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Hidefumi Kinoshita

Publications and source records attributed to Hidefumi Kinoshita.

At least 19 recordsLinked to original sources
PubMed2025

HMGA2 links morphological evolution and microenvironment dynamics to systemic therapy response in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) exhibits significant heterogeneity due to morphological changes and tumor microenvironment dynamics, influencing systemic therapy responses. While the role of high-mobility group AT-hook 2 (HMGA2) in tumor progression has been implicated in other cancers, its significance in ccRCC remains unclear. This study investigates the role of HMGA2 in these processes and its clinical impact. METHODS: Spatial transcriptomics (ST) was performed on primary ccRCC samples to investigate expression trajectories associated with HMGA2 expression and morphological evolution. In metastatic ccRCC cohorts treated with systemic therapy, immunohistochemistry and bulk RNA sequencing data were analyzed to evaluate molecular and clinical features in relation to HMGA2. Single-cell RNA sequencing (scRNA-seq) data were used to explore immune cell populations and their interactions. Based on these findings, multiplex immunohistochemistry (mIHC) assessed spatial distribution, cell-cell interactions, and pathological responses of key immune populations. RESULTS: HMGA2 expression was associated with aggressive morphological patterns, such as solid sheets and rhabdoid/sarcomatoid. ST revealed a progressive increase in HMGA2 expression along the morphological trajectory, marked by a shift from clear to eosinophilic cytoplasm, with eccentric nuclei and prominent nucleoli, and loss of vascular architecture. HMGA2-high tumors exhibited aggressive phenotypes driven by cell cycle, epithelial-mesenchymal transition, and inflammatory signaling pathways. Clinically, patients with high HMGA2 had worse progression-free survival but responded better to immune checkpoint inhibitor combination (Combo-ICI) therapy than to tyrosine kinase inhibitor monotherapy. To assess the immune landscape, scRNA-seq data revealed that HMGA2-high tumors were enriched with progenitor exhausted CD8+ T cells (Tpex), along with increased frequencies of conventional dendritic cell type 1 (cDC1) and inflammatory cDC type 2, which were found to interact with Tpex via ICAM-1. mIHC confirmed that Tpex were enriched among Combo-ICI responders in HMGA2-high tumors, with higher densities and closer proximity to ICAM-1+ cDC1. CONCLUSIONS: These findings suggest that dynamic HMGA2 expression contributes to morphological evolution and modulates immune responses through enhanced Tpex-cDCs engagement, serving as a potential marker for systemic therapy response in ccRCC. However, additional experimental studies are required to validate these mechanisms.

Humans↗
PubMed2006

Biweekly paclitaxel and gemcitabine for patients with advanced urothelial cancer ineligible for cisplatin-based regimen.

BACKGROUND: To avoid cisplatin-related gastrointestinal, renal and other toxicity while maintaining efficacy in the palliative setting or second line chemotherapeutic regimen for cisplatin-resistant urothelial cancer, chemotherapeutic regimens have been investigated that do not include cisplatin. The current study was designed to evaluate efficacy, clinical feasibility and safety of gemcitabine and paclitaxel (GP) regimen in patients with metastatic urothelial cancer who were ineligible for standard cisplatin-based combination chemotherapy. METHODS: Gemcitabine 2500 mg/m(2) and paclitaxel 150 mg/m(2) were administered intravenously every 2 weeks for 23 patients (17 males and 6 females) with advanced urothelial cancer who were ineligible for cisplatin-based chemotherapy; metastatic disease being resistant to cisplatin-based chemotherapy regimen in 14, heavy toxicity in prior cisplatin-based chemotherapy in three, poor ECOG performance in two and impaired renal function in four. Average age was 67 (53-77). Performance status was 0 in 18 patients, 1 in three patients and 2 in two patients. RESULTS: The overall response rate was 30% (95% CI 15.6-50.8%). Of the 23 patients, no patient attained CR and 7 patients had PR. In the cisplatin-resistant group, the response rate was 14.2% (2/14; 95% CI 4.0-39.9%). In the remaining patients ineligible for cisplatin, the response rate was 55.5% (5/9; 95% CI 26.6-81.1%). The median duration of response was 4 months (range 3-8). The median duration of survival for all patients was 12.1 months (95% CI 8.6-15.5). Myelosuppression, predominantly neutropenia, was the most common serious toxicity and toxicity of Grade 3 or greater was observed in six patients (26%). Among non-hematological toxicity, neuralgia was the most commonly observed and occurred in nine patients (39%) although no patient had toxicity of Grade 3 or greater. Three patients had interstitial pneumonitis possibly attributed to gemcitabine. One patient developed severe bilateral disease after two cycles of the regimen, which was partially resolved with corticosteroid therapy. CONCLUSION: GP regimen is effective in some patients with cisplatin-resistant urothelial cancer and promising as second line chemotherapy. GP regimen is more effective and well tolerated as first line chemotherapy in patients ineligible for cisplatin-based chemotherapy. Toxicity is generally mild but care must be taken for patients with risk of interstitial pneumonitis. A further larger scale study is required to confirm the efficacy of the GP regimen.

