Narihiko Hayashi

Early assessment by FDG-PET/CT of patients with advanced renal cell carcinoma treated with tyrosine kinase inhibitors is predictive of disease course

BackgroundWe reported previously that 18F-2-fluoro-2-deoxyglucose positron emission tomography/ computed tomography (FDG PET/CT) had potential for evaluating early response to treatment by tyrosine kinase inhibitors (TKIs) in advanced renal cell carcinoma (RCC). This time we investigated the relation of the early assessment by FDG PET/CT to long-term prognosis with an expanded number of patients and period of observation.MethodsPatients for whom TKI treatment for advanced RCC was planned were enrolled. FDG PET/CT was performed before TKI treatment and after one month of TKI treatment. The relations of the FDGPET/CT assessment to progression free survival (PFS) and overall survival (OS) were investigated.ResultsThirty-five patients were enrolled (sunitinib 19 cases, sorafenib 16 cases). The patients with RCC showing high SUVmax in pretreatment FDG PET/CT demonstrated short PFS (P =0.024, hazard ratio 1.137, 95% CI 1.017-1.271) and short OS (P =0.004, hazard ratio 1.210 95% CI 1.062-1.379). Thirty patients (sunitinib 16 cases, sorafenib 14 cases) were evaluated again after 1 month. The PFS of the patients whose SUVmax decreased<20% was shorter than that of the patients whose SUVmax decreased<20% (P = 0.027, hazard ratio 3.043, 95% CI 1.134-8.167). The PFS of patients whose tumor diameter sum increased was shorter than that of the patient with tumors whose diameter sum did not (P =0.006, hazard ratio 4.555, 95% CI 1.543-13.448).The patients were classified into three response groups: good responder (diameter sum did not increase, and SUVmax decreased ≥ 20%), intermediate responder (diameter sum did not increase, and SUVmax decreased<20%), and poor responder (diameter sum increased, or one or more new lesions appeared). The median PFS of good, intermediate, and poor responders were 458 ± 146 days, 131 ± 9 days, and 88 ± 26 days (good vs. intermediate P = 0.0366, intermediate vs. poor P = 0.0097, log-rank test). Additionally the mean OSs were 999 ± 70 days, 469 ± 34 days, and 374 ± 125 days, respectively (good vs. intermediate P = 0.0385, intermediate vs. poor P = 0.0305, log-rank test).ConclusionsThe evaluation of RCC response to TKI by tumor size and FDG uptake using FDG PET/CT after 1 month can predict PFS and OS.

Molecular Mechanisms Related to Parturition-Induced Stress Urinary Incontinence

BACKGROUND The molecular mechanisms underlying stress urinary incontinence (SUI) at the tissue level are poorly understood. OBJECTIVE To study genetic and molecular alterations in the urethras of animals with experimentally induced SUI. DESIGN, SETTING, AND PARTICIPANTS Cohort analysis of primiparous 2-month-old female Sprague-Dawley rats with experimentally induced SUI versus those who did not develop SUI in a university research laboratory setting. INTERVENTION Rats underwent intravaginal balloon dilation within 24 hours of parturition followed by bilateral ovariectomy one week later. Transvesical cystometry was performed 12 weeks after parturition. Rats were classified as continent (C) or incontinent (I) according to the results of cystometry. MEASUREMENTS The expression of over 22,000 genes in urethral tissue from the two groups was assessed with the use of an oligo microarray. The expression of relevant genes was confirmed by real-time polymerase chain reaction. Protein expression of small mothers against decapentaplegic 2 (Smad2), one of the differentially expressed genes, was extensively studied by immunohistochemistry and Western blot analysis. Regulation of Smad2 activity by transforming growth factor-beta (TGF-beta) was assessed in cultured urethral smooth muscle cells (USMCs). RESULTS AND LIMITATIONS After intervention, 14 (58.3%) rats remained continent and 10 (41.7%) became incontinent. There were significant differences in the expression of 42 urethral genes between continent and incontinent rats. The expression of genes involved in the TGF cellular signaling pathway (Smad2), collagen breakdown (matrix metalloproteinase 13 [Mmp13]), and smooth muscle inhibition (regulator of G-protein signaling 2 [Rgs2]) was significantly increased in the incontinent group. SMAD2 protein expression was significantly upregulated in the incontinent rats. In cultured USMCs, SMAD2 phosphorylation and nuclear translocation increased after Tgf-beta treatment. CONCLUSIONS Genes important in inflammation, collagen breakdown, and smooth muscle inhibition are upregulated in the urethras of female rats with parturition-associated incontinence.

