Publications by authors named "Hiroshi Yaegashi"

60 Publications

Three-dimensional morphological analysis of spermatogenesis in aged mouse testes.

Sci Rep 2021 11 26;11(1):23007. Epub 2021 Nov 26.

Department of Integrative Cancer Therapy and Urology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.

Spermatogenesis, which is a continuous process from undifferentiated spermatogonia to spermatozoa in the seminiferous tubules, declines with age. To investigate changes in spermatogenesis with aging, we reconstructed the seminiferous tubules of 12 mice aged 12 to 30 months from serial sections and examined age-related and region-specific alterations in the seminiferous epithelium and spermatogenic waves in three dimensions. The basic structure of the seminiferous tubules, including the numbers of tubules, terminating points, branching points, and total tubule length, did not change with age. Age-related alterations in spermatogenesis, primarily assessed by the formation of vacuoles in Sertoli cells, were detected in the seminiferous tubules at 12 months. The proportion of altered tubule segments with impaired spermatogenesis further increased by 24 months, but remained unchanged thereafter. Altered tubule segments were preferentially distributed in tubule areas close to the rete testis and those in the center of the testis. Spermatogenic waves became shorter in length with age. These results provide a basis for examining the decline of spermatogenesis not only with aging, but also in male infertility.
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http://dx.doi.org/10.1038/s41598-021-02443-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626501PMC
November 2021

Variations in photodynamic diagnosis for bladder cancer due to the quality of endoscopic equipment.

Photodiagnosis Photodyn Ther 2021 Nov 19;37:102628. Epub 2021 Nov 19.

Department of Integrative Cancer Therapy and Urology, Kanazawa University.

Background: Photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT) has different treatment outcomes across institutions, as seen in conventional TURBT. We retrospectively compared the difference in quality between the two types of endoscopic equipment used for PDD-assisted TURBT in our institution.

Methods: This study enrolled 205 consecutive patients who underwent PDD-assisted TURBT. Patients were divided into two groups according to the endoscopic equipment used for PDD-assisted TURBT: Group A using the conventionally used endoscopic system and Aladuck LS-DLED and Group S using the Storz PDD system. Cystoscopy findings of white light (WL), fluorescence light (FL), and combination (positive if either WL or FL was positive) were recorded, and diagnostic quality of PDD was compared between both groups.

Results: Group A had 105 cases and 336 specimens, while Group S had 100 cases and 361 specimens, with no significant differences between patient characteristics. The tumor sensitivities of WL, FL, and combination in Group A was 71.9%, 77.1%, 90.5%, respectively, while in Group S, these were 71.5%, 92.2%, 96.1%, respectively. Group S had significantly higher sensitivity of FL and combination than Group A, as well as higher detection of carcinoma in situ lesions.

Conclusion: Both endoscopic systems had improved sensitivity with PDD-assistance versus WL only, with Group S having higher sensitivity. Differences in the quality of endoscopic equipment may influence the differences in treatment results with PDD-assisted TURBT across institutions.
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http://dx.doi.org/10.1016/j.pdpdt.2021.102628DOI Listing
November 2021

The effectiveness of high-dose-rate brachytherapy with external beam radiotherapy for clinically locally advanced and node-positive prostate cancer: long-term results of a retrospective study.

Int J Clin Oncol 2021 Dec 7;26(12):2310-2317. Epub 2021 Sep 7.

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.

Background: No standard treatment exists for locally advanced prostate cancer (PC). This study evaluated the long-term treatment outcomes and toxicity in patients with clinically locally advanced and/or lymph node (LN)-positive PC who underwent high-dose-rate brachytherapy (HDR-BT) with external beam radiotherapy (EBRT).

Methods: The treatment outcomes and toxicities of 152 patients with PC who underwent HDR-BT with EBRT and had at least 2 years of observation were examined. The treatment dose was 19- and 13-Gy HDR-BT in two and single fractions, respectively, both combined with external irradiation of 46 Gy in 23 fractions. Long-term androgen deprivation therapy (ADT) for patients harboring very high-risk tumors was used in combination.

Results: The median observation period was 59.7 (24.4-182.1) months. The 5-year prostate cancer-specific and recurrence-free (RFS) survival rates were 99.0% and 91.8%, respectively, with only two PC mortalities. When 5-year RFS was examined for each parameter, RFS was significantly lower in pre-radiotherapy (pre-RT) prostate-specific antigen (PSA) > 0.5 ng/mL (77.1%; p = 0.008), and presence of LN metastasis (68.1%; p = 0.017). Multivariable analysis demonstrated that pre-RT PSA (HR, 4.68; 95% CI, 1.39-15.67; p = 0.012) and presence of LN metastasis (HR, 4.70; 95% CI, 1.24-17.74; p = 0.022) were independent recurrence predictors. The 5-year cumulative incidence rate of grade ≥ 2 toxicities in genitourinary and gastrointestinal tracts were 15.4% and 1.3%, respectively.

Conclusions: HDR-BT combined with EBRT and long-term ADT shows promising disease control and tolerant toxicities for clinically locally advanced and LN-positive PC.
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http://dx.doi.org/10.1007/s10147-021-02023-6DOI Listing
December 2021

Examination of Necessity for Pelvic Drain Placement After Robot-assisted Radical Prostatectomy.

In Vivo 2021 Sep-Oct;35(5):2895-2899

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Background/aim: Pelvic drain (PD) placement is commonly performed after robot-assisted radical prostatectomy (RARP), but the need for PD placement is unclear. This study aimed to assess the need for PD placement after RARP.

