ABSTRACT
OBJECTIVES: We investigated the clinical outcomes of radical cystectomy without cisplatin-based neoadjuvant chemotherapy (NAC) and identified factors affecting the effectiveness of cisplatin-based adjuvant chemotherapy (AC). METHODS: Between September 2002 and February 2020, 288 bladder cancer patients who did not receive NAC underwent radical cystectomy. We retrospectively analyzed the recurrence rates, primary recurrence sites, recurrence-free survival (RFS), and overall survival (OS) of 115 advanced bladder cancer patients (pT3-4 or pN1-3) who were divided into the AC and observation groups. Subgroup analysis was performed, focusing on pathological stage. RESULTS: In total, 51 patients received AC, and 64 patients were observed. The median follow-up duration was 95 months. The recurrence rate was lower in the AC group than in the observation group (35.3% vs. 54.7%, p = 0.041). The rate of recurrences in the lymph node area (dissection site and proximal lymph nodes) was lower in the AC group (9.8% vs. 26.6%; p = 0.031). In the subgroup analysis of patients with pN1, the probability of RFS and OS was higher in the AC group than in the observation group. The hazard ratio for RFS and OS was 0.243 (95% confidence interval [CI]: 0.077-0.768) and 0.259 (95% CI: 0.082-0.816), respectively. The 5-year RFS and OS were significantly higher in the AC group (80.0% and 79.4%) than in the observation group (35.7% and 42.9%; p < 0.008 and p < 0.012, respectively). CONCLUSIONS: AC improved RFS and OS in patients with pN1 disease who did not receive NAC and should be considered for this population.
Subject(s)
Cisplatin , Cystectomy , Neoplasm Recurrence, Local , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/surgery , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/mortality , Urinary Bladder Neoplasms/therapy , Retrospective Studies , Male , Female , Chemotherapy, Adjuvant/statistics & numerical data , Chemotherapy, Adjuvant/methods , Aged , Middle Aged , Neoplasm Recurrence, Local/epidemiology , Neoplasm Recurrence, Local/prevention & control , Cisplatin/administration & dosage , Cisplatin/therapeutic use , Neoplasm Staging , Lymph Nodes/pathology , Lymphatic Metastasis , Treatment Outcome , Neoadjuvant Therapy/methods , Disease-Free SurvivalABSTRACT
BACKGROUND: Microsatellite instability (MSI) is a key marker for predicting the response of immune checkpoint inhibitors (ICIs) and for screening Lynch syndrome (LS). AIM: This study aimed to see the characteristics of cancers with high level of MSI (MSI-H) in genetic medicine and precision medicine. METHODS: This study analyzed the incidence of MSI-H in 1000 cancers and compared according to several clinical and demographic factors. RESULTS: The incidence of MSI-H was highest in endometrial cancers (26.7%, 20/75), followed by small intestine (20%, 3/15) and colorectal cancers (CRCs)(13.7%, 64/466); the sum of these three cancers (15.6%) was significantly higher than that of other types (2.5%)(P < 0.0001). MSI-H was associated with LS-related cancers (P < 0.0001), younger age (P = 0.009), and family history, but not with smoking, drinking, or serum hepatitis virus markers. In CRC cases, MSI-H was significantly associated with a family history of LS-related cancer (P < 0.0001), Amsterdam II criteria [odds ratio (OR): 5.96], right side CRCs (OR: 4.89), and multiplicity (OR: 3.31). However, MSI-H was very rare in pancreatic (0.6%, 1/162) and biliary cancers (1.6%, 1/64) and was null in 25 familial pancreatic cancers. MSI-H was more recognized in cancers analyzed for genetic counseling (33.3%) than in those for ICI companion diagnostics (3.1%)(P < 0.0001). Even in CRCs, MSI-H was limited to 3.3% when analyzed for drug use. CONCLUSIONS: MSI-H was predominantly recognized in LS-related cancer cases with specific family histories and younger age. MSI-H was limited to a small proportion in precision medicine especially for non-LS-related cancer cases.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms/genetics , Medical History Taking/statistics & numerical data , Microsatellite Instability , Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Female , Humans , Incidence , Male , Middle Aged , Precision MedicineABSTRACT
OBJECTIVES: To determine the incidence and location of lower extremity deep vein thrombosis in patients undergoing radical cystectomy. METHODS: We performed radical cystectomy in 137 patients with bladder cancer between August 2014 and February 2020. Since 2014, we have had a policy to screen for deep vein thrombosis using lower extremity ultrasonography both before and after radical cystectomy. We determined the incidence and location of deep vein thrombosis and classified it as either proximal or distal type. Furthermore, we explored the incidence of pulmonary embolism within 3 months after radical cystectomy. RESULTS: After excluding six patients with a lack of ultrasonographic data, we evaluated 131 patients. Preoperative deep vein thrombosis (one proximal and 17 distal) was diagnosed in 18 patients (14%) with no symptoms. Postoperative deep vein thrombosis was diagnosed in 41 patients (31%; three proximal and 38 distal), of whom 26 (63%) had new-onset deep vein thrombosis after cystectomy. Three patients, two with proximal and one with distal type deep vein thrombosis, developed nonfatal pulmonary embolism postoperatively. Multivariate analysis showed that preoperative D-dimer levels (odds ratio 5.35, 95% confidence interval 1.74-16.50; P < 0.003), type of urinary diversion (ileal neobladder; odds ratio 11.15, 95% confidence interval 2.16-57.55; P = 0.004), and preoperative deep vein thrombosis (odds ratio 15.93, 95% confidence interval 3.82-66.30; P < 0.001) were significant risk factors for postoperative deep vein thrombosis. CONCLUSIONS: Pre- and post-radical cystectomy whole-leg ultrasonography can lead to an early perioperative diagnosis and immediate treatment of proximal deep vein thrombosis, thereby potentially preventing fatal pulmonary embolism.