Aged↗
PubMed2006

Results of radiation therapy combined with neoadjuvant hormonal therapy for stage III prostate cancer: comparison of two different definitions of PSA failure.

BACKGROUND: We herein report the clinical outcome of radical radiation therapy combined with neoadjuvant hormonal therapy (NHT) for stage III (International Union Against Cancer [UICC] 1997: UICC 97) prostate cancer. Prostate-specific antigen (PSA) failure-free survival was assessed according to two different definitions, and the appropriateness of each definition is discussed. METHODS: Between October 1997 and December 2000, 27 patients with stage III prostate cancer were enrolled in this study. The median pretreatment PSA level was 29 ng/ml (range, 7.4-430 ng/ml). The Gleason score (GS) was 7 or more in 22 patients (81%). All patients received 3 months of NHT with a luteinizing hormone-releasing hormone (LH-RH) analogue, in combination with an antiandrogen (flutamide), given during the first 2 weeks, followed by 70-Gy external-beam radiation therapy (EBRT) in 35 fractions. The initial 46 Gy was given with a four-field technique, while the remainder was given with a dynamic conformal technique. No adjuvant hormonal therapy (AHT) was given. RESULTS: The median follow-up time was 63 months. PSA levels decreased to the normal range (<4 ng/ml) after irradiation in all but one patient. The 5-year PSA failure-free survival was 34.8% according to the American Society for Therapeutic Radiology and Oncology (ASTRO) definition and it was 43.0% according to the "nadir plus 2" definition. Discordance of the results between the two definitions was seen in two patients. The 5-year overall and cause-specific survivals were 83.0% and 93.3%, respectively. No severe acute or late adverse effects were observed. CONCLUSION: Seventy Gy of EBRT following 3 months of NHT produced therapeutic results comparable to those reported in other studies which used long-term AHT. The value of long-term AHT for Japanese men should be tested in a clinical trial.

Adenocarcinoma↗
PubMed2006

Retroperitoneoscopic pyeloplasty: using reconstructive methods based on intraoperative findings.

AIM: Reconstructive laparoscopic procedures have been recognized as a less invasive treatment than conventional open procedures. However, although the laparoscopic pyeloplasty has also been accepted as useful, few findings have been reported relevant to the retroperitoneal approach. To elucidate its effectiveness and safety, laparoscopic surgery via the retroperitoneal approach was examined in our institution. Furthermore, the importance of laparoscopic observation for ureteropelvic junction and urine passage ureteropelvic junction without indwelling ureteral stent. METHODS: Between July 1998 and December 2004, 13 men and 15 women underwent laparoscopic retroperitoneal surgery for ureteropelvic junction obstruction. The mean patient age was 33.6 years (range: 13-70 years). Methods of repair were determined by intraoperative findings for the relationship between the ureteropelvic junction and surrounding vessels. An indwelling ureteral stent was removed before initiating laparoscopic operation to observe the relationship between ureteropelvic junction and aberrant vessels more precisely. RESULTS: An aberrant renal vessel was found in 13 patients (46%). Dismembered pyeloplasty was carried out in 21 patients, Y-V plasty in five patients and Hellstrom technique in two patients. Ureteral transposition was not required in dismembered pyeloplasty cases. All patients achieved retroperitoneoscopic pyeloplasty without open conversion. The mean operative time was 272 min (range: 155-490 min). The mean estimated blood loss was 44 mL (range: 10-200 mL). No major complications were observed during the intraoperative period, but urinary tract infection occurred in two patients in the postoperative period. In all patients except one, obstruction was improved or resolved. CONCLUSIONS: Laparoscopic retroperitoneal surgery is not only able to repair ureteropelvic junction obstruction, but can also be done safety and less invasively. We believe that laparoscopic observation without indwelling stent will contribute to a more appropriate choice of pyeloplasty.

