Ichiro Ikeda

Plasma Free Amino Acid Profiling of Five Types of Cancer Patients and Its Application for Early Detection

Background Recently, rapid advances have been made in metabolomics-based, easy-to-use early cancer detection methods using blood samples. Among metabolites, profiling of plasma free amino acids (PFAAs) is a promising approach because PFAAs link all organ systems and have important roles in metabolism. Furthermore, PFAA profiles are known to be influenced by specific diseases, including cancers. Therefore, the purpose of the present study was to determine the characteristics of the PFAA profiles in cancer patients and the possibility of using this information for early detection. Methods and Findings Plasma samples were collected from approximately 200 patients from multiple institutes, each diagnosed with one of the following five types of cancer: lung, gastric, colorectal, breast, or prostate cancer. Patients were compared to gender- and age- matched controls also used in this study. The PFAA levels were measured using high-performance liquid chromatography (HPLC)–electrospray ionization (ESI)–mass spectrometry (MS). Univariate analysis revealed significant differences in the PFAA profiles between the controls and the patients with any of the five types of cancer listed above, even those with asymptomatic early-stage disease. Furthermore, multivariate analysis clearly discriminated the cancer patients from the controls in terms of the area under the receiver-operator characteristics curve (AUC of ROC >0.75 for each cancer), regardless of cancer stage. Because this study was designed as case-control study, further investigations, including model construction and validation using cohorts with larger sample sizes, are necessary to determine the usefulness of PFAA profiling. Conclusions These findings suggest that PFAA profiling has great potential for improving cancer screening and diagnosis and understanding disease pathogenesis. PFAA profiles can also be used to determine various disease diagnoses from a single blood sample, which involves a relatively simple plasma assay and imposes a lower physical burden on subjects when compared to existing screening methods.

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.

Loss of Heterozygosity at the p53, RB, DCC and APC Tumor Suppressor Gene Loci in Human Bladder Cancer

PURPOSE Allelic losses within several tumor suppressor genes have been detected frequently in various types of human cancer. We investigated the roles and possible interactions of the tumor suppressor genes p53, Rb, DCC and APC in bladder cancer. MATERIALS AND METHODS Loss of heterozygosity (LOH) of these 4 genes was examined in 45 human bladder cancers by polymerase chain reaction and restriction fragment length polymorphism assay. RESULTS Of the evaluated cases, LOH was seen at P53 in 38%, at Rb in 22%, at DCC in 36% and at APC in 6% of tumors. Loss of heterozygosity at p53 and Rb was predominantly observed in high grade (grade 3) and/or invasive (T2 or greater) tumors, whereas LOH at DCC was present irrespective of tumor grade and stage. Allelic losses at either p53, Rb, DCC or APC were seen in 82% of high grade tumors, but in only 21% of low grade (grade 1 and 2) tumors (p<0.005). Similarly, 71% of invasive tumors had LOH at one or more loci compared with 20% of superficial (Ta and T1) tumors (p<0.005). Interestingly, p53-LOH and Rb-LOH were often observed simultaneously in the same tumor. CONCLUSIONS These results suggest that loss of the p53, Rb and/or DCC genes is involved in most of the late and some of the early steps of bladder carcinogenesis.

DNA polymerase β gene mutations in human bladder cancer

We examined 24 human bladder cancer tissues for possible mutations in the entire coding region of the human DNA polymerase β gene using polymerase chain reaction analysis, single‐strand conformational polymorphism analysis of RNA, and sequence analysis. DNA polymerase β gene mutations were observed in four of the 24 cases (16.7%) and included three missense point mutations and a single base insertion. The single base insertion was also observed in our previous study of human prostate cancer, suggesting that this region may be a hot spot for mutation of the DNA polymerase β gene. No clinical or pathological association was found among the four cases that contained the mutation. Three of the four cases with DNA polymerase β gene mutation had mutations of the p16 or RB genes or loss of heterozygosity of the p53 and APC gene loci. The results of the study presented here suggest that DNA polymerase β gene mutations, in combination with mutations of tumor suppressor genes, may be involved in certain cases of human bladder cancer.