FK1706 Enhances the Recovery of Erectile Function Following Bilateral Cavernous Nerve Crush Injury in the Rat

INTRODUCTION Advances in neurobiology have led to a surge of clinical interest in the development of protective and regenerative neuromodulatory strategies, as surgical therapies for prostate cancer often result in neuronal damage and debilitating loss of sexual function. AIM To investigate the dose-dependent efficacy of FK1706, a nonimmunosuppressant immunophilin ligand, for the recovery of erectile function following bilateral cavernous nerve crush injury in the rat. MAIN OUTCOME MEASURES Recovery of erectile function was assessed by cavernous nerve electrostimulation and reported as maximal increase of intracavernous pressure (ICP) and area under the curve (AUC). Changes in animal weights, percentage completion of treatment course, and survival were compared between groups. METHODS; Thirty-five Sprague-Dawley male rats were randomly divided into five equal groups: seven animals received a sham operation, whereas 28 animals underwent bilateral cavernous nerve crush injury, followed by subcutaneous injection of vehicle alone (1.0 mL/kg), or low (0.1 mg/kg), medium (0.32 mg/kg), or high dose (1.0 mg/kg) FK1706 5 days per week for 8 weeks. RESULTS Erectile dysfunction did not occur in the sham group (mean maximal ICP increase of 100.8 +/- 6.3 cmH(2)O), whereas nerve injury and vehicle treatment produced a significant reduction in ICP response to 34.4 +/- 12.8 cmH(2)O. The mean ICP increase for high-dose FK106 treatment was 73.9 +/- 6.3 cmH(2)O (P < 0.01 vs. vehicle) compared with 58.3 +/- 7.4 cmH(2)O and 56.9 +/- 8.3 for low and medium doses (P > 0.05). Similar stepwise findings were observed using AUC data. No significant maximal aortic blood pressure or weight differences occurred between groups and all animals completed treatment. CONCLUSION High-dose subcutaneous FK1706 therapy promoted recovery of erectile function following bilateral cavernous nerve crush injury in the rat. No significant differences between groups were observed for changes in weight, and the 8-week treatment course was completed for all animals.

Risk Factors for Metastatic Castration-Resistant Prostate Cancer (CRPC) Predict Long-Term Treatment with Docetaxel

Purpose For patients with metastatic castration-resistant prostatic cancer (mCRPC), docetaxel plus prednisone leads to superior survival and a higher response rate compared with mitoxantrone plus prednisone. We analyzed the efficacy of long-term treatment with ≥10 cycles of docetaxel, and validated the risk group classification in predicting overall survival (OS) in Japanese patients with mCRPC. Patients and Methods Fifty-two patients with mCRPC were administered 55 mg/m2 docetaxel and 8 mg dexamethasone, every 3 or 4 weeks, simultaneously with hormonal therapy and daily oral dexamethasone. They were divided into two groups, short-term (9 or fewer cycles) and long-term (10 or more cycles). Four risk factors including the presence of anemia, bone metastases, significant pain and visceral metastases were utilized for the risk group classification. Results Fourteen patients (27%) had an elevation of PSA in spite of docetaxel treatment, while 23 patients (44%) had a decline in PSA level, including 9 patients (17%) whose PSA level declined by ≥50%. The median duration of OS after the initiation of this therapy was 11.2 months in the short-term group and 28.5 months in the long-term group. The good risk group showed a significant difference in OS compared with the intermediate and poor risk groups (P<0.001). The median number of cycles of treatment was 14, 4 and 3 for each risk group, respectively (p<0.01). Conclusions The present study indicated that ≥10 cycles of this docetaxel therapy can significantly prolong survival in Japanese men with CRPC. This risk group classification for men with mCRPC at the initiation of this chemotherapy is useful.