Subject(s)
Urinary Bladder Neoplasms , Urinary Diversion , Venous Thrombosis , Cystectomy/adverse effects , Humans , Incidence , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Postoperative Complications/surgery , Urinary Bladder Neoplasms/complications , Urinary Diversion/adverse effects , Venous Thrombosis/diagnostic imaging , Venous Thrombosis/epidemiology , Venous Thrombosis/etiologyABSTRACT
Background Immune-related hepatotoxicity is often regarded as immune-related hepatitis (irHepatitis) despite including immune-related sclerosing cholangitis (irSC). This study examined the clinical differences between irSC and irHepatitis. Methods A single-center retrospective study of 530 consecutive patients who received immunotherapy between August 2014 and April 2020 was performed. IrSC and irHepatitis were respectively defined as the radiological presence and absence of bile duct dilation and wall thickness. Results Forty-one patients (7.7%) developed immune-related hepatotoxicity. A CT scan was performed on 12 patients, including 11 of 12 with ≥ grade 3 aminotransferase elevations. IrSC and irHepatitis were diagnosed in 4 (0.8%) and 8 (1.5%) patients, respectively. All the irSC patients had been treated with anti-PD-1. IrHepatitis was more common among patients receiving anti-CTLA-4 than among those receiving anti-PD-1/PD-L1 inhibitors (14%, 7/50 vs. 0.2%, 1/480, P < 0.001). A ≥ grade 2 alkaline phosphatase (ALP) elevation resulting in a cholestatic pattern was seen in all 4 irSC patients. Among the irSC patients, 3 (3/4, 75%) developed ≥ grade 3 aminotransferases elevation. The median duration from the start of immunotherapy until ≥ grade 2 liver enzymes elevation was 257 and 55.5 days in irSC and irHepatitis patients. The median times for progression from grade 2 to 3 liver enzyme elevation were 17.5 and 0 days, respectively. Conclusions IrSC and irHepatitis have different characteristics in the class of immune checkpoint inhibitor and onset pattern. Radiological examination for the diagnosis of irSC should be considered for patients with ≥ grade 2 ALP elevation resulting in a cholestatic pattern. (Registration number J2020-36, Date of registration June 3, 2020).