Patients And Methods: This retrospective study analysed the effect of PD placement on postoperative complications in patients who underwent RARP between 2009 and 2018. All patients prior to October 1, 2016 had a PD placed; those after did not.

Results: Of the 308 study patients, 231 received a PD (PD group) and 77 did not (ND group). The incidence of ileus, urinary tract infection and anastomotic leak did not differ significantly between the groups; nor did the incidence of asymptomatic and symptomatic lymphocele at 2 weeks and 1 year after surgery. Multivariate analysis showed that lymph node dissection is a predictor of asymptomatic lymphocele development two weeks after surgery.

Conclusion: PD placement is not necessary after RARP.
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http://dx.doi.org/10.21873/invivo.12579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408730PMC
August 2021

Test clamp procedure in robot-assisted partial nephrectomy: is it a safe procedure?

J Robot Surg 2021 Jul 27. Epub 2021 Jul 27.

Department of Urology, Kanazawa University Hospital, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-8640, Japan.

We performed test clamp procedure in robot-assisted partial nephrectomy (RAPN) to prevent massive bleeding during tumor resection and to omit dissection of non-feeding arteries around the tumor. We subsequently analyzed the safety and usefulness of the procedure. The Test clamp procedure was performed for 1 to 3 min during renal artery test ischemia prior to the actual ischemia and tumor resection. We confirmed the disappearance of blood flow around the renal tumor using color Doppler ultrasonography. If arterial blood flow around the tumor remained, we surveyed the site for other arteries that needed to be clamped and repeated the test clamp procedure until renal blood flow around the tumor disappeared. We retrospectively analyzed consecutive RAPN cases performed from July 2016 to March 2020 at our institutions and reviewed medical records. The clinical data of the RAPN cases were statistically analyzed. Sixty-four RAPN cases underwent the test clamp procedure, which was categorized as the TEST group. Test clamping was performed safely without any clamping-related complications in all cases. Eleven cases (17%) underwent partial ischemia, which was a significantly higher number than that in the control group. Massive bleeding during tumor resection was more frequent in the control group. Postoperative deterioration of estimated glomerular filtration rate did not differ significantly between both groups. Although further investigation was still necessary, our findings indicate that the test clamp procedure may be a safe and secure procedure to perform in RAPN for both patients and surgeons.
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http://dx.doi.org/10.1007/s11701-021-01288-3DOI Listing
July 2021

Androgen replacement therapy for cancer-related symptoms in male: result of prospective randomized trial (ARTFORM study).

J Cachexia Sarcopenia Muscle 2021 08 24;12(4):831-842. Epub 2021 May 24.

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.

Background: Hypogonadism associated with cancer is reported to cause cachexia and a variety of physical and psychological symptoms. This study aims to evaluate whether androgen replacement therapy can improve cancer-related symptoms in male advanced cancer patients.

Methods: An investigator-initiated, prospective, and randomized controlled study was conducted. Patients with low serum testosterone levels (total or free testosterone levels were <2.31 ng/mL or <11.8 pg/mL, respectively) were randomly assigned to the control or testosterone enanthate administration (testosterone group) groups. Testosterone enanthate was injected into the muscle tissue at a dose of 250 mg every 4 weeks (baseline, week 4, and week 8). Differences in quality of life questionnaires and cachexia-related serum protein levels between groups were assessed.

Results: This study enrolled and randomized 106 and 81 patients, respectively. Moreover, 41 and 40 patients were in the control and testosterone groups, respectively. Although no significant differences in the change of subscales and total scores in Functional Assessment of Anorexia/Cachexia Treatment were noted from the baseline between the two groups, the testosterone group showed a significantly better change in the 'unhappiness' item of the Edmonton Symptom Assessment System at week 12 compared with baseline versus the control group (-1.4 and 0.0 points, respectively; mean, P = 0.007). No significant differences exist in the change of serum interleukin-6 and insulin-like growth factor-1 levels at week 12 from the baseline between the control and testosterone groups. Consequently, the testosterone group significantly inhibited the change in serum tumour necrotic factor-α level at week 12 from the baseline compared with the control group (+0.4 and +0.1 pg/mL, respectively; mean, P = 0.005).

Conclusions: Although testosterone enanthate did not improve most of the items in health-related quality of life questionnaires, testosterone enanthate induced a significantly better change in the 'unhappiness' item at week 12 compared with the control. Testosterone enanthate may be a potential treatment option for male advanced cancer patients.
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http://dx.doi.org/10.1002/jcsm.12716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350213PMC
August 2021

Sarcopenia and Visceral Metastasis at Cabazitaxel Initiation Predict Prognosis in Patients With Castration-resistant Prostate Cancer Receiving Cabazitaxel Chemotherapy.

In Vivo 2021 May-Jun;35(3):1703-1709

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Background/aim: Cabazitaxel is recommended as first-line treatment after docetaxel for metastatic castration-resistant prostate cancer. However, the efficacy, adverse events and prognostic factors associated with cabazitaxel are unclear.

Patients And Methods: This single-centre retrospective study including 30 patients with CRPC treated with cabazitaxel between 2014 and 2020 investigated efficacy, outcomes and prognostic factors.

Results: Fourteen patients had visceral metastases. The median cabazitaxel dose was 20 mg/m The prostate-specific antigen response rate, time to prostate-specific antigen response, and overall survival were 13.3%, 3.48 months, and 7.92 months, respectively. The rates of grade 3 or more neutropenia and febrile neutropenia were 20% and 6.7%, respectively. By multivariate analysis, sarcopenia and visceral metastasis at the time of cabazitaxel initiation were independent and significant factors conferring a poor prognosis.

