Norihiko Tsuchiya

Significance of Serum N-glycan Profiling as a Diagnostic Biomarker in Urothelial Carcinoma

BACKGROUND The clinical diagnosis of urothelial carcinoma (UC) relies on invasive methods in patients with hematuria. Although more sensitive and noninvasive screening methods are required, a specific serum biomarker for UC is lacking. OBJECTIVE To examine whether serum glycan-based biomarkers can be applied to UC detection. DESIGN, SETTING, AND PARTICIPANTS Between April 1994 and June 2016, serum N-glycan concentrations were retrospectively measured in 212 patients with UC before treatment (UC group) and 212 pair-matched controls using glycoblotting and mass spectrometry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS N-glycan levels were compared between the groups using receiver operating characteristic curves to select candidate N-glycans. We created an N-glycan score based on the combination of candidate N-glycans. The specificity and sensitivity of the candidate N-glycan score were evaluated using receiver operating characteristic curves. RESULTS AND LIMITATIONS The N-glycan score was calculated using six N-glycans (m/z 1566, m/z 1687, m/z 1769, m/z 1871, m/z 2011, and m/z 2337) that were significantly associated with UC. The median N-glycan score was significantly higher in the UC group than in the pair-matched control group (5.0 vs 1.0, p<0.001). The N-glycan score correctly classified UC patients with a sensitivity, specificity, and area under the curve of 93%, 81%, and 0.95, respectively. The limitations of our study included its retrospective nature and nonclinical setting. CONCLUSIONS Serum N-glycan content has the potential to be a specific and sensitive novel serum biomarker that may improve the accuracy of the detection for UC and reduce unnecessary invasive screening. Validation of this test in a large-scale prospective study is needed. PATIENT SUMMARY Combination of serum N-glycan (N-glycan score) is a novel serum marker for urothelial carcinoma that is expressed by 93% of patients and thus is far more sensitive than classic urine cytology. Validation in a large patient cohort is needed.

Clinical implications of serum N-glycan profiling as a diagnostic and prognostic biomarker in germ-cell tumors

Serum biomarker monitoring is essential for management of germ‐cell tumors (GCT). However, not all GCT are positive for conventional tumor markers. We examined whether serum N‐glycan‐based biomarkers can be applied for detection and prognosis in patients with GCT. We performed a comprehensive N‐glycan structural analysis of sera from 54 untreated GCT patients and 103 age‐adjusted healthy volunteers using glycoblotting methods and mass spectrometry. Candidate N‐glycans were selected from those with the highest association; cutoff concentration values were established, and an N‐glycan score was created based on the number of positive N‐glycans present. The validity of this score for diagnosis and prognosis was analyzed using a receiver operating characteristic (ROC) curve. We identified five candidate N‐glycans significantly associated with GCT patients. The accuracy of the N‐glycan score for GCT was significant with an area‐under‐the‐curve (AUC) value of 0.87. Diagnostically, the N‐glycan score detected 10 of 12 (83%) patients with negative conventional tumor markers. Prognostically, the N‐glycan score comprised four candidate N‐glycans. The predictive value of the prognostic N‐glycan score was significant, with an AUC value of 0.89. A high value prognostic N‐glycan score was significantly associated with poor prognosis. Finally, to identify a potential carrier protein, immunoglobulin (Ig) fractions of sera were subjected to N‐glycan analysis and compared to whole sera. Candidate N‐glycans in Ig‐fractions were significantly decreased; therefore, the carrier protein for candidate N‐glycans is likely not an immunoglobulin. In summary, our newly developed N‐glycan score seems to be a practical diagnostic and prognostic method for GCT.

Cystometric evaluation of recovery in hypocompliant defunctionalized bladder as a result of long-term dialysis after kidney transplantation

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.

The pattern of GPI-80 expression is a useful marker for unusual myeloid maturation in peripheral blood

Myeloid‐derived suppressor cells (MDSCs) have a wide spectrum of immunosuppressive activity; control of these cells is a new target for improving clinical outcomes in cancer patients. MDSCs originate from unusual differentiation of neutrophils or monocytes induced by inflammatory cytokines, including granulocyte‐colony stimulating factor (G‐CSF) and granulocyte–macrophage (GM)‐CSF. However, MDSCs are difficult to detect in neutrophil or monocyte populations because they are not uniform cells, resembling both neutrophils and monocytes; thus, they exist in a heterogeneous population. In this study, we investigated GPI‐80, a known regulator of Mac‐1 (CD11b/CD18) and associated closely with neutrophil maturation, to clarify this unusual differentiation. First, we demonstrated that the mean fluorescence intensity (MFI) of GPI‐80 and coefficient of variation (CV) of GPI‐80 were increased by treatment with G‐CSF and GM‐CSF, respectively, using a human promyelocytic leukaemia (HL60) cell differentiation model. To confirm the value of GPI‐80 as a marker of unusual differentiation, we measured GPI‐80 expression and MDSC functions using peripheral blood cells from metastatic renal cell carcinoma patients. The GPI‐80 CV was augmented significantly in the CD16hi neutrophil cell population, and GPI‐80 MFI was increased significantly in the CD33hi monocyte cell population. Furthermore, the GPI‐80 CV in the CD16hi population was correlated inversely with the proliferative ability of T cells and the GPI‐80 MFI of the CD33hi population was correlated with reactive oxygen species production. These results led us to propose that the pattern of GPI‐80 expression in these populations is a simple and useful marker for unusual differentiation, which is related to MDSC functions.