Subject(s)
Cholangitis, Sclerosing/chemically induced , Cholangitis, Sclerosing/pathology , Hepatitis/etiology , Hepatitis/pathology , Immune Checkpoint Inhibitors/adverse effects , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cholangitis, Sclerosing/diagnostic imaging , Cholangitis, Sclerosing/immunology , Female , Hepatitis/diagnostic imaging , Hepatitis/immunology , Humans , Immune Checkpoint Inhibitors/therapeutic use , Male , Middle Aged , Neoplasms/drug therapy , Retrospective Studies , Tomography, X-Ray Computed , Transaminases/bloodABSTRACT
This study aimed to establish the Japanese Cancer Genome Atlas (JCGA) using data from fresh frozen tumor tissues obtained from 5143 Japanese cancer patients, including those with colorectal cancer (31.6%), lung cancer (16.5%), gastric cancer (10.8%) and other cancers (41.1%). The results are part of a single-center study called "High-tech Omics-based Patient Evaluation" or "Project HOPE" conducted at the Shizuoka Cancer Center, Japan. All DNA samples and most RNA samples were analyzed using whole-exome sequencing, cancer gene panel sequencing, fusion gene panel sequencing and microarray gene expression profiling, and the results were annotated using an analysis pipeline termed "Shizuoka Multi-omics Analysis Protocol" developed in-house. Somatic driver alterations were identified in 72.2% of samples in 362 genes (average, 2.3 driver events per sample). Actionable information on drugs that is applicable in the current clinical setting was associated with 11.3% of samples. When including those drugs that are used for investigative purposes, actionable information was assigned to 55.0% of samples. Germline analysis revealed pathogenic mutations in hereditary cancer genes in 9.2% of samples, among which 12.2% were confirmed as pathogenic mutations by confirmatory test. Pathogenic mutations associated with non-cancerous hereditary diseases were detected in 0.4% of samples. Tumor mutation burden (TMB) analysis revealed 5.4% of samples as having the hypermutator phenotype (TMB ≥ 20). Clonal hematopoiesis was observed in 8.4% of samples. Thus, the JCGA dataset and the analytical procedures constitute a fundamental resource for genomic medicine for Japanese cancer patients.
Subject(s)
Biomarkers, Tumor/genetics , Databases, Factual , Mutation , Neoplasms/genetics , Female , Gene Expression Profiling , Genomics/methods , Humans , Japan , Male , Oligonucleotide Array Sequence Analysis , Precision Medicine , Exome SequencingABSTRACT
BACKGROUND: Skeletal-related events (SRE) are common in patients with renal cell carcinoma (RCC) that includes bone metastasis. The purpose of this study was to clarify the effectiveness of zoledronate with and without sunitinib, combined with radiotherapy, for the treatment of bone metastasis from RCC. METHODS: We retrospectively analyzed 62 RCC patients with bone metastasis, who had been treated with radiotherapy at our institution. We divided the study cohort into two groups: patients treated with radiotherapy alone (RT; n = 27) and those treated with radiotherapy combined with zoledronate (RT + Z; n = 35). We investigated the overall survival and post-irradiation (PI)-SRE-free rate for each group, as well as the effect of sunitinib in the RT + Z treatment group. In addition, we determined treatment effectiveness by imaging assessments and relative response rates. RESULTS: There was no significant difference in the survival rates between the RT and RT + Z treatment groups (p = 0.11). However, the PI-SRE-free rate in the RT + Z group was significantly higher than that in the RT group (p = 0.02). The PI-SRE-free rate was significantly higher in patients who were treated with sunitinib after radiotherapy than in those who were treated without sunitinib (p = 0.03). However, there was no significant difference in the relative response rates, as assessed by imaging, in each group. CONCLUSION: Radiotherapy combined with zoledronate is an effective treatment for RCC with bone metastasis to prevent PI-SRE. Sunitinib may reduce PI-SRE if used after radiotherapy and combined with zoledronate.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Neoplasms/therapy , Carcinoma, Renal Cell/therapy , Chemoradiotherapy , Fractures, Spontaneous/prevention & control , Kidney Neoplasms/therapy , Spinal Cord Compression/prevention & control , Adult , Aged , Aged, 80 and over , Bone Neoplasms/secondary , Carcinoma, Renal Cell/pathology , Female , Humans , Kidney Neoplasms/pathology , Male , Middle Aged , Retrospective Studies , Sunitinib/administration & dosage , Survival Rate , Treatment Outcome , Zoledronic Acid/administration & dosageABSTRACT
Persistent androgen synthesis under castration status in adrenal gland, testes and tumor cells is thought to be one of the major causes of development and progression of castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA), the prodrug of abiraterone, which is an inhibitor of androgen synthesis enzymes, was evaluated for pharmacokinetics, pharmacodynamics, preliminary efficacy and safety in Japanese patients with CRPC in a phase-1, open-label and dose-escalation study. Chemotherapy-naïve Japanese CRPC patients (N = 27) received one of four AA daily doses (250 mg [n = 9], 500 mg [n = 6], 1000 [1 h premeal] mg [n = 6] and 1000 [2 h postmeal] mg [n = 6]) continuously through 28-day treatment cycles. In the first cycle, AA monotherapy was given on days 1-7 for pharmacokinetics, and AA plus prednisone (5 mg twice daily) from days 8 to 28. Of 27 patients, 9 continued treatment with AA until the data cut-off date (18 July 2013). Over the evaluated dose range, plasma abiraterone concentrations increased with dose, with median tmax 2-3 h. At each dose level, mean serum corticosterone concentrations increased, while testosterone and dehydroepiandrosterone sulfate concentrations rapidly decreased following a single AA dose and were further reduced to near the quantification limit on day 8 regardless of the dose. At least 3 patients from each dose-group experienced ≥50% prostate-specific antigen reduction, suggesting clinical benefit from AA in Japanese CRPC patients. AA was generally well-tolerated, and, therefore, the recommended AA dosage regimen in Japanese CRPC patients is 1000 mg oral dose under modified fasting conditions (at least 1 h premeal or 2 h postmeal). This study is registered at ClinicalTrials.gov: NCT01186484.