Adolescent↗
PubMed2006

High-grade and hormone-treated prostate cancer express high levels of thymidylate synthase.

OBJECTIVE: To evaluate the expression of thymidylate synthase and dihydropyrimidine dehydrogenase in prostate tissue. MATERIALS AND METHODS: Tissue from 79 patients with localized prostate cancer was used. Thymidylate synthase and dihydropyrimidine dehydrogenase expression were determined semiquantitatively by immunohistochemistry. RESULTS: Thymidylate synthase and dihydropyrimidine dehydrogenase immunostaining grades of benign tissue were significantly higher than those of cancer tissue (both P < 0.01). Cancer tissue with a primary Gleason grade of > or = 4 expressed a higher thymidylate synthase staining grade than those with a primary Gleason grade of <4 (P < 0.01). Cancer tissue spots from patients treated with neoadjuvant therapy revealed significantly higher thymidylate synthase and dihydropyrimidine dehydrogenase grades than those with no neoadjuvant therapy (P < 0.01). CONCLUSION: High thymidylate synthase expression in localized prostate cancer might reflect an aggressive status. High expression in high-grade prostate cancers and prostate cancers after hormonal therapy suggest that thymidylate synthase could be a new therapeutic target for advanced prostate cancer.

Aged↗
PubMed2006

Surgical treatment for urethral recurrence after ileal neobladder reconstruction in patients with bladder cancer.

OBJECTIVE: To report a retrospective study evaluating the management of superficial urethral recurrence after ileal neobladder construction in patients with bladder cancer. PATIENTS AND METHODS: In 77 consecutive patients with ileal neobladder after radical cystectomy for invasive bladder cancer, urethral recurrence was evaluated and transurethral resection (TUR) used as an initial treatment for superficial urethral recurrence. Urethrectomy with urinary re-diversion was performed when further recurrence developed. RESULTS: Four patients (5%) presented with a superficial urethral recurrence and all four were treated by TUR as initial therapy. One patient has had no evidence of recurrence after initial TUR, although the other three patients were later treated with salvage urethrectomy due to repeated urethral recurrence. As a result, the stage of urethral recurrence advanced from pTa to pT1-pT2 in two of the three patients. For urinary re-diversion, one patient had a conversion from a Studer pouch to an ileal conduit, using the afferent limb, and the other two were converted from a Hautmann pouch to a continent reservoir using the Appe-Mainz procedure. There was no evidence of metastasis or local recurrence in any of the four patients. CONCLUSION: Urethral preservation at initial therapy for superficial recurrence might be reasonable, and sequential urethrectomy after attempted urethral preservation might be strategically feasible. Urinary re-diversion from a neobladder to a catheterizable continent reservoir using the appendix would be a good choice and maintains the quality of life.

Aged↗
PubMed2006

[Experience of laparoscopic nerve-sparing radical cystectomy and construction of ileal neobladder at Kansai Medical University].

Laparoscopic nerve-sparing radical cystectomy and construction of ileal neobladder was performed on a 76-year-old man with atrophic bladder after the intravesical instillation therapy for bladder cancer. Ileal neobladder was constructed by the combined extracorporeal technique through the camera port dilated to 45 mm. Operation time was 8 hours, with 3.5 hours for the nerve-sparing cystoprostatectomy, 2.5 hours for the extracorporeal neo-bladder construction and 2 hours for the laparoscopic urethra neo-bladder anastomosis and wound closing. The post-operative course was uneventful with minimum use of analgesia. This operation was minimally invasive therapy and from the functional aspect the potency was preserved. Although this method was technically challenging, various advantages can be promising for the patients compared to the standard open technique. Indication of this operation should be carefully expanded. Various methods, such as the complete intracorporeal technique and minimally invasive laparoscopic neobladder (MILaN) technique, have been reported for urinary diversion. In this report, we compared our method with other techniques.