Prognostic utility of seasonal changes for diagnosis of ureteral stones

Table 1 shows the results of the multivariate analysis with seven and eight (seven independent variables + seasonal factor) independent variables. All factors were associated with the presence of ureteral stones in the univariate analysis. The baseline and extended models were created with multiple logistic regression using each intercept and coefficient (Table 1). The optimal cut-off value of the ROC curves indicating the diagnostic performance of the baseline and extended models was 0.703. The AUC was 0.9667 [95% confidence interval (CI), 0.9448–0.9878] for the baseline model and 0.9737 (95% CI, 0.9553–0.9921) for the extended model. The sensitivity, specificity, PPV and NPV of the baseline model were 0.913, 0.962, 0.985, and 0.805, respectively, and those of the extended model were 0.983, 0.955, 0.983, and 0.955, respectively. Although both models were excellent for prediction of ureteral stones, the AUC for the extended model was significantly higher than that for the baseline model (p = 0.0057). Notably, the sensitivity improved from 0.913 to 0.983 and the NPV improved from 0.805 to 0.955 in the extended model after addition of the seasonal factor to the baseline model. The diagnostic performance between the baseline and extended models was compared with an arbitrary cut-off value of 0.703 using the continuous NRI and IDI methods. By incorporating the seasonal factor into the baseline model, 25 of 31 patients diagnosed with ureteral stones and classified as <0.703 were reclassified to a better category (≥0.703), and only one of 128 patients diagnosed with alternative disease and classified as <0.703 was reclassified incorrectly (≥0.703). This result suggests that the seasonal factor more effectively reclassified the patients with the ureteral stones without moving the patients with alternative diseases. The continuous NRI was 0.209 (95% CI, 0.074–0.343; p = 0.0023), and the IDI was 0.053 (95% CI, 0.035–0.072; p < 0.001), demonstrating that the extended Dear Editor,

Genetic Polymorphism Analysis in Predicting Prognosis of Advanced Prostate Cancer

The human genome project has revealed significant interindividual genomic variation, including over ten million single-nucleotide polymorphisms (SNP). The finding accelerated a large number of studies exploring genes involved in the predisposition of various types of cancer. Previous case-control studies or genome-wide association studies discovered hundreds of prostate cancer (PC)-associated genes. Meanwhile, clinical applications of the genetic polymorphisms have been investigated. Polymorphisms associated with early-onset aggressive phenotypes, prognosis of hormone-sensitive metastatic or castration-resistant prostate cancer, and outcomes after specific treatments are expected as useful markers, which are of great help in the therapeutic decision making of PC.

Incidence and location of positive surgical margin among open, laparoscopic and robot-assisted radical prostatectomy in prostate cancer patients: a single institutional analysis

Objective To evaluate the positive surgical margin rates and locations in radical prostatectomy among three surgical approaches, including open radical prostatectomy, laparoscopic radical prostatectomy and robot-assisted radical prostatectomy. Methods We retrospectively reviewed clinical outcomes at our institution of 450 patients who received radical prostatectomy. Multiple surgeons were involved in the three approaches, and a single pathologist conducted the histopathological diagnoses. Positive surgical margin rates and locations among the three approaches were statistically assessed, and the risk factors of positive surgical margin were analyzed. Results This study included 127, 136 and 187 patients in the open radical prostatectomy, laparoscopic radical prostatectomy and robot-assisted radical prostatectomy groups, respectively. The positive surgical margin rates were 27.6% (open radical prostatectomy), 18.4% (laparoscopic radical prostatectomy) and 13.4% (robot-assisted radical prostatectomy). In propensity score-matched analyses, the positive surgical margin rate in the robot-assisted radical prostatectomy was significantly lower than that in the open radical prostatectomy, whereas there was no significant difference in the positive surgical margin rates between robot-assisted radical prostatectomy and laparoscopic radical prostatectomy. In the multivariable analysis, PSA level at diagnosis and surgical approach (open radical prostatectomy vs robot-assisted radical prostatectomy) were independent risk factors for positive surgical margin. The apex was the most common location of positive surgical margin in the open radical prostatectomy and laparoscopic radical prostatectomy groups, whereas the bladder neck was the most common location in the robot-assisted radical prostatectomy group. The significant difference of positive surgical margin locations continued after the propensity score adjustment. Conclusions Robot-assisted radical prostatectomy may potentially achieve the lowest positive surgical margin rate among three surgical approaches. The bladder neck was the most common location of positive surgical margin in robot-assisted radical prostatectomy and apex in open radical prostatectomy and laparoscopic radical prostatectomy. Although robot-assisted radical prostatectomy may contribute to the reduction of positive surgical margin, dissection of the bladder neck requires careful attention to avoid positive surgical margins.