Subject(s)
Androstadienes/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Steroid 17-alpha-Hydroxylase/antagonists & inhibitors , Abiraterone Acetate , Aged , Aged, 80 and over , Androstadienes/adverse effects , Androstenes , Androstenols/blood , Humans , Male , Middle Aged , Prostate-Specific Antigen/blood , Prostatic Neoplasms, Castration-Resistant/bloodABSTRACT
In January 2005, a 66-year-old man underwent radical cystectomy and ileal neobladder reconstruction for invasive bladder cancer. A total of 3 years after the cystectomy, left-side ureteral cancer was diagnosed, and a nephroureterectomy was carried out in May 2008. In October 2011, he complained of asymptomatic macroscopic hematuria. We detected multiple papillary pedunculated and broad-based tumors in the left side and the dome of the neobladder. The patient underwent transurethral resection of the bladder tumor, and a pathological diagnosis of high-grade pTa urothelial carcinoma was made. A total of 4 months later, tumors recurred in the right side and anterior wall of the neobladder. We carried out transurethral resection of the bladder tumor again; the pathological diagnosis was high-grade pTa urothelial carcinoma with carcinoma in situ. Bacillus Calmette-Guérin instillation was carried out seven times into the neobladder, without any severe side-effects. Tumor recurrence was not observed up to 8 months after bacillus Calmette-Guérin treatment.
Subject(s)
Adjuvants, Immunologic/therapeutic use , BCG Vaccine/therapeutic use , Carcinoma, Transitional Cell/drug therapy , Neoplasms, Second Primary/drug therapy , Urinary Bladder Neoplasms/drug therapy , Aged , Carcinoma, Transitional Cell/surgery , Cystectomy , Humans , Ileum/transplantation , Male , Urinary Bladder/surgery , Urinary Bladder Neoplasms/surgery , Urinary DiversionABSTRACT
Testicular epidermoid cysts have characteristic findings. Testicular tumor markers are negative in patients with epidermoid cysts. Clear margins and sole and small testicular tumors (20 mm or less) suggest the possibility of epidermoid cyst. Testicular-sparing surgery with intraoperative frozen section examination should be performed when suspecting epidermoid cysts. Testicular epidermoid cysts are rare tumors that account for 1% of all testicular tumors and are often clinically misdiagnosed as malignant lesions. We report three cases of epidermoid cysts. The chief manifestations were scrotal induration in two patients and pruritus scrotum in one. The median age of the patients was 23 years (18-30). All tumors were determined to be sole lesions (<20 mm in diameter). Testing for tumor markers in all patients revealed negative results. We could not rule out malignancy; hence, we performed high inguinal orchiectomy in all cases. Histologically, the inner walls of the cysts were lined with stratified squamous epithelium; their contents were keratinized. All patients were diagnosed with epidermoid cysts.
ABSTRACT
Objectives: This study aimed to evaluate the cumulative incidence of upper tract urothelial carcinoma (UTUC) recurrence and identify its risk factors in patients who underwent radical cystectomy (RC). Patients and methods: We performed RC on 385 patients between September 2002 and February 2020. After excluding 20 patients-13 with simultaneous nephroureterectomy, 6 with distal ureteral stump positivity and 1 with urachal cancer-365 patients were included in the analysis. To predict UTUC recurrence, we examined the cancer extension pattern in cystectomy specimens and categorized them into three types: cancer located only in the bladder (bladder-only type), cancer extending to the urethra or distal ureter (one-extension type) and cancer extending to both the urethra and distal ureter (both-extension type). We determined hazard ratios for UTUC recurrence for each covariate, including this cancer extension pattern. Results: Of the 365 patients, 60% had the bladder-only type, 30% had the one-extension type and 10% had the both-extension type. During a median follow-up period of 72 months for survivors, UTUC recurred in 25 of the 365 patients, with cumulative incidences of 3.7% at 5 years and 8.3% at 10 years. The median interval from cystectomy to recurrence was 65 months (interquartile range: 36-92 months). In the multivariate analysis, the extension pattern was a significant predictor of UTUC recurrence. The hazard ratios for UTUC recurrence were 3.12 (95% confidence interval [CI] = 1.15-8.43, p = 0.025) for the one-extension type and 5.96 (95% CI = 1.98-17.91, p = 0.001) for the both-extension type compared with the bladder-only type. Conclusions: The cancer extension pattern in cystectomy specimens is predictive of UTUC recurrence. A more extensive cancer extension in cystectomy specimens elevates the risk of subsequent UTUC recurrence. Intensive long-term monitoring is essential, particularly for patients with the both-extension type.