Gallbladder Metastasis from Renal Cell Carcinoma

A 73-year-old female was operated with radical nephrectomy and cholecystectomy for renal cell carcinoma and suspected gallstones after 9 courses of sunitinib treatment. Gallbladder specimen showed gallbladder metastasis originating from the renal cell carcinoma. Gallbladder metastasis from renal cell carcinoma is rare. Here, we discuss a case of gallbladder metastasis from renal cell carcinoma.

Primary Synovial Sarcoma of the Kidney

The case was a 40-year-old female. She visited a local doctor with a chief complaint of right side abdominal pain. A right kidney tumor measuring 10 cm in diameter was observed in an abdominal Computed Tomography (CT) scan. Based on the CT image, the possibility of angiomiolipoma (AML) could not be ruled out, but a high maximum standardized uptake value (SUVmax) of 7.8 was observed in a Positron Emission Tomography CT (PET-CT) scan and there was a possibility of malignancy. We therefore performed a transperitoneal right radial nephrectomy. Although adhesion of the tumor to the duodenum and the inferior vena cava was observed, it was possible to perform an excision. The tumor accounted for a large proportion of the excised kidney; the surrounding areas had taken on a cyst-like structure, and the interior comprised grayish brittle tissue exhibiting solid growth. Histologically, gland-like and cyst-like structures composed of cylindrical cuboidal cells and mainly characterized by the solid growth of short fusiform-shaped and oval-shaped basophilic cells were observed, and we believed it was a synovial sarcoma. There were no malignant findings in the adrenal gland. There have been approximately 30 reported cases around the world of synovial sarcoma that developed in the kidney, and we herein report this case with bibliographic considerations.

Measurement of serum isoform [–2]proPSA derivatives shows superior accuracy to magnetic resonance imaging in the diagnosis of prostate cancer in patients with a total prostate-specific antigen level of 2–10 ng/ml

Abstract Objective: More accurate diagnostic procedures for prostate cancer are needed to avoid unnecessary biopsy due to the low specificity of prostate-specific antigen (PSA). Recent studies showed that the percentage of serum isoform [–2]proPSA (p2PSA) to free PSA (%p2PSA), the Prostate Health Index (PHI) and magnetic resonance imaging (MRI) were more accurate than PSA. The aim of this study was to test the accuracy of %p2PSA, PHI and MRI in discriminating patients with and without prostate cancer. Materials and methods: The subjects were 50 consecutive men with a PSA level of 2.0–10.0 ng/ml, who underwent prostate biopsy from October 2012 to July 2014. These patients underwent multiparametric MRI before biopsy, and their serum samples were measured for PSA, free PSA and p2PSA. The sensitivity, specificity and accuracy of PHI, %p2PSA and MRI were compared with PSA in the diagnosis of biopsy-confirmed prostate cancer. Results: In a univariate analysis, %p2PSA [area under the curve (AUC): 0.811] and PHI (AUC 0.795) were more accurate than MRI (AUC: 0.583) and PSA (AUC: 0.554) for prostate cancer detection. At 60% sensitivity, the specificity of PHI (76.5%) was higher than that of MRI (52.9%). For significant cancer detection, %p2PSA (AUC: 0.745), PHI (AUC: 0.791) and MRI (AUC: 0.739) were marginally more accurate than PSA (AUC: 0.696). At 85% sensitivity, the specificity of MRI (62.1%) was higher than that of PHI (34.5%). Conclusion: PHI and %p2PSA can be used for screening the general population and MRI can be used for detection of significant cancer in patients suspected, from screening tests, of having prostate cancer.

