.16, p = 0.028). The incidence of severe adverse events was higher in the IAC+R group (36.7%) than in the SC (9.8%) and IAC groups (16.0%).
IAC+R was useful for patients with MIBC. Successful completion and optimal patient selection were important for this treatment strategy.
European Journal of Surgical Oncology 09/2014; 41(3). DOI:10.1016/j.ejso.2014.07.043 · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Cardiac metastasis of renal cell carcinoma is an exceptional event, particularly when there is lack of inferior vena cava involvement. Indeed, only a few cases have been reported worldwide thus far. Moreover, discussion of treatment and follow-up strategies for cardiac metastasis of renal cell carcinoma is important because of the high risk of sudden death.
We report the case of a 75-year-old Japanese man with metastatic tumor in the left atrium from renal cell carcinoma. He had a history of right renal cell carcinoma, for which he had undergone hand-assisted laparoscopic nephrectomy. Lung and bone metastases were detected after nephrectomy, and treatment with interferon-alpha was initiated. After disease progression, he was treated concurrently with targeted molecular therapy and radiotherapy for bone metastasis. After these therapies, a 42 × 24 mm mass was found on transthoracic echocardiography in left atrium without involvement of the right atrium or inferior vena cava. The provisional diagnosis was metastatic mass or myxoma, and surgical resection was performed. Histopathological examination led to a final diagnosis of metastatic tumor from clear cell renal cell carcinoma.
Cardiac metastasis, metastasis to the left atrium in particular, is rare in patients with renal cell carcinoma. In our study, surgery of the cardiac mass was effective to avoid sudden death and quality of life decline resulting from heart failure. We describe this case and review cardiac metastasis of renal cell carcinoma.
BMC Research Notes 08/2014; 7(1):520. DOI:10.1186/1756-0500-7-520
[Show abstract][Hide abstract] ABSTRACT: Key Clinical Message
Pelvic organ prolapse (POP) is common among multiparous elderly women. POP related to obstructive anuria is very uncommon, but can be life-threatening if untreated. In this report, the patient survived from a septic shock with multidisciplinary treatment and was completely cured of POP after tension-free vaginal mesh repair.
[Show abstract][Hide abstract] ABSTRACT: Aims:
Twist has been reported to play crucial roles for malignant aggressiveness; however, detailed pathological significance of Twist in renal cell carcinoma (RCC) is not fully understood. The present study was to clarify clinical significance and molecular functions of Twist in patients with RCC.
Twist expression was examined by immunohistochemical techniques in 156 formalin-fixed specimens. Cell proliferation, angiogenesis, and apoptosis were measured as the percentage of Ki-67-positive cells (proliferation index, PI), CD31-stained vessels (microvessel density, MVD), and TUNEL-positive cells (apoptotic index, AI). In addition, semi-quantification of matrix metalloproteinase (MMP)-2 was performed. Macrophages were identified with anti-CD68 antibody, and the tumor associated macrophage (TAM) density was calculated as CD68-positive cells per high-power field.
Twist expression was positively associated with grade, pT stage, and metastasis (p<0.001). We also noticed that its expression was considerably higher in cancer cells of sarcomatoid RCC and in those at the edge of the tumors. Twist expression was positively correlated with PI, MVD, MMP2 expression, and TAM density (P<0.001), but not with AI, and MMP-2 expression and TAM density were independently correlate by multi-variate analyses. Kaplan-Meir survival curves showed high Twist expression was a worse predictor for cause-specific survival (P<0.001).
Twist plays important roles in tumor growth, progression, and survival in patients with RCC patients. Such pathological mechanisms are significantly associated with increased cancer cell proliferation, angiogenesis, MMP2 expression, and macrophage recruitment. These findings are important information for discussion of treatment and observation strategies in these patients.
