After the introduction of prostate cancer screening with the prostate-specific antigen (PSA) test, we have witnessed a dramatic stage migration. As a result, an increasing number of patients are diagnosed at earlier stages and receive local treatments including surgery or radiation. When these local treatments fail by the definition of increasing PSA levels, patients are usually treated with androgen-deprivation therapy. A fraction of these patients will finally reach a state of castration-resistant prostate cancer (CRPC) even without radiological evidence of metastasis, which is referred to as nonmetastatic CRPC (NM-CRPC). Most men with advanced or metastatic prostate cancer initially respond to various types of androgen ablation, but a considerable portion of them eventually progress to NM-CRPC. Among patients with NM-CPRC, about one-third will develop bone metastasis within 2 years. In these patients, PSA kinetics is the most powerful indicator of progression and is usually used to trigger further imaging studies and enrollment in clinical trials. Although CRPC remains largely driven by the androgen receptor, the benefit of second-line hormonal manipulations, including first-generation antiandrogens, adrenal synthesis inhibitors, and steroids, has not been investigated in men with NM-CRPC. To date, denosumab is the only agent that has been shown to delay the onset of bone metastasis. However, overall survival did not differ. In treating NM-CRPC patients, physicians should recognize the heterogeneity of the disease and acknowledge that the recently approved second-line treatments have been studied only in advanced stages of the disease.
Androgen Antagonists ; Humans ; Kinetics ; Male ; Mass Screening ; Neoplasm Metastasis ; Population Characteristics ; Prostate* ; Prostate-Specific Antigen ; Prostatic Neoplasms* ; Prostatic Neoplasms, Castration-Resistant ; Receptors, Androgen ; Steroids

PURPOSE: Bone morphogenetic protein (BMP) is a pleiotropic growth factor, which has been suggested to play a critical role during the development and homeostasis of the kidney. We evaluated the response of the human renal cell carcinoma (RCC) cell lines to BMPs. MATERIALS AND METHODS: We evaluated the growth rate of the human RCC cell lines, 112, 117 and 181, according to the concentrations of BMP-4, -6 and -7, and detected the levels of the BMP receptors (BMPRs) expressed in the cell lines. To demonstrate that the defect in BMP-6 signaling is at the receptor level, BMP-6 resistant cell lines were transfected, with adenovirus containing the constitutively active form of the BMP receptor types II (BMPR-II). After transfection, the cells were transfected with pSBE4, the construct of the BMP-6-responsive luciferase reporter gene, and a luciferase assay performed. RESULTS: The BMP-6 inhibited the proliferation of the 112, but not those of the 117 and 181 cells, in a dose-dependent manner. From Northern blot and immunoblot analyses, it was demonstrated that the 117 and 181 cells had undetectable levels of BMPR-II expression. The levels of luciferase activity, following adenovirus infections, was elevated in both the 117 and 181 cells, suggesting that the down-stream signaling molecules of the BMP-6 was intact in these cell lines. CONCLUSIONS: Taken together, these results demonstrate that the human RCC cell lines 117 and 181 are resistant to the growth inhibitory effects of the BMP-6 due to their decreased levels of BMPR-II expression.
Adenoviridae ; Adenoviridae Infections ; Blotting, Northern ; Bone Morphogenetic Protein 6 ; Bone Morphogenetic Protein Receptors* ; Bone Morphogenetic Proteins* ; Carcinoma, Renal Cell* ; Cell Line ; Genes, Reporter ; Homeostasis ; Humans* ; Kidney ; Luciferases ; Transfection

Purpose: The management of intraductal papilloma (IDP) without atypia remains controversial. This study evaluated the manifestations and incidence of malignancy during observation without surgery in patients diagnosed with IDP by core needle biopsy (CNB), to confirm whether close follow-up instead of surgical treatment is the preferred treatment option in selected patients. Methods: We retrospectively reviewed the data of 589 patients diagnosed with IDP by CNB between January 2009 to December 2018. The data of the 102 IDP lesions from 90 women who did not undergo immediate excision were analyzed. Of these, 84 patients received imaging follow-up without excision, while 18 patients underwent delayed excision during follow-up. Results: During the median follow-up period of 18.6 months, the mean change in tumor size and mean percent change in tumor size were −0.06 cm and −0.22%, respectively. Delayed excision was performed in 18 patients (17.6%). In the delayed excision group, three (16.7%) patients and one (5.6%) patient were diagnosed with atypical papilloma and intraductal papillary carcinoma, respectively, based on the final pathological findings. The upstaged group (atypia and malignancy; four patients) showed a 62.0% increase in the tumor size, which is higher than the benign group that showed a 10.4% increase in tumor size. However, the difference was not statistically significant (p=0.185). Conclusion Observation without excision is possible for small IDP without atypia, because of the minimal changes in tumor size and low incidence of malignancy after excision. However, to avoid a missed diagnosis of malignancy, excision should be considered if the lesion increases in size during follow-up.

