Objective
To confirm the reproducibility of the effectiveness and safety in photodynamic diagnosis of non‐muscle‐invasive bladder cancer using 5‐aminolevulinic acid in a prospective multicenter ...non‐randomized phase III trial.
Methods
A total of 61 patients with primary or recurrent non‐muscle‐invasive bladder cancer were prospectively enrolled from five hospitals between May 2015 and March 2016. 5‐Aminolevulinic acid (20 mg/kg) was orally administered 3 h before transurethral resection of bladder tumors using white light or fluorescent light. Of 60 evaluable patients, 511 specimens were obtained from tumor‐suspicious lesions and normal‐looking mucosa. The primary end‐point was sensitivity. The secondary end‐points were specificity, positive and negative predictive values, and safety.
Results
The sensitivity of the fluorescent light source (79.6%) was significantly higher (P < 0.001) than that of the white light source (54.1%). In total, 25.4% (46/181) of tumor specimens were diagnosed as positive with only the fluorescent light source. In nine (15%) of 60 patients, the risk classification and recommended treatment after transurethral resection of bladder tumors were changed depending on the additional types of tumor diagnosed by the fluorescent light source. The specificity of the fluorescent light versus white light source was 80.6% versus 95.5%. No grade 4–5 adverse event was noted. Hypotension and urticaria were severe adverse events whose relationship to oral 5‐aminolevulinic acid could not be excluded.
Conclusions
These findings confirm the diagnostic efficacy and safety of photodynamic diagnosis with 20 mg/kg of oral 5‐aminolevulinic acid, and show that transurethral resection of bladder tumors with a fluorescent light source using oral 5‐aminolevulinic acid is well tolerated.
Background
Pembrolizumab is effective in a limited number of patients with advanced urothelial carcinoma (UC). Therefore, we evaluated the prognostic value of clinical biomarkers following ...pembrolizumab treatment in patients with advanced UC.
Methods
We retrospectively reviewed the medical records of 121 patients with platinum-refractory advanced UC who received pembrolizumab. Inflammation-based prognostic scores before and 6 weeks after the treatment were recorded. The categorical variables influencing overall survival (OS) and objective response rate (ORR) were analyzed.
Results
Multivariate analyses showed that pretreatment Eastern Cooperative Oncology Group (ECOG) performance score (PS), presence of only lymph node metastasis (only LN mets), C-reactive protein (CRP), and neutrophil/lymphocyte ratio (NLR) were independent prognostic factors for OS (
P
= 0.0077; RR = 2.42,
P
= 0.0049; RR = 0.36,
P
= 0.0047; RR = 2.53, and
P
= 0.0079; RR = 2.33, respectively). The pretreatment risk stratification using ECOG PS, only LN mets, CRP, and NLR was used for estimating the OS (
P
< 0.0001) and ORR (
P
< 0.0001). Furthermore, changes in NLR in response to pembrolizumab were significantly associated with the OS (
P
= 0.0002) and ORR (
P
= 0.0023). This change was also significantly correlated with OS even in the high-risk group stratified by this pretreatment risk stratification (
P
= 0.0069).
Conclusions
This pretreatment risk stratification may be used for estimating the OS and ORR of patients with advanced UC treated with pembrolizumab. If changes in NLR in response to pembrolizumab treatment improve, pembrolizumab should be continued.
Radical cystectomy remains the standard treatment for muscle-invasive bladder cancer; however, a substantial number of patients with muscle-invasive bladder cancer are not appropriate candidates to ...radical cystectomy due to co-morbidities or anxiety regarding bladder preservation. Trimodal bladder-sparing therapy is an intelligent and attractive treatment option for such patients. We established a novel treatment strategy using trimodal treatment with gemcitabine and cisplatin.
