Although docetaxel-based chemohormonal therapy (CHT) is one of the standard treatments for castration-resistant prostate cancer (CRPC), pertinent biomarkers and precise mechanisms involved in the ...resistance for CHT for CRPC remain unknown. We investigated the relationship between chemohormonal resistance and the expression of steroid receptors and Hippo pathway proteins using a docetaxel-resistant prostate cancer (PCa) cell line and human PCa tissues in patients who underwent surgery with and without neoadjuvant therapy.
A docetaxel-resistant subline (22Rv1-DR) was generated to assess Hippo pathway protein expression and the effect of YAP1 inhibition on cellular characteristics. A tissue microarray with 203 cores from 70 high-risk localized PCa tissues was performed to assess steroid receptor and Hippo pathway protein expressions.
Nuclear YAP (nYAP) expression was higher in 22RV-1-DR than in parental 22Rv-1 and YAP1 knockdown suppressed cell proliferation of 22Rv1-DR. Steroid receptor and Hippo pathway protein expressions varied among three different neoadjuvant groups, and nYAP1 expression was the highest in the CHT group. The patients with high nYAP in residual cancer after neoadjuvant CHT had a significantly higher biochemical recurrence (BCR) rate than those with low nYAP1. On multivariate analysis, the high nYAP1 was an independent prognostic factor for BCR.
nYAP expression is a potential biomarker in high-risk patients treated with docetaxel-based CHT. Steroid receptors and Hippo pathway proteins may play a role in the chemohormonal resistance in advanced PCa.
Objectives
To evaluate the association of tumor burden with the prognosis in real‐world patients with metastatic castration‐sensitive prostate cancer and to investigate the eligibility for upfront ...intensification therapy.
Methods
We retrospectively evaluated 679 patients with metastatic castration‐sensitive prostate cancer who were initially treated with conventional androgen deprivation therapy between August 2001 and November 2018. The primary purpose was to investigate the eligibility for upfront intensification therapy based on the progression of metastatic castration‐resistant prostate cancer. The secondary purpose included the comparison of the metastatic castration‐resistant prostate cancer progression rate, metastatic castration‐resistant prostate cancer‐free survival and overall survival after castration‐resistance in CHAARTED low‐ or high‐volume disease patients.
Results
The number of patients with metastatic castration‐resistant prostate cancer progression was 119 (52%) and 319 (71%) in the low‐ and high‐volume disease groups, respectively. The metastatic castration‐resistant prostate cancer progression rate (P < 0.001) and castration‐resistant prostate cancer‐free survival (P < 0.001) were significantly different between the low‐ and high‐volume disease groups, but no difference was found for overall survival after castration resistance (P = 0.363). Multivariate Cox regression analysis showed no significant association between tumor burden and overall survival after castration resistance (P = 0.522; hazard ratio 1.14).
Conclusions
The progression rate in metastatic castration‐resistant prostate cancer patients with the low‐volume disease under conventional androgen deprivation therapy is approximately 50%. Upfront intensification therapy might be beneficial for approximately half of patients with low‐volume disease. A novel maker to predict the castration‐resistant status is required to select optimal patients for upfront intensification therapy.
This study investigated pharmacokinetic and pharmacogenetic differences between a modified-release once-daily formulation of tacrolimus (Tac-QD) and the original formulation requiring twice-daily ...intake (Tac-BID) in de novo renal transplant recipients.
Forty-seven and 25 patients who received Tac-BID and Tac-QD, respectively, were enrolled. The pharmacokinetics and CYP3A5 6986A>G and ABCB1 3435C>T pharmacogenetics of each formulation were analyzed on day 28 posttransplantation.
The dose-adjusted trough level (C0) and area under the concentration-time curve (AUC0-24) of tacrolimus were approximately 25% lower for Tac-QD than Tac-BID. However, there was a good correlation between the AUC0-24 and C0 in the Tac-BID and Tac-QD groups (r=0.575, P<0.001; and r=0.638, P<0.001, respectively) and a similar coefficient in each regression equation. The dose-adjusted AUC0-24 was approximately 25% lower in carriers of the CYP3A*1 allele (CYP3A5 expressers), but not individuals with the CYP3A*3/*3 genotype (nonexpressers), for TAC-QD than Tac-BID. In the Tac-QD group, the interpatient variability for dose-adjusted parameters was small, and the interquatile ranges of dose-adjusted parameters differed between CYP3A5 expressers and nonexpressers and did not overlap. The ABCB1 polymorphism was not associated with any pharmacokinetic parameters of Tac-QD.
C0-guided monitoring may lead to similar AUC0-24 values for both formulations. However, to maintain the same AUC0-24 value, a higher dose of Tac-QD than Tac-BID may be needed, especially for CYP3A5 expressers, in the early stage posttransplantation. The narrow interindividual variability of Tac-QD pharmacokinetics and its difference between CYP3A5 expressers and nonexpressers might contribute to a dosing strategy based on CYP3A5 genotype.
