Biomedical subjects

Isao Hara

Publications and source records attributed to Isao Hara.

At least 37 records · Page 2Linked to original sources

PubMed2006

Analysis of factors predicting intravesical recurrence of superficial transitional cell carcinoma of the bladder without concomitant carcinoma in situ.

BACKGROUND: The objective of this study was to investigate risk factors for intravesical recurrence in patients with superficial bladder cancer without concomitant carcinoma in situ (CIS). METHODS: In this series, we analyzed data from patients with newly diagnosed superficial Ta or T1 transitional cell carcinoma (TCC) of the bladder without concomitant CIS who underwent complete transurethral resection (TUR) without any adjuvant intravesical instillation therapies. Multivariate analysis was used to determine significant risk factors affecting intravesical recurrence after TUR. Differences in clinicopathological features between primary and recurrent tumors were also characterized. RESULTS: Among 341 patients undergoing TUR of Ta or T1 bladder cancer, 187 diagnosed as having concomitant CIS and/or treated with adjuvant intravesical therapy were excluded, and the remaining 154 were evaluated. Intravesical recurrence was detected in 64 of the 154 patients, showing a 5-year recurrence-free survival rate of 58.3%. Among several factors examined, only tumor size was significantly associated with intravesical recurrence. Multivariate analysis identified tumor size as an independent predictor for intravesical recurrence irrespective of other parameters including age, gender, multiplicity, growth pattern, grade and stage. Recurrent tumors were significantly smaller and of a lower grade and lower stage than primary tumors, despite the absence of differences in growth pattern and the multiplicity between them. CONCLUSIONS: These findings suggest that primary tumor size could be used as a potential risk factor for predicting intravesical recurrence following TUR of superficial TCC of the bladder without concomitant CIS, and that the pathological characteristics of recurrent tumors are more favorable than those of primary tumors.

Adolescent↗

PubMed2006

Limited significance of routine excretory urography in the follow-up of patients with superficial bladder cancer after transurethral resection.

OBJECTIVES: To evaluate the utility of routine excretory intravenous urography (IVU) for detecting subsequent upper urinary tract cancer (UUTC) during the follow-up of patients with superficial bladder cancer. PATIENTS AND METHODS: The study included 413 patients who had transurethral resection (TUR) of superficial bladder cancer between January 1986 and December 2003, and were followed for at least 1 year. After TUR, patients were followed by periodic cystoscopy, urinary cytology and IVU. The risk factors for UUT recurrence after TUR were analysed, and based on this outcome, we then determined whether routine IVU should be used for patients with superficial bladder cancer. RESULTS: During the observation period, UUTCs developed in 20 of the 413 patients (4.8%) within a median of 33 months from the initial TUR to the detection of UUTCs. Among several factors examined, only multiplicity was significantly associated with UUT recurrence after TUR. Of the 20 patients with secondary UUTCs, only two, who had multiple superficial bladder cancers at initial presentation, were diagnosed as having UUTCs by routine IVU, while the remaining 18 presented with symptoms suggesting possible UUT recurrence before IVU, including macrohaematuria (10 patients), intravesical recurrence (five), positive urinary cytology (five), abdominal pain (three) and high fever (two). CONCLUSIONS: Most patients with recurrent UUTCs presented with some subjective and/or objective symptoms, and routine IVU failed to detect recurrent diseases in such patients. Therefore, routine IVU may not be required for all patients who have TUR of superficial bladder cancer.

Aged↗

PubMed2006

Reconstruction of urinary tract combined with surgical management of locally advanced non-urological cancer involving the genitourinary organs.