FDG-PET/CTが診断の一助となった原発性精嚢癌の1例

We reported a case of primary seminal vesicle cancer, detected by FDG-PET/CT. A 65-year-old man with constipation and appetite loss was admitted to our hospital. An ultrasound examination revealed evidence of bilateral hydronephrosis. He was diagnosed as acute post renal failure, and nephrostomy was done. CT and MRI showed a solid mass in the area of seminal vesicle. He underwent transrectal core biopsy, which histologically showed poorly differentiated adenocarcinoma. Immunohistochemistry showed the tumor to be CA125 positive, CEA positive and CK7 positive but PSA negative. FDG-PET/CT revealed an increased uptake of FDG only in the area of seminal vesicle. Serum CA125 was elevated and PSA stayed within normal limit. Primaly rectal carcinoma was ruled out by colonoscopy. The result of transperineal prostate biopsy was negative. We diagnosed him as suffering from primary seminal vesicle carcinoma. Anti-androgen blockade and radiotherapy to whole pelvis were performed, and serum CA125 level was improved. But, 6 months later serum CA125 re-elevated and 19 months later multiple liver metastases were noted. The patient received two cycles of docetaxel and cisplatin chemotherapy, however he developed pulmonaly embolism and rectal bleeding by tumor invasion and he died of his disease 22 months after the diagnosis.

Prognostic Value of Automated Bone Scan Index in Men With Metastatic Castration-resistant Prostate Cancer Treated With Enzalutamide or Abiraterone Acetate

Purpose Bone scan index (BSI) is an objective tool for quantifying bone metastasis load. We assessed its prognostic usefulness in patients with metastatic castration‐resistant prostate cancer (CRPC) treated with enzalutamide (ENZ) or abiraterone acetate (AA). Materials and Methods We analyzed 40 patients who received ENZ or AA treatment (ENZ/AA) for metastatic CRPC. The Cox proportional hazards model and a C‐index were used to investigate associations between overall survival (OS) and BSI, and patient age, prostate‐specific antigen, time to CRPC, previous docetaxel use, and pain. Results Median OS after ENZ/AA was 17.8 months. All patient deaths (n = 19; 47.5%) were from prostate cancer. In multivariate analysis, decreased BSI was an independent predictor for longer OS (hazard ratio, 8.97; P = .011). Inclusion of BSI improved the C‐index from 0.721 to 0.792 in predicting OS after ENZ/AA. Conclusions Decreased BSI after ENZ/AA independently predicts longer OS. Micro‐Abstract We retrospectively assessed the bone scan index as a predictor of overall survival in patients with metastatic castration‐resistant prostate cancer treated with enzalutamide or abiraterone acetate. Improved bone scan index after these treatments independently predicted longer overall survival.

One-month assessment of renal cell carcinoma treated by everolimus using FDG PET/CT predicts progression-free and overall survival

PurposeWe evaluated 18F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG PET/CT) results as outcome predictors for patients with metastatic renal cell carcinoma (RCC) treated by everolimus (EVL), an inhibitor of mammalian target of rapamycin.MethodsWe retrospectively reviewed 30 patients who were treated with EVL for metastatic RCC between May 2010 and March 2015, by evaluating their FDG PET/CT result before and 1 month after starting EVL treatment. We examined the relationships between each patient’s maximum standardized uptake value (max SUVmax) assessed by FDG PET/CT on progression-free survival (PFS) and overall survival (OS).ResultsMedian PFS for all 30 patients was 3.77 months (range 0.72–24.56 months) and median OS after EVL treatment of all 30 patients was 11.67 months (range 1.0–62.98 months). Enrolled patients were divided into two groups by max SUVmax prior to EVL (median = 7.6) and at 1 month after EVL treatment (median = 5.7). PFS were significantly shorter in higher max SUVmax prior to EVL (<7.6, PFS 7.8 vs 3.5 months, log-rank P = 0.017) and at 1 month after EVL (<5.7, PFS 10.6 vs 2.7 months, log-rank P = 0.002) than lower max SUVmax. OS were also significantly shorter in higher max SUVmax prior to EVL (<7.6, OS 18.1 vs 7.5 months, log-rank P = 0.010) and at 1 month after EVL (<5.7, OS 17.2 vs 7.5 months, log-rank P = 0.009) than lower max SUVmax. Multivariate Cox hazard regression analysis indicated that max SUVmax at 1 month after EVL is an independent predictor of both PFS and OS in patients treated with EVL although univariate regression analysis showed max SUVmax before EVL is a possible predictor.ConclusionsMax SUVmax assessed by FDG PET/CT prior to EVL and at 1 month after EVL treatment can accurately predict PFS and can guide decisions on whether to continue or change treatments for patients with EVL-treated RCC who suffer from adverse events.