Conclusion: The early introduction of cabazitaxel, prior to the development of sarcopenia and visceral metastasis, might contribute to improved prognosis in CRPC.
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http://dx.doi.org/10.21873/invivo.12430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193302PMC
June 2021

Histiocytic sarcoma following combination chemotherapy for primary mediastinal germ cell tumor: a diagnostic dilemma.

Int Cancer Conf J 2021 Apr 9;10(2):144-148. Epub 2021 Jan 9.

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.

Histiocytic sarcoma is considered an extremely rare condition. We herein report on a case of histiocytic sarcoma following combination chemotherapy for a primary mediastinal germ cell tumor in a 26-year-old Asian man who visited the General Medicine Department of a hospital with complaints of cough and high fever. Chest computed tomography (CT) imaging revealed a tumor (diameter 10.5 cm) in the anterior mediastinum, with no signs of metastasis, and CT-guided biopsy of the mediastinal tumor revealed the presence of some necrotic cartilages. The patient's serum α-fetoprotein (AFP) level was determined to be high at 160.4 ng/mL and a primary mediastinal non-seminomatous germ cell tumor was suspected, so the patient was referred to the Department of Urology. Despite the presence of severe thrombocytopenia, the patient was treated using a combination of chemotherapy and intermittent transfusion, which was able to normalize his serum AFP level. However, resection of the mediastinal tumor was unsuccessful due to persistent thrombocytopenia and the patient was subsequently transferred to our hospital for further examination and treatment. Despite management by hematologists, the condition of the patient did not improve; although his AFP level remained normal, the tumor increased in size and then metastasized to the liver and spleen. The general condition of the patient deteriorated and he died 9 months after his first visit. The patient was diagnosed with histiocytic sarcoma following a pathological autopsy. Due to the extremely rare incidence of histiocytic sarcoma, this condition should be a differential diagnosis and the appropriate tests must be conducted to give an exact treatment.
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http://dx.doi.org/10.1007/s13691-020-00467-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947123PMC
April 2021

Transvaginal polytetrafluoroethylene mesh surgery for pelvic organ prolapse: 1-year clinical outcomes.

Int J Urol 2021 03 28;28(3):268-272. Epub 2020 Nov 28.

Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Osaka, Osaka, Japan.

Objectives: To evaluate the safety and efficacy of transvaginal mesh surgery using a polytetrafluoroethylene mesh to treat pelvic organ prolapse.

Methods: This prospective observational study included women undergoing transvaginal mesh surgery for pelvic organ prolapse that used new polytetrafluoroethylene mesh cut into a shape similar to that of Elevate. We evaluated the subjective and objective outcomes at 3 and 12 months, as well as postoperative complication rates.

Results: This study included 55 patients. The pelvic organ prolapse quantification scores improved significantly at 3 and 12 months after surgery compared with scores before surgery. In four patients (7.3%), a pelvic examination showed stage 2 objective recurrence without subjective symptoms. Clavien-Dindo grades 2 and 3 perioperative complications were observed in 9.1% and 1.8% of the patients, respectively. Vaginal mesh exposure occurred in one patient (1.8%) at the time of the 3-month follow-up evaluation. The mesh was exposed at the proximal midline of the anterior vaginal wall.

Conclusions: These findings show the safe and effective use of the polytetrafluoroethylene mesh for transvaginal mesh surgery.
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http://dx.doi.org/10.1111/iju.14444DOI Listing
March 2021

A novel risk classification score for malignant ureteral obstruction: a multicenter prospective validation study.

Sci Rep 2021 02 24;11(1):4455. Epub 2021 Feb 24.

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.

Emergence of malignant ureteral obstruction (MUO) has been reported as a sign of poor prognosis; however, the distribution of survival time in patients with MUO is considerably wide, and no risk classification score has been constructed. To evaluate whether a novel risk classification score for overall survival that we previously developed, is effective in a large cohort. Investigator-initiated, prospective, multicenter diagnostic/prognostic study was conducted. Patients with MUO were divided into three risk groups based on the score calculated using four prognostic factors (PLaCT: Primary site, Laterality, serum Creatinine level, and Treatment for primary site) at the first visit, and prospective follow-up was performed. Overall survival and ureteral stent failure-free survival of each risk group were compared. In total, 300 patients with 21 different primary sites were enrolled. The numbers of patients in good, intermediate, and poor risk groups were 105, 106, and 89, respectively. Median survival times of patients in good, intermediate, and poor risk groups were 406, 221, and 77 days, respectively (P < 0.0001). In 217 patients with ureteral stenting, median ureteral stent failure-free survival times of good, intermediate, and poor risk groups were 385, 183, and 57 days, respectively (P < 0.0001). Limitations include the limited ethnicity and the extended duration of study enrollment. The novel PLaCT risk classification score could divide MUO patients into three risk groups with distinct survival times and ureteral stent patencies. This score will aid in establishing prognosis and treatment strategy for all physicians engaged in cancer treatment.
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http://dx.doi.org/10.1038/s41598-021-84054-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904864PMC
February 2021

Effectiveness of Vintage Hormone Therapy as Alternative Androgen Deprivation Therapy for Non-metastatic Castration-resistant Prostate Cancer.

In Vivo 2021 Mar-Apr;35(2):1247-1252

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Background/aim: Vintage hormone therapy for non-metastatic castration-resistant prostate cancer (nmCRPC) is not recommended under the current guidelines, but is widely practiced in Japan. This study assessed effectiveness of vintage hormone therapy as alternative androgen deprivation therapy (AADT) for treatment of nmCRPC.