INTRODUCTION: The objective of this study was to review our experience with urinary reconstruction in patients undergoing surgical management for locally advanced pelvic cancer, and to evaluate the role of urologists in these procedures. MATERIALS AND METHODS: This study included a total of 37 patients undergoing some type of urinary reconstruction due to invasion of the urological organs by locally advanced pelvic cancers, including 17 rectal cancers, 9 cervical cancers, 4 sigmoid cancers, 4 retroperitoneal sarcomas, 2 ovarian cancers and 1 appendiceal cancer. Among these 37, 18 were recurrent cancers following initial surgery for primary tumors. The clinical outcomes of these approaches were retrospectively analyzed. RESULTS: Of the 37 patients, 9 underwent cystectomy (group A) with the following urinary diversions: ileal neobladder in 3, ileal conduit in 5 and colon conduit in 1, and 12 underwent partial cystectomy (group B), among whom 11 received additional urinary reconstruction as follows: bladder flap repair in 5, psoas hitch in 2, ileal ureter in 2, bladder augmentation in 1 and ureteroureterostomy in 1, while the remaining 16 (group C), in whom complete bladder preservation was possible, underwent the following types of urinary reconstruction: bladder flap repair in 6, psoas hitch in 3, en bloc removal of the rectum with prostate in 3, ileal ureter in 2, and ureteroureterostomy in 2. There were 10 early urological complications, including leakage of urine in 7 and acute pyelonephritis in 3. As a late urological complication, hydronephrosis was observed in 8 patients, but ureteral stent was not required in any of these 8. There were no significant differences in the incidence of postoperative complications, the status of surgical margin and the survival among groups A-C. CONCLUSION: Our experience with extended surgical management of non-urological pelvic cancer with reconstruction of the urinary tract suggests that the urological portion of this procedure can be performed with acceptable morbidity, and that the role of the urological surgeon during this procedure is potentially important.

Adult↗

PubMed2006

Usefulness of the nadir value of serum prostate-specific antigen measured by an ultrasensitive assay as a predictor of biochemical recurrence after radical prostatectomy for clinically localized prostate cancer.

INTRODUCTION: The objective of this study was to determine whether the nadir value of serum prostate-specific antigen (PSA) measured by an ultrasensitive assay could be a useful predictor of biochemical recurrence after radical prostatectomy for clinically localized prostate cancer. MATERIALS AND METHODS: This study included 127 patients who underwent radical prostatectomy for clinically localized prostate cancer without neoadjuvant hormonal therapy and were pathologically diagnosed as negative for lymph node metastasis. The serum PSA value was measured using an ultrasensitive PSA assay system (Roche Diagnostics, Mannheim, Germany), and the findings were analyzed with respect to several clinicopathological factors. In this series, biochemical recurrence was defined as PSA persistently >0.2 ng/ml. RESULTS: Based on the nadir PSA value, we divided 127 patients into three groups as follows: group A (n=99): or=0.05 ng/ml. The nadir PSA value was significantly associated with preoperative PSA value, but not other conventional clinicopathological prognostic parameters. During the observation period (median 31 months, range 6-75 months), biochemical recurrence occurred in 16 patients, that is, 1 in group A (6.3%), 4 in group B (25.0%), and 11 in group C (91.7%). Multivariate analysis using the Cox proportional hazards regression model indicated that the nadir PSA value was an independent predictor for biochemical recurrence after radical prostatectomy. CONCLUSION: These findings suggest that the nadir serum PSA value measured by an ultrasensitive assay could be a useful predictor of biochemical recurrence after radical prostatectomy for clinically localized prostate cancer, and that careful follow-up should be considered in cases demonstrating a nadir PSA value>0.01 ng/ml because of the significantly higher probability of biochemical recurrence in such cases.

Aged↗

PubMed2006

Larger prostate causes higher frequency of infectious complications in prostate biopsy.

INTRODUCTION: Prostate biopsy (PBX) is being performed more often than ever before for the early detection of prostate cancer, but some patients may have febrile infectious complications after biopsy. The risk factors of infectious complications need to be considered. METHODS: We investigated the pre-biopsy risk factors and febrile infectious complications in 120 patients who underwent PBX in our institution. The pre-biopsy risk factors set were prostate volume (> or = 40 ml), transitional zone (TZ) volume (> or = 20 ml), core number of biopsy (> or = 10 cores), and additional performance of TZ biopsy. We analyzed statistically the correlations between these risk factors and C-reactive protein and peripheral white blood cell (WBC) count elevation on day 1 and day 7 after biopsy. RESULTS: Our results showed that a prostate volume > or = 40 ml and a TZ volume > or = 20 ml caused a significantly higher elevation of the C-reactive protein level compared with a prostate volume < 40 ml (p = 0.0055 on day 1 and p = 0.0225 on day 7, respectively) on day 1 and day 7, and a TZ volume < 20 ml (p = 0.0008) on day 1. Regarding WBC count, those patients with a prostate volume > or = 40 ml and a TZ volume > or = 20 ml had a tendency to have an elevated WBC count on day 1 compared with those patients with a prostate volume < 40 ml and a TZ volume < 20 ml, and however these changes were not significant. CONCLUSIONS: This study showed that a larger prostate volume and a larger TZ volume may possibly be risk factors in infectious complications after PBX, although we can perform additional TZ biopsy and increase biopsy core number safely if necessary.