Patients diagnosed with muscle-invasive bladder cancer by transurethral resection of bladder tumor and who wished for bladder preservation were recruited. The regimens were gemcitabine 300 mg/m2 and cisplatin 30 mg/m2 in day 1 and concomitant irradiation 1.8 Gy/Fr, five fractions per week. Irradiation was administered to the true pelvis up to 36 Gy and was then boosted to the entire bladder until a total of 54 Gy. Transurethral resection of bladder tumor was also performed after chemoradiotherapy to evaluate pathological response to treatment. We evaluated treatment efficacy and survival, safety of chemoradiotherapy with gemcitabine and cisplatin.
Thirty-eight patients were enrolled, and three patients were excluded. Pathological complete response after chemoradiotherapy was observed in 31 patients, and the 5-year bladder-intact metastasis-free survival rate was 76%. The 5-year cancer-specific and overall survival rates for chemoradiotherapy were 85 and 75%, respectively, which were not significantly different from those for radical cystectomy (73 and 71%, respectively). Grade 3/4 adverse events included neutropenia (63%), anemia (18%) and thrombocytopenia (37%); however, treatment-related deaths were not observed.
Chemoradiotherapy using gemcitabine and cisplatin for muscle-invasive bladder cancer is effective for local cancer control and shows no significant difference in oncological prognosis compared with radical cystectomy.
CD44, a major surface receptor for hyaluronic acid, has multiple isoforms and represents a major cancer stem cell marker for various epithelial tumors. CD44 variant 9 (CD44v9) was correlated with ...recurrence and metastasis in gastric and colon cancer. We examined its role in invasion and as a biomarker for the basal muscle invasive molecular subtype showing worse prognosis, and for tumor progression in high risk (pT1/high grade) non‑muscle invasive bladder cancers (NMIBCs). CD44v9, cytokeratin 5/6 (CK5/6), and cytokeratin 20 (CK20) expression was evaluated by immunohistochemistry in 98 pathologically confirmed specimens (36 muscle and 62 high‑risk non‑muscle) and correlated to clinical outcome. In vitro analysis was performed using two human bladder cancer cell lines (HT1376 and 5637). The CD44v9 high‑expressing group exhibited significantly lower progression‑free and cancer‑specific survival rates in both muscle (P=0.0349 and 0.0382, respectively) and non‑muscle (P=0.0002 and 0.0079) invasive patients. CD44v9 expression was significantly correlated with CK5/6 (P<0.001), colocalizing at the muscle invasion front but distinctly separated from CK20 in non‑muscle invasion. CD44 and CD44v9 siRNA knockdown demonstrated significantly lower Matrigel invasion ability and significantly shorter migration distance (all P<0.01). CD44 and CD44v9 knockdown increased E‑cadherin and decreased N‑cadherin, snail, and slug epithelial‑mesenchymal transition marker protein expression. Thus, higher CD44v9 expression was associated with worse prognosis, likely impacting invasion and migration via the epithelial‑mesenchymal transition. Together, these findings suggest that CD44v9 expression might be a useful predictive biomarker in basal‑type muscle and high-risk NMIBC.
To identify potential therapeutic target in clear cell renal cell carcinoma (ccRCC), we performed a transcriptome analysis. Our analysis showed that fatty acid binding protein 7 (FABP7) has the ...highest mean differential overexpression in ccRCC compared to normal kidney. We aimed to investigate the significance of FABP7 in ccRCC.
Immunohistochemical staining for 40 advanced ccRCC cases was performed to investigate correlation between clinicopathological parameters and FABP7. They were composed of 40-83 years old cases with 33 male, 22 cases with pT ≥ 3, 19 cases with M1, and 16 cases with grade 3. The effect of gene knockdown was analysed by a cell viability assay and invasion assay in FABP7-overexpressing cell lines (SKRC7 and SKRC10).