International journal of clinical and experimental pathology 07/2014; 7(6):3158-65. · 1.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Angiogenesis plays an important role in cancer progression in many types of cancer. Evaluation of angiogenesis is often performed, but the optimal methodology for human cancer has not been agreed upon. As adequate evaluation of angiogenesis in cancer tissues might be important for prediction of prognosis and treatment decisions, we evaluated angiogenesis semiquantitatively by assessing microvessel density (MVD) in urothelial cancer of the upper urinary tract (UC-UUT). We compared the performance of three endothelial cell markers (CD31, CD34, and CD105) on formalin-fixed tissues from 122 patients diagnosed with UC-UUT without metastasis. Vascular endothelial growth factor (VEGF)-A expression was also evaluated immunohistochemically. Correlations between MVD with each marker and pT stage, grade, survival, and VEGF-A expression were investigated. Mean (standard deviation) MVD as estimated by immunohistochemical staining with anti-CD31, anti-CD34, and anti-CD105 were 47.1 (17.9)/high-power field (HPF), 70.9 (19.5)/HPF, and 31.2 (16.7)/HPF, respectively. Although all MVDs were significantly associated with pT stage and grade, CD105-MVD showed the strongest association. Similarly, CD105-MVD showed the strongest correlation with VEGF-A expression (r = 0.530, p < 0.001). Although all MVDs were associated with metastasis-free survival and cause-specific survival on univariate analysis, only CD105-MVD was retained as an independent predictor in multivariate analysis including pT stage and grade. CD105-MVD may be the preferred marker for semiquantitative assessment of angiogenesis in patients with UC-UUT.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 08/2013; 463(5). DOI:10.1007/s00428-013-1463-8 · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human antigen R (HuR) regulates the stability of mRNA and is associated with cell proliferation, angiogenesis, and lymphangiogenesis. However, the clinical significance and pathological role of HuR in bladder cancer remains unclear. The main objective of this investigation was to clarify the relationships between HuR expression and clinical significance and cancer cell proliferation, angiogenesis, lymphangiogenesis, and expressions of cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF)-A, -C, and -D.
All expressions were examined by immunohistochemical techniques in 122 formalin-fixed specimens of bladder cancer patients. HuR expression was evaluated separately with cytoplasmic and nuclear staining. Cell proliferation, angiogenesis and lymphangiogenesis were measured as the percentage of Ki-67-positive cell (proliferation index, PI), CD34-stained vessels (microvessel density, MVD), and D2-40-stained vessels (lymph vessel density, LVD). Relationships between each HuR expression and clinicopathological features, prognosis, and expressions of COX-2 and VEGFs were analyzed by multi-variate analyses. HuR expression was also investigated in 10 mice of N-Butyl-N-[4-hydroxybutil] nitrosamine (BBN) induced bladder cancer model.
In human tissues, high cytoplasmic expression was seen in 5% and 25.4% of normal and cancer cells, respectively. Nuclear HuR expression bore no significant relationship to any pathological features. However, cytoplasmic HuR expression appeared positively associated with pT stage and grade (P<0.001). In mouse tissues, similar trends were confirmed. Cytoplasmic expression correlated with PI, MVD, and LVD, as well as expression of VEGF-A and -C, but not VEGF-D. High cytoplasmic expression of HuR was a significant predictor of metastasis and cause-specific survival, and was identified as a prognostic correlative factor for metastasis (hazard ratio, 4.75; P = 0.028) in a multivariate analysis model that included pathological features.
Cytoplasmic HuR appears to play important roles in cell proliferation, progression, and survival of bladder cancer patients. Its expression was associated with angiogenesis, lymphangiogenesis, and expressions of VEGF-A and -C.
PLoS ONE 03/2013; 8(3):e59095. DOI:10.1371/journal.pone.0059095 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The biological activities of prostaglandin E2 are mediated through their specific receptors, E prostanoid receptors (EPRs). This family comprises 4 subtypes (EP1R-4R), and has been associated with cancer development and progression. In urological cancers, expression of EP2R and EP4R can be significant predictors of survival for renal cell carcinoma (RCC). On the other hand, EP1R, EP2R, and EP4R are known to be associated with carcinogenesis and malignant aggressiveness in prostate cancer. In addition, EP4R has been associated with tumor progression and prognosis in urothelial cancer of the upper urinary tract. There is a general agreement that non-steroidal anti-inflammatory drugs (NSAIDs) can reduce the risk of several malignancies including colorectal cancer. However, NSAIDs often cause gastrointestinal injury and nephropathy. On the other hand, cyclooxygenase (COX)-2-selective inhibitors can reduce the progression of cancer via the suppression of cell proliferation angiogenesis without decreasing adverse reactions. However, COX-2-selective inhibitors might increase the risk of cardiovascular disease, including myocardial infarction. More selective and detailed control of COX-2-mediated signals is thus needed to improve anti-tumor effects and to decrease adverse reactions. EPRs are expected to serve as new therapeutic targets in urological cancer, because they are more selective in malignant phenotypes. Finally, we speculate that some EPRs inhibitors may reduce adverse events and exert more intense effects on urological cancer.