Aged↗

PubMed2006

The limited significance of a longer duration of neoadjuvant hormonal therapy prior to radical prostatectomy for high-risk prostate cancer in Japanese men.

INTRODUCTION: The objective of this study was to evaluate the therapeutic significance of a longer duration of neoadjuvant hormonal therapy (NHT) followed by radical prostatectomy (RP) in Japanese men with high-risk prostate cancer. MATERIALS AND METHODS: This study included a total of 42 patients with high-risk prostate cancer who were treated with NHT for >or=8 months prior to RP. In this series high-risk prostate cancer was defined as clinical stage T2c or T3, pretreatment serum prostate-specific antigen (PSA) >20 ng/ml and/or a biopsy Gleason score of 8-10. Biochemical recurrence was defined as a serum PSA level of >or=0.2 ng/ml. The data of these patients were retrospectively reviewed to clarify the relationships between treatment outcomes and various clinicopathological parameters. RESULTS: The clinical stage was T2c in 13 patients and T3 in 29, the median value of pretreatment serum PSA was 43.3 ng/ml (range 9.7-322.2), and the biopsy Gleason score was 6 in 3 patients, 7 in 16 and >or=8 in 23. Following NHT (median 12 months, range 8-27), the median value of serum PSA decreased to 0.05 ng/ml (<0.01-18.3 ng/ml), and 15 patients (35.7%) were pathologically downstaged. During the median follow-up of 38 months (range 8-58), 11 patients (26.2%) developed biochemical recurrence, and the multivariate analysis identified pretreatment serum PSA, biopsy Gleason score and percentage of positive biopsy core as independent predictors of biochemical recurrence. The 3-year biochemical recurrence-free survival rate of the 42 patients was 68.3%, which was not significantly different from that of 34 patients who underwent RP for high-risk prostate cancer without NHT during the same period. CONCLUSION: A longer duration of NHT followed by RP for patients with high-risk prostate cancer resulted in a comparatively favorable outcome. However, despite the nonrandomized retrospective analysis, the present findings suggest no significant impact of long-term NHT on biochemical recurrence. Longer follow-up is needed to determine whether this therapeutic strategy is beneficial for high-risk prostate cancer patients.

Aged↗

PubMed2006

Clinicopathological features of patients with biochemical recurrence after radical prostatectomy without progressive rise in serum prostate-specific antigen.

INTRODUCTION: The objective of this study was to characterize clinicopathological features of patients with biochemical recurrence after radical prostatectomy who did not exhibit a progressive rise in serum prostate-specific antigen (PSA) during the follow-up period. MATERIALS AND METHODS: We analyzed data from 162 consecutive patients who underwent radical prostatectomy for clinically organ-confined prostate cancer without neoadjuvant hormonal therapy and were followed postoperatively for at least 1 year. The serum PSA value was measured using an ultrasensitive PSA assay system (Roche Diagnostics, Mannheim, Germany), and biochemical recurrence was defined as a serum PSA of >or=0.1 ng/ml. RESULTS: A total of 32 patients (19.8%) were diagnosed as having biochemical recurrence. Among these patients, we identified 10 (31.3%) with a serum PSA>0.1 ng/ml who had not shown PSA or clinical progression during a median follow-up of 34 months after radical prostatectomy. In these 10 patients, the median time to biochemical recurrence was 17 months, the median PSA velocity after biochemical recurrence was 0.034 ng/ml/year, and there was no patient whose serum PSA value became >0.4 ng/ml. There were no clinicopathological parameters except for PSA velocity that were significantly associated with the features of these 10 patients. CONCLUSION: Because of the presence of a subset of patients with biochemical recurrence after radical prostatectomy who will not show a progressive increase in serum PSA value, the indication for adjuvant therapy for such patients should be cautiously determined considering several factors, such as PSA kinetics.