Case of Vesico-Appendiceal Fistula Secondary to Mucinous Adenocarcinoma of the Appendix

We present a rare case of vesico-appendiceal fistula secondary to mucinous adenocarcinoma of the appendix. Transurethral biopsy of the bladder revealed a mucinous adenocarcinoma of probable colonic origin. Adenocarcinoma of the appendix that directly invaded the bladder was diagnosed preoperatively by air-contrast barium enema, colonoscopy and magnetic resonance imaging. When one encounters a case of adenocarcinoma of the bladder suspected to be of colonic origin, one should examine the colon and rectum as well as the appendix and cecum.

Prognostic significance of Ki-67 labeling index in urothelial tumors of the renal pelvis and ureter.

PURPOSE We evaluated the prognostic significance of the Ki-67 labeling index in 70 patients with primary urothelial tumors of the renal pelvis and ureter. MATERIALS AND METHODS Immunohistochemical staining for Ki-67 in archival tumor materials was done by the streptavidin-biotin method. RESULTS Univariate survival analysis showed that the prognosis of patients with a high Ki-67 labeling index of 21.7 or more was significantly worse than that of patients with an intermediate labeling index of 13.3 to less than 21.7 (p < 0.01) or a low labeling index of less than 13.3 (p < 0.001). Multivariate survival analysis showed that staining for Ki-67 labeling index was significantly correlated with prognosis (p < 0.01). CONCLUSIONS Analysis of Ki-67 labeling index provides useful prognostic information about patients with primary urothelial tumors of the renal pelvis and ureter.

Nomogram for overall survival of Japanese patients with bone-metastatic prostate cancer

BackgroundWe analyzed the relationship between prostate cancer outcomes and pretreatment clinical factors and developed a prognostic nomogram of overall survival (OS) of patients with bone metastasis.MethodsFrom 1993 to 2011, 463 consecutive patients were treated for bone-metastatic prostate cancer. Data sets from 361 patients were used to develop a nomogram (training data), and data sets of 102 patients were used for validation of the nomogram (validation data). Using the external validation data set, the nomogram was assessed for discriminatory ability, and the predictions were assessed for calibration accuracy by plotting actual survival against predicted risk.ResultsOf the 361 patients in the training data set, 205 (56.8%) patients died, 169 (46.8%) deaths of which were due to prostate cancer. The median follow-up period was 55.2 months. In the multivariate analysis, patient age, serum prostate-specific antigen level, clinical T stage, extent of disease on bone scan, and biopsy Gleason sum were independent prognostic factors. We developed a prognostic model comprising these five factors for patients with bone-metastatic prostate cancer. This nomogram can be used to estimate 1-, 3-, and 5-year survival probability. External validation of this model using 102 validation data sets showed reasonable accuracy (concordance index, 0.719).ConclusionOur pretreatment prognostic nomogram might be useful for Japanese patients with bone-metastatic prostate cancer.

Cyclin-dependent kinase inhibitor p27Kip1 expression in transitional cell carcinoma of renal pelvis and ureter

We examined the expression and significance of p27(Kip1) protein in 79 patients with transitional cell carcinoma of the renal pelvis and ureter. Immunohistochemical staining of archival tissue specimens was done using a labeled streptavidin-biotin-peroxidase method. There was no significant association between p27(Kip1) labeling index and histologic grade or pathologic stage. Patients with p27(Kip1) labeling indices of 27 or greater had more favorable prognoses in comparison to those with p27(kip1) labeling indices less than 27 (P<0.01). Multivariate analysis indicated that p27(Kip1) had an independent predictive prognostic value (P<0.05). The p27(Kip1) may be a novel prognostic marker for transitional cell carcinoma of the renal pelvis and ureter.

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.

Cardiac metastasis of renal pelvic cancer.

Abstract:  A 66‐year‐old man was referred to our hospital with chest discomfort and shortness of breath. Seven months previously he had undergone a laparoscopic left nephroureterectomy for a left renal pelvic tumor and was given two cycles of adjuvant chemotherapy (methotrexate, epirubicin and cisplatin). Echocardiogram showed an 8‐mm sized mass extending from the right atrium into the right ventricle. On computed tomography, multiple lung tumors, as well as the right atrial and ventricular mass, were seen. The patient died of acute heart failure caused by right ventricular outflow obstruction. On autopsy, a right atrial and ventricular metastasis of the initial transitional cell carcinoma was found. The patient’s cause of death was acute heart failure as a result of cardiac metastasis of his initial renal pelvic carcinoma.