[Show abstract][Hide abstract] ABSTRACT: Objective:
To clarify the detailed pathologic roles of prostaglandin E(2) in prostate cancer tissues, the present study investigated the clinical significance and prognostic roles of the density of tumor-associated stromal cells expressing specific receptors for prostaglandin E2, termed "E-prostanoid (EP)1-4 receptors (EP1R-4Rs)."
The expression of each receptor was immunohistochemically examined in 114 formalin-fixed biopsy specimens. Correlations with clinicopathologic features were investigated in these specimens. Angiogenesis and lymphangiogenesis were measured by the percentage of CD34-stained vessels (microvessel density) and D2-40-stained vessels (lymph vessel density). The relationships between the density of each EPR-stained cells and the microvessel density or lymph vessel density were evaluated in 62 prostate cancer tissues obtained by radical surgery for more detailed analysis in a wider area of prostate cancer tissue.
The density of tumor-associated cells with EP2R expression was positively associated with the N (P<.001) and M (P=.002) stages. Similarly, EP3R-positive stromal cell density was significantly associated with the N (P=.033) and M (P=.026) stages. The density of EP2R- and EP3R-stained cells correlated with the microvessel density (r=0.42, P<.001) and lymph vessel density (r=0.36, P=.012), respectively. A greater density of EP2R-stained cells was recognized as an independent predictor of progression (hazard ratio 7.26, P=.002) on multivariate analysis.
EP2R- and EP3R-stained cells might play important roles in tumor progression, angiogenesis, and lymphangiogenesis in prostate cancer. The density of EP2R-stained stromal cells could offer a useful predictor of biochemical recurrence after radical surgery.
[Show abstract][Hide abstract] ABSTRACT: The prognosis of patients with advanced and recurrent urothelial cancer (UC) is poor. Although cisplatin (CDDP)-containing chemotherapy is the most effective regimen in these patients, there is no other established chemotherapeutic regimen. We administered combination therapy with low-dose gemcitabine (GEM) and paclitaxel (PTX), named low-dose gemcitabine-paclitaxel (LD-GP) therapy, as salvage therapy for these patients. The aim was to evaluate the anti-tumoral effects, relief of pain, and toxicity of LD-GP therapy in patients with resistance to CDDP-containing therapy.
Thirty-five patients with advanced UC, previously treated with CDDP-containing regimens, were treated with LD-GP therapy (GEM, 700 mg/m(2) + PTX, 70 mg/m(2) on day 1 and 8, repeated every 28 days). Pain was measured on a visual analog scale before and after treatment. Pain relief and survival were compared between this and other treatment regimens.
None of the patients had complete response to LD-GP therapy. Partial response and stable disease were seen in 25.7 and 62.9 % of patients, respectively. Kaplan-Meier curves showed better survival in patients with LD-GP therapy than with others (p = 0.034). Twenty-eight patients (80.0 %) had adequate pain relief, and only two patients needed to increase their analgesics. Other regimens demonstrated pain relief in 30.4 % of patients. Common toxicities included leukopenia, with five patients requiring granular colony-stimulating factor therapy (14.3 %). The most common non-hematologic toxicity was fatigue (n = 7, 17.1 %).
LD-GP therapy is feasible and well tolerated as salvage therapy in patients with advanced UC with resistance to CDDP-containing therapy.
Cancer Chemotherapy and Pharmacology 08/2012; 70(3):451-9. DOI:10.1007/s00280-012-1938-3 · 2.77 Impact Factor