Patients And Methods: In this retrospective study we examined patients with nmCRPC that received vintage hormone therapy as AADT between 1999 and 2018.

Results: Of 53 patients with nmCRPC, 25 patients (47.2%) had stage 1 nodal disease (N1) at diagnosis of nmCRPC. Prostate specific antigen (PSA) reduction rate≥30% was observed in 32 patients (72.7%). The median PSA nadir was 0.7, and the duration of the response was 14.3 months. The median metastasis-free survival (MFS) for the entire patient population was 62.2 months, and the median overall survival (OS) was not reached. In the multivariate analysis, the duration of response in AADT>18 months was a predictor of prolonged OS.

Conclusion: There is a certain number of nmCRPC patients who respond well to vintage hormone therapy as AADT. Further studies are expected to differentiate such cases.
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http://dx.doi.org/10.21873/invivo.12375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045078PMC
June 2021

Durable response achieved using Pazopanib for germ tumor cells: A case report.

Mol Clin Oncol 2021 Mar 19;14(3):48. Epub 2021 Jan 19.

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8641, Japan.

Germ cell tumors with somatic-type malignancy (GCTSTM) are rare, and patients with GCTSTM have extremely poor prognoses with a median survival of nine months. Somatic-type malignancy, which are mainly sarcomas, usually exhibit chemoresistance. The recommended therapy for GCTSTM is radical resection; however, Pazopanib, which is a multityrosine kinase inhibitor, has indicated therapeutic effects for some soft tissue sarcoma components. The current study reports the case of a 21-year-old Asian man who presented with GCTSTM after combined chemotherapy for a primary mediastinal germ cell tumor with multiple lung metastases. Despite the metastases, his disease was stable after continuous administration of Pazopanib for two years and then stopping the medication for four years. To the best of our knowledge, the current report is the first report of a durable response by Pazopanib for GCTSTM, which is a rare outcome.
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http://dx.doi.org/10.3892/mco.2021.2210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849064PMC
March 2021

A new flavonoid derivative exerts antitumor effects against androgen-sensitive to cabazitaxel-resistant prostate cancer cells.

Prostate 2021 04 25;81(5):295-306. Epub 2021 Jan 25.

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.

Background: Our previous report has shown that the flavonoid 2'-hydroxyflavanone (2'-HF) showed inhibition of androgen receptor (AR) activity against androgen-sensitive prostate cancer (PCa) cells, LNCaP, and exhibited antitumor effects against androgen-insensitive PCa cells, PC-3, and DU145. In the present study, we prepared a derivative of 2'-HF, 16MS7F1924, and confirmed the effects of this derivative on PCa cells.

Methods: The antiproliferation effects of 16MS7F1924 were investigated in PCa cells using LNCaP, PC-3, DU145 and docetaxel-resistant and cabazitaxel-resistant cell lines of PC-3-TxR/CxR and DU145-TxR/CxR. Prostate-specific antigen (PSA) and AR expression level in whole cells and the nucleus were confirmed in LNCaP by reverse transcriptase polymerase chain reaction and Western blot analysis. AR activity in LNCaP cells was confirmed by luciferase assay using PSA promoter-driven reporter. To analyze the antiproliferative effects, cell-based assays using flow cytometry, immunocytochemistry, and TUNEL assay as well as Western blot analysis were employed. Furthermore, PC-3, DU145 and each chemoresistant strain of human PCa cells were subcutaneously xenografted. The antitumor effects of 16MS7F1924 were evaluated in vivo.

Results: 16MS7F1924 showed antitumor effect on all PCa cells in a dose-dependent manner. 16MS7F1924 reduced the expression of PSA messenger RNA (mRNA) and protein and inhibited AR activity in a dose-dependent manner, while expression of AR protein and mRNA was reduced by 16MS7F1924. 16MS7F1924 induced mitotic catastrophe and apoptosis. Apoptotic cells were increased in a dose-dependent manner, and the apoptosis was mediated through the Akt pathway. Tumor growth was safely and significantly inhibited by both intraperitoneal and oral administration of 16MS7F1924 in vivo.

Conclusion: 16MS7F1924 had sufficient antitumor activity against androgen-sensitive and cabazitaxel-resistant PCa cells and may be useful as a novel therapeutic agent overcoming hormone- and chemoresistant PCas.
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http://dx.doi.org/10.1002/pros.24106DOI Listing
April 2021

Anti-proliferative and anti-migratory properties of coffee diterpenes kahweol acetate and cafestol in human renal cancer cells.

Sci Rep 2021 01 12;11(1):675. Epub 2021 Jan 12.

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan.

Despite improvements in systemic therapy options for renal cancer, it remains one of the most drug-resistant malignancies. Interestingly, reports have shown that kahweol and cafestol, natural diterpenes extracted from coffee beans, exhibit anti-cancer activity. However, the multiple potential pharmacological actions of both have yet to be fully understood. This study therefore investigated the effects of kahweol acetate and cafestol on human renal cancer ACHN and Caki-1 cells. Accordingly, the combination of kahweol acetate and cafestol administration synergistically inhibited cell proliferation and migration by inducing apoptosis and inhibiting epithelial-mesenchymal transition. Mechanistic dissection revealed that kahweol acetate and cafestol inhibited Akt and ERK phosphorylation. Moreover, kahweol acetate and cafestol downregulated the expression of not only C-C chemokine receptors 2, 5, and 6 but also programmed death-ligand 1, indicating their effects on the tumor microenvironment. Thus, kahweol acetate and cafestol may be novel therapeutic candidates for renal cancer considering that they exert multiple pharmacological effects.
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http://dx.doi.org/10.1038/s41598-020-80302-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804192PMC
January 2021

Similar Recurrence Rate Between Gleason Score of Six at Positive Margin and Negative Margin After Radical Prostatectomy.