Aged↗

PubMed2006

The potential of clusterin inhibiting antisense oligodeoxynucleotide therapy for prostate cancer.

This review summarise the authors' recent experience in the development of antisense (AS) oligodeoxynucleotide (ODN) therapy that targets a cytoprotective gene, clusterin, for the treatment of prostate cancer. The acquisition of resistance to a wide variety of proapototic stimuli was initially demonstrated by introducing the clusterin gene into prostate cancer cells. Furthermore, silencing clusterin expression using AS ODN synergistically enhanced the effects of several conventional therapeutic modalities through the effective induction of apoptosis in prostate cancer xenograft models. Based on these outcomes, Phase I clinical trials were conducted using AS clusterin ODN incorporating 2'-O-(2-methoxy)ethyl-gapmer backbone (OGX-011), and the optimal dose of OGX-011 capable of inducing </= 90% suppression of clusterin in human prostate cancer tissue was determined. Collectively, these findings suggest the utility of inactivating clusterin function using AS ODN technology as a novel therapeutic strategy for prostate cancer treatment. There have been four kinds of Phase II studies that have begun to further evaluate the efficacy of OGX-011 in patients with prostate, breast and lung cancers.

Animals↗

PubMed2006

Conventional MRI capabilities in the diagnosis of prostate cancer in the transition zone.

OBJECTIVES: Our objectives were to evaluate the diagnostic capabilities of conventional MRI for the accurate detection of prostate cancer within the transition zone and to compare the results with histopathologic examination results. MATERIALS AND METHODS: One hundred sixteen prostate specimens with prostate cancer were consecutively obtained. Axial, sagittal, and coronal T2- and T1-weighted MR images with gadopentetate dimeglumine were independently reviewed by two radiologists. The diagnostic base criteria of the MR images were determined for detecting transition zone cancer as follows: lesions with A, uniform low intensity on T2-weighted images; B, homogeneous gadolinium enhancement; and C, irregular margins both on gadolinium-enhanced and T2-weighted images. Wilcoxon's rank sum and chi-square tests and receiver operating characteristic curves were used. Differences of less than 0.05 were considered significant. RESULTS: Eighty-six lesions in the transition zone were analyzed. Histopathologic analysis showed 53 cancers and 33 benign lesions. The diagnostic sensitivity, specificity, and accuracy for cancer were 50%, 51%, and 51%, respectively with criteria A; 68%, 75%, and 71% with criteria B; and 60%, 72%, and 65% with criteria C. When base criteria were combined into criteria A-B, A-C, and B-C and then further divided into three subgroups, accuracy was found to be highest when the lesion satisfied any two criteria from A, B, and C than those of base criteria, combination criteria, and the other two subgroups. CONCLUSION: The addition of gadolinium-enhanced MRI to T2-weighted imaging provides better accuracy for detecting cancerous transition zone lesions than the use of T2-weighted imaging alone.

Aged↗

PubMed2006

[Laparoscopic pyeloplasty for ureteropelvic junction obstruction].

PURPOSE: We performed laparoscopic pyeloplasty in 11 patients with ureteropelvic junction (UPJ) obstruction and evaluated the clinical outcomes of this surgery. MATERIALS AND METHODS: Between August 2001 and February 2004, 11 patients with UPJ obstruction underwent laparoscopic pyeloplasty in our institute. In all patients, symptoms were presented and UPJ obstruction was confirmed by radiographic examinations. Ten patients had primary obstruction, while one patient had secondary obstruction. Retroperitoneal approach was applied in all but one patient who needed intraperitoneal approach due to secondary obstruction. We performed Anderson-Hynes dismembered pyeloplasty, Hellström technique and Fenger plasty in 8, 2 and 1 patient, respectively. Nephropexy was performed in 2 patients with nephroptosis, and isthmusectomy was performed in 1 patient with horseshoe kidney, simultaneously. RESULTS: The mean operative time was 312 minutes (210-371) and the mean blood loss (including urine) was 75 ml. No blood transfusion was required, and all procedures were performed safely. Crossing vessels were found in 5 patients (45%). Pyelonephritis was the only postoperative complication, managed by the administration of antibiotics. Symptoms were disappeared without recurrences in all patients at mean follow up time of 18 months (6-36). ( CONCLUSION: Although the number of cases was small with relatively short follow up period, the clinical outcomes of laparoscopic pyeloplasty in our institute were almost satisfied, as previously reported by other investigators. Laparoscopic pyeloplasty might be one of the standard treatments for patients with UPJ obstruction, although we should carefully consider about indication, approach and operation method.