The enzyme telomerase maintains a constant telomere length in immortalized cells, allowing unlimited cell proliferation. Almost all cancer cells express telomerase activity. However, little data is available regarding the role of telomerase activity in the detection of bladder cancer with a bladder wash specimen. We detected telomerase activity in a bladder wash specimen of bladder cancer and normal tissues, and compared them with final pathologic diagnosis. Twenty-three patients with transitional cell carcinoma (TCC) of the bladder were enrolled in our study. A bladder wash specimen was obtained before transurethral resection of the bladder (TURB) and normal and cancer tissues from the same patients during TURB. Telomerase activity was analyzed in each specimen a using telomeric repeat amplification protocol (TRAP) assay based on polymerase chain reaction (PCR) technique. Cytologic diagnosis was performed using Papanicolaou's stain with cytocentrifuged cytology preparation. We observed telomerase activity in 95.7% (22/23) of bath cancer tissues and bladder wash specimens; only one case did not express telomerase activity. Telomerase activity was undetected in all normal tissues except one, which was obtained from a patient with carcinoma in situ. A total of 69.6% (16/23) of wash specimens were positive in cytopathologic diagnosis. The accuracy of cytopathologic diagnosis in pathologic grade 2 or 3 was relatively high (83.3%, 15/18). However, in five cases of grade 1 TCC only 20% (1/5) of cytologic diagnosis was positive whereas the telomerase activity of wash specimens was detected in 80% (4/5). Our data demonstrates that not only the majority of human bladder cancer tissues, but also the bladder wash specimens obtained from patients with TCC, expressed telomerase activity. It indicates that telomerase activity may be a reliable marker in detecting bladder cancer especially in cases with a low grade that bladder wash cytology can miss.
Aged ; Aged, 80 and over ; Bladder Neoplasms/enzymology* ; Carcinoma, Transitional Cell/metabolism* ; Female ; Human ; Irrigation ; Male ; Middle Age ; Telomerase/metabolism* ; Tumor Markers, Biological

MOTIVATION: Many have observed a nonlinear relationship between the signal intensity and the transcript abundance in microarray data. The first step in analyzing the data is to normalize it properly, and this should include a correction for the nonlinearity. The commonly used linear normalization schemes do not address this problem. RESULTS: Nonlinearity is present in both cDNA and oligonucleotide arrays, but we concentrate on the latter in this paper. Across a set of chips, we identify those genes whose within-chip ranks are relatively constant compared to other genes of similar intensity. For each gene, we compute the sum of the squares of the differences in its within-chip ranks between every pair of chips as our statistic and we select a small fraction of the genes with the minimal changes in ranks at each intensity level. These genes are most likely to be non-differentially expressed and are subsequently used in the normalization procedure. This method is a generalization of the rank-invariant normalization (Li and Wong, 2001), using all available chips rather than two at a time to gather more information, while using the chip that is least likely to be affected by nonlinear effects as the reference chip. The assumption in our method is that there are at least a small number of nondifferentially expressed genes across the intensity range. The normalized expression values can be substantially different from the unnormalized values and may result in altered down-stream analysis.
DNA, Complementary ; Gene Expression ; Generalization (Psychology) ; Motivation ; Oligonucleotide Array Sequence Analysis*

As in other domains, artificial intelligence is becoming increasingly important in medicine. In particular, deep learning-based pattern recognition methods can advance the field of pathology by incorporating clinical, radiologic, and genomic data to accurately diagnose diseases and predict patient prognoses. In this review, we present an overview of artificial intelligence, the brief history of artificial intelligence in the medical domain, recent advances in artificial intelligence applied to pathology, and future prospects of pathology driven by artificial intelligence.
Artificial Intelligence ; Humans ; Pathology ; Prognosis

The necessity of routine prostate biopsy prior to transurethral resection of the prostate (TURP) in elderly comorbid patients with a high prostate specific antigen (PSA) level remains controversial. We assessed the role of TURP in prostate cancer diagnosis in these individuals. A total of 197 patients underwent TURP in conjunction with prostatic needle biopsy. Pathologic reviews of specimens of TUR chips and biopsy cores were analyzed. Overall, prostate cancer (CaP) was detected in 114 patients (57.6%). Ninety-eight cancers (86%) were detected with TURP and biopsy, and seven cancers (6.1%) with only TURP. The Gleason score of a TUR-specimen was identical to that of the biopsy-core in 43.9% of cases. Variables associated with diagnostic accuracy in the TUR-specimens included the prebiopsy PSA level, prostate specific antigen density (PSAD), and the Gleason score in biopsy cores. In patients with a PSA level and a PSAD that was greater than 15.4 ng/mL and 0.69 ng/mL/g, respectively, 100% of the cancers were detected in the TUR-specimens. Our results suggest that a prostatic biopsy might be omitted prior to TURP in elderly patients with significant co-morbidity and levels for PSA of >15.4 ng/mL.
Aged ; Aged, 80 and over ; Area Under Curve ; Biopsy, Needle ; Comorbidity ; Humans ; Male ; Neoplasm Grading ; Prostate/*surgery ; Prostate-Specific Antigen/*blood ; Prostatic Neoplasms/*diagnosis/epidemiology/*pathology/surgery ; ROC Curve ; Transurethral Resection of Prostate