Myeloid-derived suppressor cells (MDSCs), which include neutrophilic MDSCs and monocytic MDSCs, exhibit high immunosuppressive activity. Glycosylphosphatidylinositol-anchored 80 kD protein (GPI-80) ...is selectively expressed on mature neutrophils in healthy individuals. Increased GPI-80 expression on monocytes and variations in GPI-80 expression on neutrophils indicate the appearance of MDSCs in the peripheral blood of cancer patients. However, it is still unclear whether GPI-80 expression on myeloid cells, neutrophilic MDSCs and monocytic MDSCs, is correlated with the clinical outcomes of patients with cancer. In this study, we investigated the characteristics of myeloid cells expressing GPI-80 and the implication of GPI-80 expression in the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC), in which primary renal cell carcinoma spreads from the kidney to other organs. The study included 20 patients with mRCC (a mean age of 66.0 years) and 16 healthy volunteers (a mean age of 47.8 years). To determine the heterogeneity of myeloid cells in peripheral blood samples, we performed the three-dimensional principal component analysis using the combination of GPI-80, CD16, and latency-associated peptide-1 (LAP), derived from the N-terminal region of transforming growth factor-β1 precursor. The results showed that myeloid cells in mRCC patients were widely distributed and clearly distinguishable from those in the healthy volunteers. The survival analysis revealed that GPI-80 expression on neutrophils and monocytes was correlated with poor prognostic outcomes of patients with mRCC. In conclusion, the expression of GPI-80 on myeloid cells, a useful index for the heterogeneity of MDSCs, serves as a potential prognostic biomarker for mRCC.
The regulation of the redox balance in the tumor microenvironment is thought to be an adaptive response of tumor cells to hypoxic environments. In recent years, it has been reported that the ...hemoglobin β-chain (HBB), which is involved in scavenging reactive oxygen species (ROS), is expressed in several carcinomas. However, the relationship between HBB expression and the prognosis of renal cell carcinoma (RCC) remains unclear.
HBB expression was immunohistochemically analyzed in 203 nonmetastatic clear cell RCC (ccRCC) cases. Cell proliferation, invasion, and ROS production were measured in ccRCC cell lines treated with HBB-specific siRNA.
The prognosis of HBB-positive patients was worse than that of HBB-negative patients. Cell proliferation and invasion were inhibited, and ROS production was increased by treatment with HBB-specific siRNA. Oxidative stress increased HBB expression in cells exposed to H
O
.
HBB expression in ccRCC contributes to cancer cell proliferation by suppressing ROS production under hypoxic conditions. Taken together with clinical results and in vitro experiments, HBB expression may serve as a new prognostic biomarker for RCC in the future.
Objectives
The utility of brain metastasis screening in asymptomatic metastatic renal cell carcinoma is controversial. Our study evaluated the utility of routine head computed tomography during ...systemic therapy.
Methods
We retrospectively investigated 152 metastatic renal cell carcinoma patients who did not initially have brain metastasis at Yamagata University Hospital from January 2008 to July 2019. Patients who routinely received head computed tomography scan together with routine contrast‐enhanced chest/abdominal/pelvic computed tomography scan every 2–4 months during systemic therapy (“Routine head computed tomography” group, n = 95) and patients without routine head computed tomography (“No routine head computed tomography” group, n = 57) were compared.
Results
Brain metastasis occurred in 16 patients in the “Routine head computed tomography” group and six patients in the “No routine head computed tomography” group. There was no statistical difference in overall survival after metastatic renal cell carcinoma diagnosis between groups (53.4 vs 37.3 months, respectively, P = 0.357) and neurological symptom‐free survival after metastatic renal cell carcinoma diagnosis (53.4 vs 36.6 months, P = 0.336). Although there was no statistical difference on incidence of unrecovered neurological symptom (25.0% vs 50.0%, P = 0.334), fewer patients in the “Routine head computed tomography” group required craniotomy (0% vs 66.7%, P = 0.002). In the “No routine head computed tomography” group, the neurological symptom resolved for all patients without craniotomy.
Conclusions
Routine head computed tomography during systemic therapy for metastatic renal cell carcinoma is not significantly associated with improved brain metastasis prognosis. However, routine head computed tomography enables brain metastasis diagnosis in the asymptomatic phase, which can avoid craniotomy.
Objectives
To evaluate the functional recovery of a pretransplant hypocompliant bladder in patients without neurological disorders, and to determine its relationship with ureteral complications, ...including vesicoureteral reflux.
Methods
A total of 61 patients without neurogenic disorders, who underwent video water cystometry pre‐ and 1 year post‐transplantation, were enrolled. Cystometric bladder capacity and maximum intravesical pressure were measured, and compliance was calculated by the elevation in intravesical pressure as a result of an increase in volume. The frequencies of urinary complications, including urinary leakage, pyelonephritis and vesicoureteral reflux, were also evaluated.
Results
Pretransplant dialysis duration correlated with pretransplant bladder capacity and compliance (R2 = 0.421, P < 0.001 and R2 = 0.418, P < 0.001, respectively). A total of 16 (26.2%) patients had hypocompliant bladders <10 mL/cmH2O, whereas 10 of the 12 patients (83.3%) with pretransplant dialysis duration of more than 5 years had a pretransplant hypocompliant bladder. Bladder compliance significantly recovered to >20 mL/cmH2O (21.1–286.0) at 1 year post‐transplantation in all 16 patients with a pretransplant hypocompliant bladder. No significant differences were observed for urinary leakage, pyelonephritis or vesicoureteral reflux between patients with and without a pretransplant hypocompliant bladder.
Conclusions
Bladder compliance decreases logarithmically pretransplantation according to dialysis duration. Although the ability of the patients to recover varies, dysfunctions associated with a pretransplant hypocompliant bladder recover to normal ranges after renal transplantation. A pretransplant hypocompliant bladder seems not to be associated with the post‐transplant prevalence of urinary complications or vesicoureteral reflux.
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