Anticancer Res 2021 Jan;41(1):509-516

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Background/aim: To investigate whether surgical margin (SM) status would affect the biochemical recurrence (BCR) after robot-associated RP (RARP).

Patients And Methods: We evaluated BCR after RARP and the association between pre- and postoperative predictive factors and BCR.

Results: Positive SM (PSM) was observed in 97 out of 365 enrolled patients. On multivariate analysis, preoperative prostate specific antigen, biopsy Gleason score (GS), clinical stage, GS ≥7 at the PSM and pathological GS ≥7 were predictive factors for BCR. The 5-year BCR-free survival rate was 84.1% in the negative SM (NSM), 87.4% when GS=6 at the PSM, and 47.6% when GS ≥7 at the PSM. There was no statistically significant difference in BCR-free survival between the NSM group and GS=6 at the PSM group (p=0.966).

Conclusion: It would be desirable to evaluate GS at PSM when PSM is present in a specimen removed by RP.
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http://dx.doi.org/10.21873/anticanres.14802DOI Listing
January 2021

A case of adrenal lymphangioma resected laparoscopically with minimal invasiveness.

Urol Case Rep 2020 Nov 2;33:101400. Epub 2020 Sep 2.

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan.

A 33-year-old female presented to us with a left adrenal cystic tumor with a maximum diameter of 70 mm. Because malignant tumor and pheochromocytoma could not be excluded, she underwent left laparoscopic transperitoneal adrenalectomy. The cystic tumor was stored to an endoscopically inactive treatment device and was subsequently punctured within the device; thus, tumor removal could be performed with minimum incision. Pathological findings showed highly suggestive of a cystic lymphangioma. The punctate was found to have an extremely high catecholamine titer. To avoid unnecessarily exposing the tumor contents, the treatment approach described in this report is reasonable and worth reporting.
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http://dx.doi.org/10.1016/j.eucr.2020.101400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574034PMC
November 2020

Androgen receptor signaling-targeted therapy and taxane chemotherapy induce visceral metastasis in castration-resistant prostate cancer.

Prostate 2021 01 13;81(1):72-80. Epub 2020 Oct 13.

Department of Integrative Cancer Therapy and Urology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.

Background: Visceral metastasis (VM), an important poor prognostic factor of prostate cancer (PC), is not commonly observed in castration sensitive status but is often observed after castration-resistant progression. However, the site, timing of emergence, and incidence of VM in castration-resistant patients have not yet been fully elucidated.

Methods: Demographic, surgical, pathological, and follow-up data of PC patients treated at Kanazawa University Hospital between January 2000 and December 2016 were retrospectively analyzed using their medical charts. From this data, risk factors of VM and survival of patients with VM were elucidated.

Results: Of 1364 patients, 21 (1.5%) had VM at diagnosis. Of 179 (13.1%) castration-resistant patients, 55 experienced emergence of new VM during treatment course. Incidence of new VM, especially nonlung, such as liver and adrenal metastases, increased significantly in proportion with the number of prescribed treatments. Multivariate analysis revealed that T stage, M stage, age, and treatment history with androgen receptor (AR) signaling-targeted agents and/or taxanes significantly increased the risk of VM. Compared with the group with VM at diagnosis, survival after diagnosis of VM following treatment was significantly shorter.

Conclusion: Although sequential use of new AR signaling-targeted agents and taxanes for castration-resistant PC (CRPC) is a standard treatment strategy, it often results in development of VM. Elucidating the mechanisms of VM are essential to improve survival in patients with CRPC.
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http://dx.doi.org/10.1002/pros.24082DOI Listing
January 2021

A novel screening strategy for clinically significant prostate cancer in elderly men over 75 years of age.

Asian J Androl 2021 Jan-Feb;23(1):36-40

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan.

A standard modality for prostate cancer detection in men 75 years and older has not been established. A simple screening method for elderly patients is needed to avoid unnecessary biopsies and to effectively diagnose prostate cancer. A retrospective study was conducted on elderly patients who had prostate biopsy at Kanazawa University Hospital (Kanazawa, Japan) between 2000 and 2017. Of the 2251 patients who underwent prostate biopsy, 254 had clinically significant prostate cancer (CSPC) with a Gleason score (GS) of≥7 and 273 had a GS of <7 or no malignancy. In this study, patients aged 75 years or older were classified as elderly patients. GS ≥ 7 was characterized by a prostate-specific antigen (PSA) of the maximum area under the curve of 12 ng ml with a sensitivity of 76.2% and a specificity of 73.2%. For PSA levels between 4 ng ml and 12 ng ml, based on the maximum area under the curve, patients with three or four of the following factors may present a GS of ≥ 7: percent free PSA >24, PSA density≥ 0.24 ng ml, positive findings on digital rectal examination, and transrectal with 90.0% sensitivity and 67.4% specificity. In this study, we found that raising the PSA cutoff to 12 ng ml for CSPC in elderly individuals can significantly reduce unnecessary prostate biopsies. Furthermore, CSPC could be efficiently discovered by combining the four supplementary markers in patients with a PSA level of 4-12 ng ml. By performing this screening for elderly men over 75 years of age, unnecessary biopsies may be reduced and CSPC may be detected efficiently.
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http://dx.doi.org/10.4103/aja.aja_39_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831834PMC
October 2021

Comparison of Tolerability Between 2-Weekly and 3-Weekly Docetaxel Regimen in Castration-resistant Prostate Cancer.