ABSTRACT
BACKGROUND/AIM: Recently, inactivating somatic mutations of SWI/SNF chromatin-remodeling genes in cancers have been reported. However, few studies have been performed regarding the immunological analysis of the tumor microenvironment (TME) in chromatin remodeling complex gene-mutated tumors. In the present study, we identified cancer patients harboring various mammalian SWI/SNF complex mutations and investigated the immunological features in those mutated cancers. PATIENTS AND METHODS: Cancer patients harboring any type of chromatin remodeling complex gene mutation were selected and clinicopathological features were compared between chromatin remodeling complex gene expression-low and expression-high groups. Specifically, expression levels of immune response-associated genes and cancer-associated genes were compared between the SMARCA4 expression-low and expression-high groups using volcano plot analysis. RESULTS: Among cancers harboring PBRM1, SAMRACA4 and ARID2 gene mutations, T-cell marker and mature B-cell marker genes were up-regulated in the tumor. Specifically, T-cell effector genes (CD8B, CD40LG), central memory marker genes (CD27, CCR7) and mature B-cell marker genes (CD20, CD38, CD79 and IRF4) were up-regulated, and cancer-associated genes including MYB, MYC and AURKB genes were down-regulated in the SMARCA4 expression-low group. Remarkably, heatmap of gene expression and immunohistochemistry (IHC) data demonstrated that the tertiary lymphoid structure (TLS) gene signature of mature B cells was up-regulated in SMACA4 gene-mutated stomach cancers. CONCLUSION: These results suggest that immune tumor microenvironment status, such as mature B cell recruitment featuring the TLS gene signature and immune activation mediated by cancer signal down-regulation, might contribute to the classification of SMARCA4 gene-mutated tumors as immune checkpoint blockade therapy-sensitive target tumors.
Subject(s)
Neoplasms , Tumor Microenvironment , Animals , Humans , Tumor Microenvironment/genetics , Mutation , Neoplasms/genetics , Mammals , DNA Helicases/genetics , Nuclear Proteins/genetics , Transcription Factors/geneticsABSTRACT
Tivozanib is a potent and selective inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases. A previous clinical trial in the EU and USA indicated that tivozanib at the maximum tolerated dose of 1.5 mg/day showed an antitumor activity in patients with renal cell carcinoma. This Japanese phase I study was designed to determine the recommended phase II dose of tivozanib for Japanese patients; secondary objectives included pharmacokinetic/pharmacodynamic profiles and preliminary efficacy. Daily treatment with tivozanib in a 3-weeks-on/1-week-off cycle was examined in nine Japanese patients with advanced solid tumors in the 3 + 3 design (Level 1, 1.0 mg; Level 2, 1.5 mg). No dose-limiting toxicity was observed throughout the study, and the maximum tolerated dose was not reached. The most commonly observed drug-related adverse events were diarrhea, dysphonia, rash, thyroid stimulating hormone increase, and with severity grade ≥3, hand-foot skin reaction, hypertension, and proteinuria. Those adverse events were generally well-manageable and mostly resolved within the tolerability evaluation period. Serum exposure to tivozanib resulted in t1/2 of more than >60 h. Increase of plasma VEGF and decrease of plasma VEGFR-1 and VEGFR-2 were observed 1-3 weeks after tivozanib treatment. Although no complete or partial response was observed, long-term stable disease continuing more than 170 days was observed in three renal cell carcinoma patients who had failed prior VEGFR inhibitors. In conclusion, 1.5 mg/day of tivozanib in a 3-weeks-on/1-week-off setting was tolerable in Japanese patients, and was recommended for further clinical trials in the Japanese population. Clinical trial Registration No: JapicCTI-090854.