Aged↗
PubMed2005

Antiandrogen bicalutamide promotes tumor growth in a novel androgen-dependent prostate cancer xenograft model derived from a bicalutamide-treated patient.

Androgen ablation therapies are effective in controlling prostate cancer. Although most cancers relapse and progress despite androgen ablation, some patients experience antiandrogen withdrawal syndrome, in which those treated with antiandrogen show clinical improvement when antiandrogen is discontinued. Although the androgen receptor (AR) is suggested to play an important role in prostate cancer progression even after the androgen ablation, limited tissue availability for molecular studies and small numbers of human prostate cancer cell lines have restricted prostate cancer research. Here, we describe KUCaP, a novel serially transplantable human prostate cancer xenograft model. We established KUCaP from liver metastatic tissue of a patient treated with antiandrogen bicalutamide. KUCaP expressed the AR with a point mutation at amino acid 741 (tryptophan to cysteine; W741C) in the ligand-binding domain. This mutation was also present in cancerous tissue used for generation of KUCaP. Although the growth of KUCaP in male mice was androgen dependent, bicalutamide aberrantly promoted the growth and prostate-specific antigen production of KUCaP. For the first time, we show the agonistic effect of bicalutamide to a xenograft with clinically induced AR mutation. This bicalutamide-responsive mutant AR will serve in the development of new therapies for androgen ablation-resistant prostate cancers.

Androgen Antagonists↗
PubMed2005

Monthly paclitaxel and carboplatin with oral estramustine phosphate in patients with hormone-refractory prostate cancer.

BACKGROUND: We aimed to determine the safety and efficacy of monthly paclitaxel and carboplatin with oral estramustine phosphate in patients with hormone-refractory prostate cancer (HRPC). METHODS: Patients with prostate cancer that was progressing despite androgen ablation therapy were treated with i.v. paclitaxel, 175 mg/m2, over 3 h, followed by carboplatin (area under the curve, 5) on day 1, with oral estramustine phosphate, 280 mg twice daily, for a 28-day treatment cycle. Estramustine phosphate was precluded in those patients who had experienced adverse effects during prior chemotherapies. Patients were evaluated for response every cycle, and the treatment was continued until the cancer progressed. RESULTS: Twenty-one patients with progressive hormone-refractory disease were treated for a median of 4 cycles (range, 1 to 11 cycles). Estramustine phosphate was precluded in seven patients. Post-therapy decreases in serum prostate-specific antigen levels of 50% and 75%, respectively, were seen in 43% and 19% of the patients (95% confidence intervals, 22% to 64% and 2% to 36%). Of the nine patients with measurable disease, 1 (11%) had a complete response and 2 (22%) had a partial response. The overall median time to progression was 4 months, and the median survival time for all patients was 11 months. Major grade 3 or 4 adverse effects were anemia (29%), neutropenia (48%), and thrombocytopenia (24%). Mild peripheral neuropathy and myalgia/arthralgia were observed in 11 (52%) and 9 (43%) patients, respectively. CONCLUSION: Monthly paclitaxel and carboplatin with oral estramustine phosphate has significant antitumor activity and is well tolerated in patients with progressive HRPC.

Administration, Oral↗
PubMed2005

Androgen receptor, Ki67, and p53 expression in radical prostatectomy specimens predict treatment failure in Japanese population.

OBJECTIVES: To evaluate multiple known prognostic markers in localized prostate cancer using tissue microarrays in Japanese patients. Molecular studies have suggested that ethnicity influences prostate tumor biology. METHODS: Specimens were studied from 52 patients who underwent radical surgery at our institution between 1997 and 2001 without neoadjuvant hormonal therapy and with three or more available and complete cancer spots. Ki67, p53, and androgen receptor antigen expression were examined. Immunohistochemical scores were compared with outcomes of chemical relapse as monitored using prostate-specific antigen. RESULTS: Pathologic tumor classification (P = 0.047), World Health Organization score (P = 0.026), World Health Organization histologic grade (P = 0.026), and surgical margin status (P = 0.018) were significant conventional clinicopathologic variables for predicting biochemical failure. The tissue microarray Gleason sum (P = 0.038), tissue microarray primary Gleason grade (P = 0.013), Ki67 labeling index (P < 0.0001), p53 (P = 0.0097), and androgen receptor (P = 0.0113) antigen expression also were significant. Moreover, surgical margin status and Ki67 labeling index were independently associated with treatment failure. CONCLUSIONS: Especially together, the Ki67 labeling index and p53 and androgen receptor expression in localized prostate cancer often predicted postoperative progression in Japanese patients.