We performed gene expression profiling in bladder cancer patients to identify cancer-specific survival-related genes in muscle invasive bladder cancer (MIBC) patients. Sixty-two patients with MIBC were selected as the original cohort and another 118 MIBC patients were chosen as a validation cohort. The expression of USP18, DGCR2, and ZNF699 genes were measured and we analyzed the association between gene signatures and survival. USP18 and DGCR2, were significantly correlated to cancer-specific death (P=0.020, P=0.007, respectively). Cancer-specific survival in the low USP18 or DGCR2 expression group was significantly longer than the high expression group (P=0.018, P=0.006, respectively). In multivariate Cox regression analysis, a combination of USP18 and DGCR2 mRNA expression levels were significant risk factors for cancer-specific death (HR, 2.106; CI, 1.043-4.254, P=0.038). Overall survival and cancer-specific survival rates in the low-combination group were significantly longer than those in the high-expression group (P=0.001, both). In conclusion, decreased expressions of USP18 and DGCR2 were significantly associated with longer cancer-specific survival, and also the combination of two genes was correlated to a longer survival for MIBC patients. Thus, the combination of USP18 and DGCR2 expression was shown to be a reliable prognostic marker for cancer-specific survival in MIBC.
Adult ; Aged ; Aged, 80 and over ; Biological Markers/metabolism ; Carrier Proteins/genetics/metabolism ; Endopeptidases/genetics/*metabolism ; Female ; Gene Expression Profiling ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Muscle Neoplasms/*secondary ; Neoplasm Invasiveness ; Neoplasm Staging ; Platelet Glycoprotein GPIb-IX Complex/genetics/*metabolism ; Predictive Value of Tests ; ROC Curve ; Regression Analysis ; Risk Factors ; Urinary Bladder Neoplasms/*diagnosis/metabolism/*mortality/pathology

We evaluated the correlations between BMI, fasting glucose, insulin, testosterone level, insulin resistance, and prostate size in non-diabetic benign prostatic hyperplasia (BPH) patients with normal testosterone levels. Data from 212 non-diabetic BPH patients with normal testosterone levels, who underwent transurethral resection of the prostate (TURP) due to medical treatment failure, were evaluated retrospectively. Patients with prostate specific antigen (PSA) levels of > or = 3 ng/mL underwent multicore transrectal prostate biopsy before TURP to rule out prostate cancer. Patients with diabetes mellitus (DM) or serum testosterone levels of < 3.50 ng/mL were excluded from analysis. Correlations between clinical and laboratory parameters were determined. Prostate size correlated positively with age (r = 0.227, P < 0.001), PSA (r = 0.510, P < 0.001), and fasting glucose level (r = 0.186, P = 0.007), but not with BMI, testosterone, insulin level, or insulin resistance (each P > 0.05). Testosterone level inversely correlated with BMI (r = -0.327, P < 0.001), insulin level (r = -0.207, P = 0.003), and insulin resistance (r = -0.221, P = 0.001), but not with age, prostate size, PSA, or fasting glucose level (each P > 0.05). Upon multiple adjusted linear regression analysis, prostate size correlated with elevated PSA (P < 0.001) and increased fasting glucose levels (P = 0.023). In non-DM BPH patients with normal testosterone levels, fasting glucose level is an independent risk factor for prostate hyperplasia.
Age Factors ; Aged ; Blood Glucose/*analysis ; Body Mass Index ; Humans ; Insulin/blood ; Insulin Resistance ; Linear Models ; Male ; Middle Aged ; Organ Size ; Prostate/*anatomy & histology ; Prostate-Specific Antigen/blood ; Prostatic Hyperplasia/metabolism/*pathology ; Retrospective Studies ; Risk Factors ; Testosterone/*blood

Brain metastasis represents one of the most common causes of intracranial tumors in adults, and the incidence of brain metastasis continues to rise due to the increasing survival of cancer patients. Yet, the development of cystic brain metastasis remains a relatively rare occurrence. In this review, we describe the characteristics of cystic brain metastasis and evaluate the combined use of stereotactic aspiration and radiosurgery in treating large cystic brain metastasis. The results of several studies show that stereotactic radiosurgery produces comparable local tumor control and survival rates as other surgery protocols. When the size of the tumor interferes with radiosurgery, stereotactic aspiration of the metastasis should be considered to reduce the target volume as well as decreasing the chance of radiation induced necrosis and providing symptomatic relief from mass effect. The combined use of stereotactic aspiration and radiosurgery has strong implications in improving patient outcomes.
Adult ; Brain* ; Drainage ; Humans ; Incidence ; Necrosis ; Neoplasm Metastasis* ; Radiosurgery* ; Survival Rate