Subject(s)
Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Neoplasms/enzymology , Phenylurea Compounds/adverse effects , Phenylurea Compounds/therapeutic use , Quinolines/adverse effects , Quinolines/therapeutic use , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Antineoplastic Agents/adverse effects , Asian People , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Neoplasms/blood , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Treatment Outcome , Vascular Endothelial Growth Factor A/blood , Vascular Endothelial Growth Factor Receptor-1/blood , Vascular Endothelial Growth Factor Receptor-2/bloodABSTRACT
BACKGROUND: We investigated the safety, pharmacokinetics, tumor response, and immunological parameters of sorafenib plus interferon α-2b [corrected] (IFN) in Japanese patients with advanced RCC. PATIENTS AND METHODS: After 2 weeks of IFN-alone treatment, eligible patients received 28-day cycles of continuous sorafenib 200 mg (Cohort 1) or 400 mg (Cohorts 2 and 3) twice daily combined with intramuscular IFN 6 (Cohorts 1 and 2) or 9 (Cohort 3) million international units (MIU) three times a week. RESULTS: A total of 18 patients received at least one dose of sorafenib plus IFN. Five patients had dose-limiting toxicities (DLTs). The most common DLT was fatigue, experienced in four DLT patients. All 18 patients experienced at least one treatment-emergent adverse event (AE). The most common treatment-emergent AEs included fatigue, fever, platelets, leukocytes, hemoglobin, weight loss and anorexia. Five patients had confirmed partial response and 11 had stable disease, a response rate of 27.8%. IFN had no relevant impact on the pharmacokinetics of sorafenib. CONCLUSIONS: Sorafenib administered in combination with IFN was well tolerated, with promising results in efficacy. Continuous sorafenib 400 mg twice daily in combination with IFN 6 MIU three times a week is recommended in Japanese patients with advanced RCC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Renal Cell/drug therapy , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Asian People , Benzenesulfonates/administration & dosage , Benzenesulfonates/blood , Benzenesulfonates/pharmacokinetics , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Female , Humans , Immunologic Factors/administration & dosage , Interferon-alpha/administration & dosage , Male , Middle Aged , Neoplasm Metastasis , Niacinamide/analogs & derivatives , Phenylurea Compounds , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/blood , Protein Kinase Inhibitors/pharmacokinetics , Pyridines/administration & dosage , Pyridines/blood , Pyridines/pharmacokinetics , Sorafenib , Tumor Burden/drug effectsABSTRACT
A Phase III clinical trial has been started in Japan to determine the optimal treatment strategy for patients with high-grade pT1 bladder cancer who have pT0 histology after second transurethral resection. The aim of this trial is to demonstrate the non-inferiority of relapse-free survival (excluding Tis or Ta intravesical recurrence) for watchful waiting compared with intravesical bacillus Calmette-Guérin therapy for pT0 after second transurethral resection. Patients with high-grade pT1 bladder cancer at the first registration and pT0 after second transurethral resection at the second registration are randomized to either a watchful waiting arm or an intravesical bacillus Calmette-Guérin therapy arm. A total of 575 patients at the first registration and 260 patients at the second registration will be accrued for this study from 38 institutions over 5 years. The primary endpoint is relapse-free survival (excluding Tis or Ta intravesical recurrence), and the secondary endpoints are overall survival, metastasis-free survival with bladder preserved, annual proportion of intravesical relapse-free survival, annual proportion of T2 or deeper relapse-free survival, adverse events and serious adverse events.