Aged↗
PubMed2005

Association of a genetic polymorphism of the E-cadherin gene with prostate cancer in a Japanese population.

The E-cadherin gene has been identified as having a physiological role in cellular attachment, and is hypothesized to participate in carcinogenesis. A polymorphism (an A to C substitution) in the 5'-untranslated region has a direct effect on E-cadherin gene transcriptional regulation. We explored the association between E-cadherin gene polymorphism and the risk of prostate cancer in a Japanese population. The subjects consisted of 236 patients with prostate cancer, 209 benign prostatic hyperplasia (BPH) patients and 139 male controls. A marginally significant difference was found between prostate cancer patients and male controls (P = 0.053). No significant difference was observed between prostate cancer and BPH patients. When patients with prostate cancer were divided into two groups, stage A+B and stage C+D, a significant difference was observed between progressive cancer patients (stage C+D) and male controls (odds ratio = 1.93, P = 0.016). It is possible that the presence of one A allele resulted in an increased risk of cancer progression.

Aged↗
PubMed2005

Age-associated increase of prostate-specific antigen in a high level of men visiting urological clinics.

OBJECTIVES: To evaluate the distribution of serum prostate-specific antigen (PSA) levels as a function of age in men with no evidence of prostate cancer who visited urological clinics. METHODS: Simultaneous measurements of total PSA and PSA-alpha-1-antichymotrypsin (PSA-ACT) were performed on patients who presented at urological clinics in Japan. After excluding 490 patients because of follow-up biopsy findings indicating prostate cancer, patients' history of prostatic surgery and medication affecting the serum PSA level, 1520 patients with PSA levels of less than 20.0 ng/mL were available for the study. RESULTS: Medians (95th percentile) of the total PSA levels were 0.9 (4.7), 1.2 (5.6), 1.7 (11.0), 2.1 (9.8) and 2.8 (11.0) ng/mL in men in their 40s (n = 37), 50s (n = 211), 60s (n = 488), 70s (n = 609) and 80s (n = 175), respectively, whereas those of PSA-ACT were 0.5 (2.9), 0.7 (3.7), 1.1 (7.4), 1.2 (5.9) and 1.6 (6.4) ng/mL, respectively. Both total PSA and PSA-ACT increase with aging, although comparison between the 10-year age groups showed a significant difference in the two molecular forms only between men in their 50s and 60s. CONCLUSIONS: The PSA ranges of men who visited urological clinics were higher than those of men participating in prostate cancer screening programs reported in other published studies. An age-associated increase in PSA similar to screening populations was also observed in urological outpatients. The results of the present study indicate that age-adjusted PSA cut-off levels can be used in outpatient settings, although the PSA reference value derived from the screening population should be carefully applied to symptomatic men of clinical practices.

Adult↗
PubMed2005

[Primary transitional carcinoma of the remaining ureter after nephrectomy for pyonephrosis: a case report].

A case of primary carcinoma of the remaining ureter is reported. A 70-year-old man presented with asymptomatic gross hematuria. Three years ago, he had received right nephrectomy for pyonephrosis. Although drip infusion pyelography (DIP) and cystoscopy showed no abnormal findings, computed tomography (CT) and retrograde ureterography demonstrated the irregular thickening of the right remaining ureteral wall. He underwent right ureterectomy with bladder cuff resection. Pathological examination revealed transitional cell carcinoma of the remaining ureter. He has been free of disease for 3 years.

Aged↗
PubMed2005

[Prostate cancer with penile metastasis: a case report].