Our immunohistochemical analysis showed that higher FABP7 expression significantly correlated with distant metastasis and poor cancer-specific survival (CSS; both p < 0.05). Functional suppression of FABP7 significantly inhibited SKRC10 cell growth (p < 0.05) and resulted in a significant reduction of the invasive potential (p < 0.01), but did not cause growth inhibition of SKRC7 cells. We found that The Cancer Genome Atlas Research Network (TCGA) database shows FABP6 and 7 as equally overexpressed in the FABP family. Functional suppression of fatty acid binding protein 6 (FABP6) resulted in significant growth inhibition of SKRC7 cells (p < 0.005).
Functional suppression of FABP7 significantly reduced cell viability and invasive potential in a ccRCC cell line. FABP7 may play a role in progression in some metastatic ccRCCs. The suppressed function may be compensated by another FABP family member.
p53 immunohistochemistry is considered an accurate surrogate marker reflecting the underlying TP53 mutation status and has utility in tumor diagnostics. In the present study, 269 primary CRCs were ...immunohistochemically evaluated for p53 expression to assess its utility in diagnostic pathology and prognostication. p53 expression was wild-type in 59 cases (23%), overexpressed in 143 cases (55%), completely lost in 50 cases (19%), and cytoplasmic in 10 cases (4%). p53 immunoreactivity was associated with tumor size (p = 0.0056), mucus production (p = 0.0015), and mismatch repair (MMR) system status (p < 0.0001). Furthermore, among CRCs with wild-type p53 expression, a significantly higher number of cases had decreased CDX2 than those with p53 overexpression (p = 0.012) or complete p53 loss (p = 0.043). In contrast, among CRCs with p53 overexpression, there were significantly fewer ALCAM-positive cases than p53 wild-type cases (p = 0.0045). However, no significant association was detected between p53 immunoreactivity and the “stem-like” immunophenotype defined by CDX2 downregulation and ALCAM-positivity. Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio HR = 0.17, p < 0.0001), younger age (HR = 0.52, p = 0.021), and female sex (HR = 0.55, p = 0.046) as potential favorable factors. The analysis also revealed complete p53 loss (HR = 2.16, p = 0.0087), incomplete resection (HR = 2.65, p = 0.0068), and peritoneal metastasis (HR = 5.32, p < 0.0001) as potential independent risk factors for patients with CRC. The sub-cohort survival analyses classified according to chemotherapy after surgery revealed that CRC patients with wild-type p53 expression tended to have better survival than those with overexpression or complete loss after chemotherapy. Thus, immunohistochemistry for p53 could be used for the prognostication and chemotherapy target selection of patients with CRC.
Aseptic abscesses (AAs) are extraintestinal manifestations of inflammatory bowel disease (IBD). IBD-associated AAs are rare in Japan. We treated a 45-year-old man with ulcerative colitis ...(UC)-associated AAs. During remission, multiple progressive abscesses were detected in the spleen; he underwent splenectomy because an infectious disease was suspected. Although his condition improved temporarily after splenectomy, a large liver abscess was noted, and a diagnosis of UC-associated AAs was made. Granulocytapheresis (GCAP) and infliximab (IFX) administration resolved the abscess. This is the first reported case of UC-associated AAs in a Japanese patient treated by splenectomy, GCAP, and IFX.
Objective Vonoprazan (VPZ), clarithromycin (CAM), metronidazole (MNZ) and VPZ, MNZ, and sitafloxacin (STFX) regimen are all established Helicobacter pylori eradication therapies for patients with ...penicillin allergy in Japan. However, no study has assessed the efficacy of a VPZ, CAM, and MNZ (VCM) regimen in patients with clarithromycin resistance (CAM-R). We therefore assessed the efficacy of a VCM regimen for treating H. pylori infection in patients with CAM-R and penicillin allergy. Methods Fifty-three patients with penicillin allergy who received H. pylori eradication therapy were retrospectively analyzed. Eight patients received a 7-day proton-pump inhibitor, CAM, and MNZ (PCM) regimen; 35 patients 11 CAM-R, and 10 with clarithromycin sensitivity (CAM-S) received 7-day VCM regimens; and 10 patients received 7-day VPZ, MNZ, and STFX (VMS) regimens. A 13C-urea breath test was used to determine eradication. The efficacy of eradication was evaluated via both intention-to-treat (ITT) and per-protocol (PP) analyses. Results According to ITT and PP analyses, eradication rates (ERs) with PCM, VCM, and VMS therapies were 50.0% and 50.0%, 94.3% and 100%, and 90% and 90%, respectively. Treatment was successful in all patients with CAM-S. For patients with CAM-R, treatment was successful in 10 patients, and 1 patient discontinued treatment owing to an adverse event. According to ITT and PP analyses, ERs were 90.9% and 100% in CAM-R, and were 100% and 100% in CAM-S, respectively. Conclusion The VCM regimen for H. pylori eradication may be a viable candidate therapy for patients with penicillin allergy, regardless of CAM-R.