Subject(s)
BCG Vaccine/therapeutic use , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder/drug effects , Watchful Waiting , Administration, Intravesical , Asian People , BCG Vaccine/administration & dosage , Follow-Up Studies , Humans , Japan , Medical Oncology , Neoplasm Grading , Neoplasm Recurrence, Local , Neoplasm Staging , Survival Analysis , Treatment Outcome , Urinary Bladder/pathology , Urinary Bladder/surgery , Urinary Bladder Neoplasms/ethnology , Urinary Bladder Neoplasms/surgeryABSTRACT
OBJECTIVE: To assess the efficacy and safety of everolimus in Japanese patients with metastatic renal cell carcinoma. METHODS: A subgroup analysis of the pivotal Phase III, randomized, double-blind, placebo-controlled trial of everolimus 10 mg/day in patients with disease progression after treatment with sorafenib, sunitinib or both assessed outcomes in Japanese participants. Results were compared with those for the overall study population. RESULTS: The final trial analysis included 24 Japanese patients (everolimus, n= 15; placebo, n = 9). Median progression-free survival in the Japanese subpopulation was 5.75 months (95% confidence interval, 4.90 months to not reached) with everolimus and 3.61 months (95% confidence interval, 1.91-9.03 months) with placebo (hazard ratio, 0.19; 95% confidence interval, 0.05-0.83). Median overall survival was not reached with everolimus and was 14.9 months (95% confidence interval, 11.0-16.8 months) with placebo (hazard ratio, 0.30; 95% confidence interval, 0.07-1.27). Overall, efficacy and safety were similar when comparing the Japanese and overall populations. In the Japanese subpopulation, the most common adverse events with everolimus were stomatitis, infections and rash. Four Japanese subjects (27%) developed Grade 1 (n = 2) or 2 (n = 2) pneumonitis (all reversible and allowing for continuation of therapy, after interruption, steroids and dose reduction for both Grade 2 cases), with a lower pneumonitis incidence of 14% in the overall population (albeit associated with a Grade 3 incidence of 4%). CONCLUSIONS: These findings suggest that the demonstrated benefits of everolimus in the overall trial population are similar in Japanese patients with metastatic renal cell carcinoma.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Sirolimus/analogs & derivatives , Adult , Aged , Carcinoma, Renal Cell/secondary , Disease-Free Survival , Double-Blind Method , Drug Administration Schedule , Everolimus , Female , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Incidence , International Cooperation , Japan , Kidney Neoplasms/pathology , Male , Middle Aged , Odds Ratio , Pneumonia/epidemiology , Prospective Studies , Sirolimus/administration & dosage , Sirolimus/adverse effects , Treatment OutcomeABSTRACT
OBJECTIVES: The purpose of this study was to retrospectively analyze the characteristics of patients with retroperitoneal sarcoma and to examine pathological findings, first site of recurrence and recurrence free-survival after surgery. METHODS: From June 2003 to May 2010, we performed 10 surgeries for retroperitoneal sarcomas. We chose 9 tumors after excluding 1 tumor that had already disseminated in the abdominal cavity. We examined patient characteristics, pathological findings and the first site of recurrence (local or distant metastasis). We also analyzed recurrence-free survival after surgery with the Kaplan-Meier method. RESULTS: The patients' median age was 60 years (31-71 years), and the median tumor diameter was 10.0 cm (2.7-45 cm). Pathological diagnosis revealed 7 cases of dedifferentiated liposarcoma and 2 cases of leiomyosarcoma. En-block resection with adjacent organs was achieved in 8 of 9 patients. During follow-up, 5 of 9 patients experienced tumor local recurrence. There were no cases in which distant metastases appeared before local recurrence. The median duration between surgery and local recurrence was 13 months (3-27 months). The median duration from surgery to death was 30 months (5-78 months). CONCLUSIONS: Although we resected adjacent organs together when we could not achieve a sufficient margin, the rate of local recurrence after surgery for retroperitoneal sarcoma was high. Given this result using treatment with surgery alone, it is necessary to prospectively establish multimodal treatments with chemotherapy and radiotherapy to reduce local tumor recurrence.
Subject(s)
Retroperitoneal Neoplasms/pathology , Sarcoma/pathology , Adult , Aged , Disease-Free Survival , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local , Retroperitoneal Neoplasms/mortality , Retrospective Studies , Sarcoma/mortalityABSTRACT
A 55-year-old man who presented himself with gross hematuria and right back pain was found to have a right renal mass with evidence of metastasis to the lymph nodes, bone and lung (cT1bN1M1). He underwent a transperitoneal right nephrectomy. Tumor expressed markers of CD10, P504S and CK19 immunohistochemically, so histopathological examination revealed tubulocystic carcinoma of the right kidney (pT3a). After the patient received sunitinib therapy, computed tomography revealed reduction in the size of the metastatic lung nodule and lymph nodes, indicating a partial response. He is alive without disease progression at 12 months after nephrectomy. Tubulocystic carcinoma has been referred to by Amin et al as low-grade collecting duct carcinoma and is not yet included in the World Health Organization (WHO) 2004 classification of renal tumors. The cells lining the tumor range from cuboidal to columnar and have large nuclei with low-grade changes and abundant eosinophilic or amphophilic cytoplasm. Hobnail cells are commonly seen. Immunohistochemically, tubulocystic carcinomas are strongly positive for markers of the proximal nephron (CD10, P504S) and the distal nephron (parvalbumin, CK19). Despite a low nuclear grade, tubulocystic carcinomas occasionally show progressive behavior clinically. Although there is no established salvage therapy, sunitinib was found to be effective for this patient.