Anticancer Res 2020 Aug;40(8):4291-4297

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Background: The tolerability of 2-weekly docetaxel at 25-35 mg/m for castration-resistant prostate cancer (CRPC) has not been fully evaluated. The aim of this study was to evaluate its tolerability compared to 3-weekly docetaxel at 60-75 mg/m in patients with CRPC.

Patients And Methods: In this retrospective study, data were compared with respect to efficacy and safety between 2-weekly and 3-weekly docetaxel regimens in patients with CRPC.

Results: Time to treatment failure and prostate-specific antigen (PSA) response rate did not differ significantly between the two regimens. Compared to 3-weekly administration, incidence of severe leukopenia and febrile neutropenia was significantly lower (p<0.05), and relative dose intensity was significantly higher (p<0.05) for the 2-weekly schedule. Docetaxel dosage and PSA response were identified as independent risk factors for severe leukopenia.

Conclusion: Two-weekly treatment seems better tolerated than three-weekly treatment in Japanese patients with CRPC.
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http://dx.doi.org/10.21873/anticanres.14431DOI Listing
August 2020

The Impact of Hypertension on the Clinicopathological Outcome and Progression of Renal Cell Carcinoma.

Anticancer Res 2020 Jul;40(7):4087-4093

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Background/aim: Hypertension is a risk factor for occurrence of renal cell carcinoma; however, it remains unclear whether hypertension affects development and prognosis of renal cell carcinoma. This study evaluated the impact of hypertension on the progression of renal cell carcinoma.

Patients And Methods: Renal cell carcinoma patients who were treated from October 2007 to December 2018 at our Institution were retrospectively analyzed.

Results: Of 462 patients, the number of patients with and without hypertension was 234 (including 227 treated with anti-hypertensive agents) and 228, respectively. The tumor size was significantly smaller in the hypertension group than in the non-hypertension group (median 32 and 45 mm, respectively, p=0.010). The 5-year cancer-specific and metastasis-free survival in the hypertension group were significantly better than those in the non-hypertension group (93.6% and 80.4%, and 84.6% and 73.0%, respectively, p=0.021 and p=0.017). Propensity score matching revealed significantly better metastatic-free survival in the hypertension group than the non-hypertension group (p=0.022).

Conclusion: Renal cell carcinoma patients with hypertension show better prognosis with low metastasis possibility.
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http://dx.doi.org/10.21873/anticanres.14407DOI Listing
July 2020

Therapeutic Effect of Ethinylestradiol in Castration-resistant Prostate Cancer.

Anticancer Res 2020 Apr;40(4):2291-2296

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Background/aim: The best sequential treatment for castration-resistant prostate cancer (CRPC) remains unclear. This study evaluated the therapeutic effects of ethinylestradiol (EE) on CRPC.

Patients And Methods: A total of 80 patients with CRPC, treated with 0.5-1.5 mg/day of EE, were retrospectively assessed.

Results: The median duration from the initial treatment to the beginning of EE was 48.3 months. A decline in the prostate-specific antigen (PSA) from the baseline was noted in 60 patients (75%) and a >50% PSA decline in 27 patients (34%). The median time of PSA progression, overall survival, and cancer-specific survival after EE were 5.60 months, 24.00 months, and 27.93 months, respectively.

Conclusion: EE administration for CRPC showed a relatively high PSA response regardless of timing of sequential treatment. The frequency of cardiovascular adverse events was not significantly high. EE administration is a potential treatment option for CRPC.
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http://dx.doi.org/10.21873/anticanres.14194DOI Listing
April 2020

Reply to Comment on "Kadomoto, S. et al. Tumor-Associated Macrophages Induce Migration of Renal Cell Carcinoma Cells via Activation of the CCL20-CCR6 Axis" Cancers 2020 12, 89.

Cancers (Basel) 2020 Feb 4;12(2). Epub 2020 Feb 4.

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8641, Japan.

We appreciate Zins and Abraham [1] commenting on our paper studying the role of the CCL20-CCR6 axis on renal cell carcinoma (RCC) cells [2]. As they pointed out, our study has certain limitations. Although M1- and M2-types cannot be separated clearly and a consecutive change of character might exist between them, it has been reported that plural specific markers express on M1- and M2-types. Unfortunately, a definite difference between M1 and M2 macrophages was not confirmed in our study. For more differentiation, multiple stimulations, such as suggested in the comments of Zins and Abraham, might be needed. Hence, we needed to expediently use "M1-like" and "M2-like" to mention specific status of these macrophage-like cells. Meanwhile, CCL20 expression levels of M2-like-THP-1 cells co-cultured with RCC cells were dramatically increased compared with parental THP-1 cells, indicating that certain stimulations within the tumor microenvironment rather than theoretical stimulations make macrophages differentiated; however, further studies are needed to clarify this mechanism using a more appropriate co-culture system mimicking the tumor microenvironment. Immunohistochemistry of CCL20 and M2 markers will help to better understand the role of tissue infiltrating macrophages, even tissue CD68 staining intensity itself was reported to correlate with prognosis of RCC patients [3]. [...].
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http://dx.doi.org/10.3390/cancers12020354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073159PMC
February 2020

The Efficacy of Second-line Chemotherapy for Advanced or Metastatic Urothelial Cancer.

Anticancer Res 2020 Feb;40(2):1141-1146

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Background/aim: This study aimed to assess the efficacy and toxicity of second-line chemotherapy, especially combination chemotherapy, for advanced or metastatic urothelial cancer.