Adolescent↗

PubMed2006

[Pathological prognostic factors of renal pelvic and ureteral cancer].

OBJECTIVE: To determine the pathologic risk factors after nephroureterectomy in patients with urothelial carcinoma of the renal pelvis and ureter. PATIENTS AND METHODS: We investigated the clinicopathological features of 131 patients (94 males and 37 females) with urothelial carcinoma of the renal pelvis and ureter who underwent nephroureterectomy at our department and related facilities from August, 1994 to August, 1997. The mean age of the patients was 68 years, ranging from 24 to 86 years. RESULTS: The 1-, 3- and 5-year cause-specific survival rates (Kaplan-Meier's method) for all of the patients were 91.8%, 76.7%, and 67.8%, respectively. The significant prognostic factors for survival rates by univariate analysis using the log rank test were tumor stage, infiltration pattern, lymphatic invasion, vessel invasion and lymph node metastasis. On the other hand, multivariate analysis using Cox proportional hazards regression model showed the most influential prognostic factors to be vessel invasion and tumor stage. CONCLUSIONS: From these results, in urothelial carcinoma of the renal pelvis and ureter underwent nephroureterectomy, we suggested that vessel invasion and tumor stage were the independent prognostic factors.

Adult↗

PubMed2006

Clinical utility of serum macrophage migration inhibitory factor in men with prostate cancer as a novel biomarker of detection and disease progression.

Macrophage migration inhibitory factor (MIF) has been shown to play an important role in the growth and metastasis of prostate cancer. The objective of this study was to determine whether the serum level of MIF could be used as a diagnostic biomarker for prostate cancer as well as a predictor of disease progression. A total of 369 men who underwent systematic prostate biopsy from January 2000 to April 2004 and 30 healthy controls were included in this study. The serum MIF level was measured using an enzyme linked immunosorbent assay. Associations between the serum MIF level and several clinicopathological factors were analyzed. Among 359 patients, 137 were diagnosed as having prostate cancer. The mean values of serum MIF in the control, benign and cancer-groups were 2.1, 3.5 and 10.8 ng/ml, respectively. The MIF levels of patients with prostate cancer were significantly higher than those of the other two groups. A comparison of MIF and PSA values in all patients showed a positive correlation (correlation coefficient r(2)=0.56, p<0.0001). The MIF value in patients with prostate cancer was significantly associated with clinical T stage, Gleason score and percentage of positive biopsy core (PPBC). MIF levels in patients with metastasis were significantly elevated compared with those in patients without metastasis. Among patients undergoing radical prostatectomy, the level of MIF in those with pathologically confirmed extraprostatic disease was significantly higher than that in patients with organ-confined disease. Moreover, multivariate analysis showed that MIF values, PSA values and PPBC were independent predictors for extraprostatic disease. These findings suggest that an increased serum MIF level is closely associated with the progression of prostate cancer, and thus the serum MIF level could be useful as a novel biomarker for the detection of prostate cancer as well as a predictor of disease progression.

Adult↗

PubMed2006

[Advancement of treatment for prostate cancer].