Subject(s)
Carcinoma, Renal Cell/pathology , Biomarkers, Tumor/analysis , Carcinoma, Renal Cell/surgery , Humans , Immunohistochemistry , Kidney Neoplasms/pathology , Kidney Neoplasms/surgery , Male , Middle AgedABSTRACT
(Objectives) We evaluated the association between immune-related adverse events (irAEs) and the efficacy of pembrolizumab therapy in patients with metastatic urothelial carcinoma. (Methods) Data of 42 patients with metastatic urothelial carcinoma treated with pembrolizumab between May 2018 and February 2020 were retrospectively analyzed to determine the association between irAEs and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). (Results) IrAEs were observed in 19 patients (45.2%). Objective response was observed in 15 patients (35.7%). Thirteen (68.4%) of 19 patients who experienced irAEs showed an objective response, whereas two (8.70%) of 23 patients who did not experience irAEs (odds ratio: 15.0, 95% confidence interval [CI]: 1.70-738, P=0.006). PFS and OS in the irAE group were longer than those in the non-irAE group (PFS: hazard ratio: 0.24, 95% CI: 0.11-0.54, P<0.001; OS: hazard ratio: 0.11, 95% CI: 0.03-0.37, P<0.001). (Conclusions) During pembrolizumab treatment, the occurrence of irAEs was significantly associated with higher response and survival prolongation in patients with metastatic urothelial carcinoma.
ABSTRACT
Project High-tech Omics-based Patient Evaluation (HOPE), which used whole-exome sequencing and gene expression profiling, was launched in 2014. A total of ~2,000 patients were enrolled until March 2016, and the survival time was observed up to July 2019. In our previous study, a tumor microenvironment immune type classification based on the expression levels of the programmed death-ligand 1 (PD-L1) and CD8B genes was performed based on four types: A, adaptive immune resistance; B, intrinsic induction; C, immunological ignorance; and D, tolerance. Type A (PD-L1+ and CD8B+) exhibited upregulated features of T helper 1 antitumor responses. In the present study, survival time analysis at 5 years revealed that patients in type A had a better prognosis than those in other categories [5 year survival rate (%); A (80.5) vs. B (73.9), C (73.4) and D (72.6), P=0.0005]. Based on the expression data of 293 immune response-associated genes, 62 specific genes were upregulated in the type A group. Among these genes, 18 specific genes, such as activated effector T-cell markers (CD8/CD40LG/GZMB), effector memory T-cell markers (PD-1/CD27/ICOS), chemokine markers (CXCL9/CXCL10) and activated dendritic cell markers (CD80/CD274/SLAMF1), were significantly associated with a good prognosis using overall survival time analysis. Finally, multivariate Cox proportional hazard regression analyses of overall survival demonstrated that four genes (GZMB, HAVCR2, CXCL9 and CD40LG) were independent prognostic markers, and GZMB, CXCL9 and CD40LG may contribute to the survival benefit of patients in the immune type A group.
ABSTRACT
BACKGROUND: In a phase II, open-label, multicentre Japanese study, sunitinib demonstrated antitumour activity and acceptable tolerability in metastatic renal cell carcinoma patients. Final survival analyses and updated results are reported. METHODS: Fifty-one Japanese patients with a clear-cell component of metastatic renal cell carcinoma (25 treatment-naïve; 26 cytokine-refractory) received sunitinib 50 mg orally, once daily (Schedule 4/2). Overall and progression-free survivals were estimated by the Kaplan-Meier method. Objective response rate (per Response Evaluation Criteria in Solid Tumours) and safety were assessed with an updated follow-up. RESULTS: First-line and pretreated patients received a median 6.0 and 9.5 treatment cycles, respectively. Investigator-assessed, end-of-study objective response rate was 52.0, 53.8 and 52.9% in first-line, pretreated and overall intent-to-treat populations, respectively. The median progression-free survival was 12.2 and 10.6 months in first-line and pretreated patients, respectively. Fourteen patients per group died (56 and 54%), and the median overall survival was 33.1 and 32.5 months, respectively. The most common treatment-related Grade 3 or 4 adverse events and laboratory abnormalities were fatigue (24%), hand-foot syndrome (18%), decreased platelet count (55%), decreased neutrophil count (53%) and increased lipase (49%). No Grade 5 treatment-related adverse events occurred. Forty patients (78%) required dose reduction, and 13 (25%) discontinued, due to treatment-related adverse events. CONCLUSIONS: With the median overall survival benefit exceeding 2.5 years, and acceptable tolerability, in first-line and pretreated Japanese metastatic renal cell carcinoma patients with Eastern Cooperative Oncology Group performance status 0/1, sunitinib showed a favourable risk/benefit profile, similar to Western studies. However, there was a trend towards greater efficacy and more haematological adverse events in Japanese patients.