Patients And Methods: This retrospective analysis included patients who received second-line chemotherapy after disease progression during first-line chemotherapy between January 2009 to May 2018. Progression-free survival (PFS), overall survival (OS) and toxicity associated with second-line chemotherapy were assessed.

Results: In total 25 patients received second-line chemotherapy; 21 patients had combination chemotherapy and 4 had single-agent chemotherapy. Median PFS and OS were 3.6 months (range=0.2-23.5) and 11.9 months (range=0.5-29.0), respectively. Twenty patients (80%) exhibited grade 3 or more severe toxicities.

Conclusion: PFS and OS benefits of second-line combination chemotherapy corresponded to those of the phase 3 study of pembrolizumab, but adverse events were more severe. Pembrolizumab is potentially a better second-line treatment than combination chemotherapy.
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http://dx.doi.org/10.21873/anticanres.14055DOI Listing
February 2020

Tumor-Associated Macrophages Induce Migration of Renal Cell Carcinoma Cells via Activation of the CCL20-CCR6 Axis.

Cancers (Basel) 2019 Dec 30;12(1). Epub 2019 Dec 30.

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8641, Japan.

This study investigated tumor-associated macrophages activity in the microenvironment of renal cell carcinoma. Via a co-culture with macrophage-like cells differentiated from human monocyte cell line THP-1 and U937 cells, the migration ability of ACHN and Caki-1 cells, which are human renal cell carcinoma cell line cells, was significantly increased, as was the epithelial-mesenchymal transition change. A chemokine array identified the CCL20-CCR6 axis as a concentration-dependent signal in ACHN and Caki-1 cell migration. Akt in the ACHN and Caki-1 cells was activated by macrophage-like cells, and the CCL20 neutralizing antibody suppressed migration ability, epithelial-mesenchymal transition, and Akt phosphorylation in the ACHN and Caki-1 cells. Akt inhibitor AZD5363 also decreased the epithelial-mesenchymal transition change and migration ability in the ACHN and Caki-1 cells. In 42 renal cell carcinoma tissues, patients with CCR6 and macrophage infiltration indicated poor prognoses. In the tumor microenvironment of renal cell carcinoma, cancer cells are activated by CCL20 secreted by tumor-associated macrophages through Akt activation, followed by epithelial-mesenchymal transition and an acquired migration ability. Thus, inhibition of the CCL20-CCR6 axis may be a potential therapeutic strategy for renal cell carcinoma.
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http://dx.doi.org/10.3390/cancers12010089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017081PMC
December 2019

Prevalence of N. gonorrhoeae, C. trachomatis, M. genitalium, M. hominis and Ureaplasma spp. in the anus and urine among Japanese HIV-infected men who have sex with men.

J Infect Chemother 2020 Apr 25;26(4):403-406. Epub 2019 Dec 25.

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1, Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.

The present study investigated the prevalence of Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, M. hominis, and Ureaplasma spp. (biovars 1 and 2) in Japanese HIV-positive men who have sex with men (MSM). One-hundred-and-six Japanese HIV-infected MSM patients were enrolled. Anal and urine samples were collected and DNA testing for each microorganism was performed. Questionnaires regarding lifestyle habits and sexual behavior were administered. The prevalence of N. gonorrhoeae, C. trachomatis, M. genitalium, M. hominis, and Ureaplasma spp. in the anus was 5.6%, 8.9%, 4.4%, 5.6%, and 8.9%, respectively. A history of genital warts was an independent risk factor for detection of Mycoplasma spp. and Ureaplasma spp. The prevalence of these microorganisms in the anus of asymptomatic Japanese HIV-positive MSM was relatively high in agreement with previous reports from other countries.
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http://dx.doi.org/10.1016/j.jiac.2019.12.007DOI Listing
April 2020

Factors Associated With Treatment Satisfaction After Robot-assisted Radical Prostatectomy.

Anticancer Res 2019 Nov;39(11):6339-6346

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Background/aim: To evaluate the chronological changes in health-related quality of life and treatment satisfaction after robot-assisted radical prostatectomy (RARP).

Patients And Methods: A total of 196 patients were included, and treatment satisfaction was evaluated using the Expanded Prostate Cancer Index Composite (EPIC) score before and at 1, 3, 6, and 12 months after RARP.

Results: At 12 months after RARP, 64.8% of patients were satisfied. On the contrary, 4.6% of patients were dissatisfied at 12 months after RARP. In a multivariate analysis, only urinary bother of EPIC was significantly associated with satisfaction at 12 months after RARP (p=0.025, odds ratio=1.029).

Conclusion: Treatment satisfaction with RARP was generally acceptable from 1 to 12 months after surgery and did not change over time. Urinary bother was associated with satisfaction at 12 months after RARP. Compared with the objective 24-hour pad test, questionnaires answered subjectively were more associated with satisfaction.
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http://dx.doi.org/10.21873/anticanres.13845DOI Listing
November 2019

Intraoperative hypotension caused by oral administration of 5-aminolevulinic acid for photodynamic diagnosis in patients with bladder cancer.

Int J Urol 2019 11 11;26(11):1064-1068. Epub 2019 Sep 11.

Department of Integrative Cancer Therapy and Urology, Kanazawa University, Kanazawa, Ishikawa, Japan.

Objective: To analyze perioperative blood pressure in patients undergoing transurethral resection of bladder tumor with photodynamic diagnosis.