The number of prostate cancer patients is rapidly increasing in Japan, as aging people are more common and the lifestyle is more westernized. Another reason is that prostate specific antigen (PSA) is prevalent and PSA test can detect organ-confined prostate cancer in the early stage. In the past, endocrine therapy was the main treatment modality since many prostate cancer patients were diagnosed in the advanced stage. However, endocrine therapy is not suitable for young patients with organ-confined prostate cancer. Surgery and radiation therapy are becoming standard therapy for these patients. Although retropubic radical prostatectomy is widely performed,urinary incontinence and sexual dysfunction are still problems. Other approaches such as laparoscopic prostatectomy, portless endoscopic prostatectomy and perineal prostatectomy are also performed. Radiation therapy is commonly used for organ-confined prostate cancer in Europe and the U.S.A. The advancement in computer technology has made it possible to accumulate enough radiation dose to target without damaging the surrounding organs (3 D conformal, intensity-modulated radiotherapy). Heavy ion particle radiotherapy is also attempted in some institutes. Moreover, brachytherapy can be another choice in radiation therapy. In Japan, only high-dose brachytherapy with (192)Ir has been performed. In July 2003, permanent seed brachytherapy with (121)I was legally approved in Japan, and more organ-confined prostate cancer patients are expected to undergo this treatment. There are several treatment modalities for organ-confined prostate cancer patients these days. Therefore, not only tumor grade and stage, but also patients'lifestyle and thought should be considered in determining treatment.

Brachytherapy↗

PubMed2006

[A case of retroperitoneal malignant peripheral nerve sheath tumor in a patient with neurofibromatosis].

We report a case of retroperitoneal malignant peripheral nerve sheath tumor (MPNST) in a patient with neurofibromatosis 1. A 42-year-old woman was admitted because of a palpable left abdominal mass. Her mother, son, and daughter had neurofibromatosis 1. Computed tomography and magnetic resonance imaging revealed a 73 x 76 mm retroperitoneal mass. We performed complete resection of the tumor, confirming the margin status by frozen section examination intraoperatively. The histopathological examination revealed MPNST. Although no further therapy was performed, she is alive with no evidence of disease 11 months after surgery.

Adult↗

PubMed2006

Clinical study for management of supportive treatment for high-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) for intractable testicular tumor.

The side effects of high-dose anti-cancer drug chemotherapy with peripheral blood stem cell transplantation (PBCST) for the treatment of intractable testicular tumor are very serious. In particular, agranulocytosis in bone marrow suppression may be life threatening. In this study, we examined opportunistic infectious diseases and preventive counter measures in the compromised conditions of anti-cancer drug chemotherapy. The patients underwent anti-cancer drug chemotherapy with PBCST for the treatment of intractable testicular tumors at Kobe University Hospital from September 1996 to September 2002. The high-dose chemotherapy regimen consisted of total doses per course of 1,250 mg/m2 carboplatin, 1,500 mg/m2 etoposide, and 7,500 mg/m2 ifosfamide. Twenty-four men (median age, 30 years; range, 18-70 years) received 50 courses of chemotherapy in total. The nadir of peripheral leukocyte counts was less than 1,000/mm3 in all courses, and the mean period was for 7.1 days. None of these patients developed critical sepsis leading to disseminated intravascular coagulation or treatment-related death. Our detailed data show that we can perform high-dose anti-cancer drug chemotherapy with PBSCT for intractable testicular tumors without serious infectious complications if we take sufficient preventive countermeasures for infectious diseases.

Adolescent↗

PubMed2005

Detection of micrometastases in pelvic lymph nodes in patients undergoing radical cystectomy for locally invasive bladder cancer by real-time reverse transcriptase-PCR for cytokeratin 19 and uroplakin II.

PURPOSE: The objective of this study was to clarify the significance of micrometastases in pelvic lymph nodes in patients who underwent radical cystectomy for bladder cancer. EXPERIMENTAL DESIGN: We included 40 patients with locally invasive bladder cancer who underwent radical cystectomy and pelvic lymphadenectomy. Expression of cytokeratin 19 (CK19), uroplakin II (UP II), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in 760 lymph nodes were assessed by a fully quantitative real-time reverse transcription-PCR (RT-PCR) assay. The quantification value of CK19 or UP II mRNA was described as each value relative to GAPDH mRNA. In this study, we regarded specimen in which either CK19 or UP II mRNA was positive as "presence of micrometastasis." RESULTS: Routine pathologic examinations detected tumor cells in 29 lymph nodes from six patients. Real-time RT-PCR identified positive expression of CK19 and UP II mRNAs in 49 lymph nodes from 10 patients and 98 lymph nodes from 16 patients, respectively. Of 633 lymph nodes from 34 patients with no pathologic evidence of nodal involvement, 13 nodes from five patients and 58 nodes from 10 patients were diagnosed as positive for CK19 and UP II mRNAs expression, respectively, by real-time RT-PCR. Presence of micrometastases was significantly associated with other conventional prognostic variables, including pathologic stage and microvascular invasion. Disease recurrence was occurred in eight patients, among whom four patients were negative for lymph node metastasis by routine pathologic examination and diagnosed as having micrometastasis by real-time RT-PCR assay. Furthermore, cause-specific survival rate in patients without micrometastasis was significantly higher than that in those with micrometastasis, irrespective of the presence of pathologic-positive nodes. CONCLUSIONS: Approximately 30% of locally invasive bladder cancer shed cancer cells to pelvic lymph nodes, and disease recurrence after radical cystectomy could be explained, at least in part, by micrometastases in pelvic lymph nodes.