A 77-year-old man presented with complaints of dysuria, nocturia and painless nodule on his penis. Laboratory examination revealed elevated serum prostate-specific antigen (PSA) and CA19-9. Pathological examinations on prostate and penile biopsy specimens revealed prostate adenocarcinoma with penile metastasis. The patient was diagnosed as having prostate cancer stage D2 (T4N1M1) with bone, lymph node and penile metastases. There was no response to initial hormonal therapy with the surgical castration and diethylstilbestrol. However, decrease of the tumor size, as well as PSA and CA19-9 values were achieved after the combined chemotherapy with Estramustine, Paclitaxel and Carboplatin.

Adenocarcinoma↗
PubMed2004

Assessment of a protocol for prophylactic antibiotics to prevent perioperative infection in urological surgery: a preliminary study.

BACKGROUND: The aim of the present study was to assess the usability and efficacy of our new protocol of prophylactic antibiotic use to prevent perioperative infection in urological surgery. METHODS: We prospectively investigated 339 cases of typical urological surgery in our department between April 2001 and March 2002 (group I). We classified surgical procedures into four categories by invasiveness and contamination levels: category A, clean less invasive or endoscopic surgery; category B, clean invasive or clean contaminated surgery; category C, urinary tract diversion using the intestine; and category D, infected surgery. Antibiotics were administrated intravenously according to our protocol: category A, first or second generation cephems or penicillins during the operative day only; category B, first and second generation cephems or penicillins for 3 days; and category C, second or third generation cephems for 4 days. Category D was excluded from the analysis. To judge perioperative infections, the wound condition and general conditions were evaluated in terms of the surgical site infection (SSI) as well as remote infection (RI) up to postoperative day (POD) 14. We retrospectively reviewed 308 patients who underwent urological surgery between April 2000 and March 2001 (group II) as reference cases that were administered antibiotics without any restriction. RESULTS: Perioperative infection rates (SSI + RI) in group I and group II were 25 of 339 (7.4%) and 35 of 308 (11.4%), respectively. Surgical site infection rates of categories A, B, and C in group I were 1.8%, 7.6%, and 30.0%, respectively, while those in group II were 2.0%, 7.4%, and 46.2%, respectively. There was no significant difference in infection rates in terms of RI and SSI between group I and group II. The amounts, as well as the prices, for intravenously administrated antibiotics and oral antibiotics decreased to approximately half and one-fifth, respectively. CONCLUSION: Our protocol effectively decreased the amount of antibiotics used without increasing perioperative infection rates. Thus, our protocol of prophylactic antibiotic therapy would be recommended as an appropriate method for preventing perioperative infection in urological surgery.

Adolescent↗
PubMed2004

[A case of vaginal metastasis of transitional cell carcinoma].

A 74-year-old female with a complaint of genital bleeding was referred to our hospital. In her past history, 4 times of transurethral resection of bladder tumor (TUR-BT) for bladder cancers and right nephroureterectomy with cuff for right ureteral tumors were performed during these 17 years, followed by simple cystectomy 3 years before. A punch biopsy of anterior vaginal wall demonstrated metastases of transitional cell carcinoma. Although total histero-vaginectomy was performed, recurrence of disease was observed in bone, skin and inguinal lymph nodes 9 months after the operation. This case is the 13th report of vaginal metastases of transitional cell carcinoma in the world.

Aged↗
PubMed2004

[Transitional cell carcinoma in prostate after intravesical instillation of Bacillus Calmette-Guerin].

We report 3 cases of prostatic involvement of transitional cell carcinomas (TCCs). All cases presented positive urinary cytology after intravesical instillation of Bacillus Calmette-Guerin (BCG) and then random biopsy of bladder and transurethral resection (TUR)-biopsy of prostatic urethra were performed. TUR-biopsy demonstrated TCC in the prostate, although random biopsy failed to detect tumors in the bladder in all cases. Case 1 was treated with cystourethrectomy with ileal conduit, case 2 was treated with cystourethrectomy with bilateral ureterocutaneostomy and case 3 was treated with cystectomy with orthotopic ileal neobladder reconstruction. All cases are alive with no evidence of disease. TUR-biopsy of prostatic urethra should be perfomed when patients present positive urinary cytology after BCG instillation therapy, because prostatic involvement of TCC associated with bladder carcinoma in situ is not rare.

Administration, Intravesical↗