Dysregulation of mitochondrial quality control has been reported to be associated with cancer and degenerative diseases. SPATA18 (spermatogenesis-associated 18, also known as Mieap) encodes a ...p53-inducible protein that can induce lysosome-like organelles within mitochondria that eliminate oxidized mitochondrial proteins and has tumor suppressor functions in mitochondrial quality control. In the present study, 268 primary colorectal cancers (CRCs) were evaluated immunohistochemically for SPATA18 expression to assess its predictive utility and its association with cellular proliferation activity. Furthermore, the association with p53 immunoreactivity, a surrogate marker for TP53 mutation, was analyzed. Non-neoplastic colonic mucosa showed cytoplasmic SPATA18 expression. Seventy-two percent of the lesions (193/268) displayed high SPATA18 expression in the cytoplasm of CRC cells. Univariate analyses revealed significant associations between SPATA18 expression and tumor size (p < 0.0001), histological differentiation (p = 0.0017), and lymph node metastasis (p = 0.00039). The log-rank test revealed that patients with SPATA18-high CRCs had significantly better survival than SPATA18-low patients (p < 0.0001). Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio HR = 0.25), age < 70 years (HR = 0.50), and SPATA18-high (HR = 0.55) as potential favorable factors. Lymph node metastasis (HR = 1.98) and peritoneal metastasis (HR = 5.45) were cited as potential independent risk factors. Cellular proliferation activity was significantly higher in SPATA18-high tumors. However, no significant correlation was detected between SPATA18 expression and p53 immunoreactivity or KRAS/BRAF mutation status. On the basis of our observations, SPATA18 immunohistochemistry can be used in the prognostication of CRC patients.
Abstract Background Incidence rate of renal cell carcinoma (RCC) differs among countries. The rates of Asian countries are lower than those of countries in North America or Europe but are ...exceptionally high in Japanese males. Approximately 30% of patients with RCC have metastasis at initial diagnosis, and another 30% have metastasis after nephrectomy. Clinical studies of risk factors in patients with metastatic RCC (mRCC) are mainly based on data from non-Asian patients. Objectives We aimed to investigate the prognosis of Japanese patients and their prognostic factors. Design, setting, and participants The subjects of this study were 1463 patients who were clinically diagnosed with RCC with metastasis in 40 Japanese hospitals between January 1988 and November 2002. Measurements The primary end point was overall survival calculated from first diagnosis of mRCC to death or last follow-up. We also investigated the relationship between survival and clinical features. Results and limitations The median overall survival time was 21.4 mo. The estimated survival rates at 1, 3, 5, and 10 yr were 64.2%, 35.2%, 22.5%, and 9.1%, respectively; they contrasted with data from the United States of 54%, 19%, 10%, and 6%, respectively for the same periods. A high percentage of patients had undergone nephrectomy (80.5%) and metastasectomy (20.8%), both of which were shown to prolong survival. Conclusions The median survival time in the present study was approximately twice as long as that of previous studies from North America or Europe. Early diagnosis of metastasis, nephrectomy, metastasectomy, and cytokine-based therapy seemed to improve the prognosis of RCC patients in the present study.
PDF