Can single positive core prostate cancer at biopsy be considered a low-risk disease?

PurposeProstate cancer (PCa) may be a multifocal or bilateral disease. A single positive biopsy core is usually associated with indolent PCa, and doctors may choose to perform active surveillance or focal therapy. We investigated the correlation between finding a single positive biopsy core and the pathological outcome after radical prostatectomy (RP).MethodsData from the Michinoku Japan Urological Cancer Study Group database including pre- and post-operative information, on 1928 consecutive patients with PCa treated with RP alone at four institutions was used. Among them, 503 patients with a single positive core PCa were followed up, and the clinical and pathological parameters influencing prognosis were analyzed.ResultsOf the 503 patients, 258 (51.3%) had pathological findings ≥ pT2c and 160 (32%) had an undergraded Gleason Score (GS) based on their biopsy findings. A total of 112 patients (39.5%) with clinical T1c developed bilateral tumors (pT2c–T3). The rate of developing pT3 tumors in the single positive core group was significantly higher than that of the multiple positive core group. Moreover, there was no significant difference in the number of pT3b patients between the single and multiple positive core PCa groups.ConclusionsBased on analysis of radical prostatectomy specimens, positive core PCa can lead to clinically significant disease, with considerable rates of pT3. For patients with PCa and a positive prostate biopsy core, definitive therapy such as RP should be considered.

Pazopanib-induced crystal deposition in intestinal mucosa in a patient with retroperitoneal liposarcoma

Pazopanib was administered to a 44‐year‐old man with local recurrence of retroperitoneal liposarcoma. Computed tomography showed an intestinal edema, which gradually progressed 15 months after pazopanib administration although he had no clinical symptoms. Upper gastrointestinal endoscopy implicated marked edematous hypertrophy of the Kerklings fold. Pathological findings showed crystal deposition and fat accumulation, without a malignant component. All these abnormal findings resolved after pazopanib discontinuation.

Levels of 4EBP1/eIF4E Activation in Renal Cell Carcinoma Could Differentially Predict Its Early and Late Recurrence

Micro‐Abstract A subset of patients who undergo curative surgery for localized clear cell renal cell carcinoma (ccRCC) will experience early or late recurrence. Tumor viability depends on protein synthesis via the eukaryotic initiation factor (eIF)4E‐binding protein 1 (4EBP1/eIF4E) axis. Activation levels of the axis in ccRCC tissues could differentially affect tumor recurrence and the timing of recurrence after curative nephrectomy. Background The objective was to explore the predictive markers of late recurrence (LR) > 5 years after curative nephrectomy for renal cell carcinoma (RCC). Patients and Methods We retrospectively examined the data from 303 patients with localized clear cell RCC treated surgically at our institution from 1993 to 2011. Activation of the eukaryotic initiation factor (eIF)4E‐binding protein 1 (4EBP1)/eIF4E axis at the mammalian target of rapamycin complex 1 (mTORC1) was evaluated in the tumor specimens. Weak, intermediate, and strong immunohistochemistry staining grades were defined for 4EBP1, phosphorylated 4EBP1, and eIF4E. The effects of clinicopathologic factors and activation level grades on tumor recurrence were analyzed using multivariate Cox regression models. To validate the present findings, we investigated clinical data from The Cancer Genome Atlas and protein/phosphoprotein data from corresponding patients from The Cancer Proteome Atlas. Results Of the 303 patients, 31 and 16 patients developed early recurrence (ER, ≤ 5 years) and LR, respectively. The activation levels were comparable among the subcategories of pathologic TN stage, Fuhrman grade, and microvascular and capsular invasion. Pathologic stage ≥ T1b, Fuhrman grade 3/4, and an intermediate or strong activation level correlated significantly with overall recurrence and ER. Strong activation of the axis and pathologic stage ≥ T1b were identified as independent predictors of LR. Only 2 patients with weak activation experienced recurrence (1 each with ER and LR). Similar results were confirmed by the analyses of The Cancer Genome Atlas and The Cancer Proteome Atlas data. Conclusion The activation level of the axis in RCC tissues could independently predict for recurrence and differentially affect the timing of recurrence.