Methods: A total of 109 consecutive patients who underwent photodynamic diagnosis-assisted transurethral resection of bladder tumor at Kanazawa University, Kanazawa, Ishikawa, Japan, were included in this study and considered as the photodynamic diagnosis group. Clinical data were collected, and perioperative systolic bladder pressure and vasopressor usage were analyzed. In contrast, consecutive patients who previously underwent conventional transurethral resection of bladder tumor (without the use of oral 5-aminolevulinic acid) were used as the control group.

Results: The systolic blood pressure before anesthesia, lowest systolic blood pressure from the anesthesia induction to the start of operation and lowest systolic blood pressure during operation were significantly lower in the photodynamic diagnosis group. The rate of vasopressor use was significantly higher in the photodynamic diagnosis group. On multivariate analysis, we found that general anesthesia and regular use of renin-angiotensin system inhibitor were associated with an increased risk of hypotension (lowest systolic blood pressure from the anesthesia induction to the start of operation <80 mmHg).

Conclusions: Oral intake of 5-aminolevulinic acid can obviously cause a drop in intraoperative blood pressure in patients undergoing transurethral resection of bladder tumor. Therefore, urologists and anesthesiologists should consider withdrawal of renin-angiotensin system inhibitors and monitor the blood pressure during photodynamic diagnosis-assisted transurethral resection of bladder tumor.
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http://dx.doi.org/10.1111/iju.14099DOI Listing
November 2019

Metastatic urachal cancer treated effectively with gemcitabine/cisplatin combination chemotherapy and radiotherapy: A case report.

Mol Clin Oncol 2019 Aug 22;11(2):139-142. Epub 2019 May 22.

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8640, Japan.

Urachal cancer often presents at an advanced stage with poor prognosis due to the lack of an effective systematic therapeutic strategy. We experienced a case of metastatic urachal cancer treated effectively by combination chemotherapy and radiotherapy. A 55-year-old female presented to our department with right lower abdominal pain. A transurethral biopsy of an urachal tumor suggested urachal adenocarcinoma. The patient underwent chemotherapy with gemcitabine and cisplatin for metastatic urachal cancer. As tumor markers declined and the radiological findings indicated stability of disease, external beam radiotherapy was then administered to the primary site. Chemotherapy was then administered again in response to tumor markers gradually increasing and the progression of multiple peritoneal metastases. However, the patient did not complete chemotherapy due to hematological toxicity. The patient succumbed to primary disease 23 months after initial diagnosis. Previous studies have reported that the median time from the diagnosis of metastatic urachal cancer to mortality is just over 1 year. By contrast, in the present case the patient survived up to 2 years with combination chemotherapy and radiotherapy, a rare incidence worthy of reporting.
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http://dx.doi.org/10.3892/mco.2019.1865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587011PMC
August 2019

Reiter's syndrome following intravesical Bacillus Calmette-Guerin therapy for bladder carcinoma: a report of five cases.

Int Cancer Conf J 2018 Oct 21;7(4):148-151. Epub 2018 Aug 21.

1Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.

Reiter's syndrome is known to be a rare severe adverse of Bacillus Calmette-Guerin (BCG) therapy. We report five cases of patients with Reiter's syndrome following intravesical BCG therapy for bladder carcinoma, and review the clinical characteristics, treatments, and outcomes of these patients. Each patient developed polyarthritis after urinary tract symptoms, and developed conjunctivitis anywhere from the third to the eighth BCG induction cycle. One case presented a slight elevation of inflammatory responses in blood analysis, and the other four cases had a higher level of white blood cell (WBC) counts and C-reactive protein (CRP) values. WBC counts at the diagnosis of Reiter's syndrome had a positive correlation with the time from initial treatment to cure of the disease. In all cases, BCG therapy was discontinued, and non-steroidal anti-inflammatory drugs (NSAIDs), oral steroids, and anti-tuberculosis drugs were administered. Anti-rheumatic drugs were not used in these cases. Improvement of symptoms was reported from 1 to 13 months after initial treatment. No patients had recurrence of Reiter's syndrome, whereas 2 patients had alternative treatment 2 and 18 months later, respectively, because of cancer recurrence. For cases with conjunctivitis and joint pain occurring during intravesical BCG therapy, early clinical interventions such as NSAIDs, steroids, and anti-tuberculosis drugs should be introduced, especially in cases with a high level of inflammatory changes in blood analysis.
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http://dx.doi.org/10.1007/s13691-018-0342-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498336PMC
October 2018

Initial Experience With Radium-223 Chloride Treatment at the Kanazawa University Hospital.

Anticancer Res 2019 May;39(5):2607-2614

Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan

Background/aim: To evaluate our initial experience with radium-223 chloride (Ra-223).

Materials And Methods: A total of 26 castration-resistant prostate cancer (CRPC) patients with bone metastases, treated with Ra-223 at our hospital were evaluated. This study aimed to observe adverse events (AEs) and changes in serum markers, and Bone Scan Index (BSI). Additionally, the relationship between these values and OS was investigated.

Results: The observed AEs mainly included fatigue and nausea. Alkaline phosphatase (ALP) and bone-type alkaline phosphatase (BAP) levels decreased following the treatment; however, those of PSA and 1-CTP tended to increase, regardless of Ra-223 administration. Overall survival (OS) was significantly improved in cases with a baseline BSI value of <2 compared with those with a baseline BSI value of ≥2. Moreover, the decrease in BSI after administration of Ra-223 was an independent factor, significantly prolonging OS.

Conclusion: ALP and BAP levels and BSI values are suitable evaluation markers during treatment with Ra-223. Also, baseline BSI values and the decrease in BSI following treatment are independent factors predicting OS.
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http://dx.doi.org/10.21873/anticanres.13384DOI Listing
May 2019
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