Cystectomy↗

PubMed2005

New epitope peptides derived from parathyroid hormone-related protein which have the capacity to induce prostate cancer-reactive cytotoxic T lymphocytes in HLA-A2+ prostate cancer patients.

BACKGROUND: Parathyroid hormone-related protein (PTHrP) is produced by cancer cells and has been suggested to be responsible for malignancy-associated hypercalcemia and osteolysis after bone metatsases. Therefore, PTHrP is a promising target in the treatment of metastatic prostate cancer. METHODS: Seven PTHrP-derived peptides were prepared based on the HLA-A2 binding motif. These peptide candidates were screened by their ability to induce peptide-specific cytotoxic T lymphocytes (CTLs), and their ability to be recognized by immunoglobulin G (IgG). RESULTS: Both the PTHrP59-67 and PTHrP42-51 peptides were found to efficiently induce peptide-specific CTLs from peripheral blood mononuclear cells of HLA-A2+ prostate cancer patients with several HLA-A2 subtypes. These CTLs showed HLA-A2-restricted cytotoxicity toward prostate cancer cells. IgG reactive to the PTHrP42-51 peptide was frequently detected in prostate cancer patients. CONCLUSIONS: These results indicate that these two new PTHrP peptides will be useful in the peptide-based immunotherapy of HLA-A2+ prostate cancer patients, especially those with bone metastases.

Bone Neoplasms↗

PubMed2005

Monooxygenation of an aromatic ring by F43W/H64D/V68I myoglobin mutant and hydrogen peroxide. Myoglobin mutants as a model for P450 hydroxylation chemistry.

Myoglobin (Mb) is used as a model system for other heme proteins and the reactions they catalyze. The latest novel function to be proposed for myoglobin is a P450 type hydroxylation activity of aromatic carbons (Watanabe, Y., and Ueno, T. (2003) Bull. Chem. Soc. Jpn. 76, 1309-1322). Because Mb does not contain a specific substrate binding site for aromatic compounds near the heme, an engineered tryptophan in the heme pocket was used to model P450 hydroxylation of aromatic compounds. The monooxygenation product was not previously isolated because of rapid subsequent oxidation steps (Hara, I., Ueno, T., Ozaki, S., Itoh, S., Lee, K., Ueyama, N., and Watanabe, Y. (2001) J. Biol. Chem. 276, 36067-36070). In this work, a Mb variant (F43W/H64D/V68I) is used to characterize the monooxygenated intermediate. A modified (+16 Da) species forms upon the addition of 1 eq of H2O2. This product was digested with chymotrypsin, and the modified peptide fragments were isolated and characterized as 6-hydroxytryptophan using matrix-assisted laser desorption ionization time-of-flight tandem mass spectroscopy and 1H NMR. This engineered Mb variant represents the first enzyme to preferentially hydroxylate the indole side chain of Trp at the C6 position. Finally, heme extraction was used to demonstrate that both the formation of the 6-hydroxytryptophan intermediate (+16 Da) and subsequent oxidation to form the +30 Da final product are catalyzed by the heme cofactor, most probably via the compound I intermediate. These results provide insight into the mechanism of hydroxylation of aromatic carbons by heme proteins, demonstrating that non-thiolate-ligated heme enzymes can perform this function. This establishes Mb compound I as a model for P450 type aromatic hydroxylation chemistry.

5-Hydroxytryptophan↗