Tumor Spheroids of an Aggressive Form of Central Neurocytoma Have Transit-Amplifying Progenitor Characteristics with Enhanced EGFR and Tumor Stem Cell Signaling

Central neurocytoma (CN) has been known as a benign neuronal tumor. In rare cases, CN undergoes malignant transformation to glioblastomas (GBM). Here we examined its cellular origin by characterizing differentiation potential and gene expression of CN-spheroids. First, we demonstrate that both CN tissue and cultured primary cells recapitulate the hierarchal cellular composition of subventricular zone (SVZ), which is comprised of neural stem cells (NSCs), transit amplifying progenitors (TAPs), and neuroblasts. We then derived spheroids from CN which displayed EGFR+/ MASH+ TAP and BLBP+ radial glial cell (RGC) characteristic, and mitotic neurogenesis and gliogenesis by single spheroids were observed with cycling multipotential cells. CN-spheroids expressed increased levels of pluripotency and tumor stem cell genes such as KLF4 and TPD5L1, when compared to their differentiated cells and human NSCs. Importantly, Gene Set Enrichment Analysis showed that gene sets of GBM-Spheroids, EGFR Signaling, and Packaging of Telomere Ends are enriched in CN-spheroids in comparison with their differentiated cells. We speculate that CN tumor stem cells have TAP and RGC characteristics, and upregulation of EGFR signaling as well as downregulation of eph-ephrin signaling have critical roles in tumorigenesis of CN. And their ephemeral nature of TAPs destined to neuroblasts, might reflect benign nature of CN.

Tumor Spheroids of an Aggressive Form of Central Neurocytoma Have Transit-Amplifying Progenitor Characteristics with Enhanced EGFR and Tumor Stem Cell Signaling

Central neurocytoma (CN) has been known as a benign neuronal tumor. In rare cases, CN undergoes malignant transformation to glioblastomas (GBM). Here we examined its cellular origin by characterizing differentiation potential and gene expression of CN-spheroids. First, we demonstrate that both CN tissue and cultured primary cells recapitulate the hierarchal cellular composition of subventricular zone (SVZ), which is comprised of neural stem cells (NSCs), transit amplifying progenitors (TAPs), and neuroblasts. We then derived spheroids from CN which displayed EGFR+/ MASH+ TAP and BLBP+ radial glial cell (RGC) characteristic, and mitotic neurogenesis and gliogenesis by single spheroids were observed with cycling multipotential cells. CN-spheroids expressed increased levels of pluripotency and tumor stem cell genes such as KLF4 and TPD5L1, when compared to their differentiated cells and human NSCs. Importantly, Gene Set Enrichment Analysis showed that gene sets of GBM-Spheroids, EGFR Signaling, and Packaging of Telomere Ends are enriched in CN-spheroids in comparison with their differentiated cells. We speculate that CN tumor stem cells have TAP and RGC characteristics, and upregulation of EGFR signaling as well as downregulation of eph-ephrin signaling have critical roles in tumorigenesis of CN. And their ephemeral nature of TAPs destined to neuroblasts, might reflect benign nature of CN.

Expression of µ-Opioid Receptor in CA1 Hippocampal Astrocytes

µ-opioid receptor (MOR) is a class of opioid receptors with a high affinity for enkephalins and beta-endorphin. In hippocampus, activation of MOR is known to enhance the neuronal excitability of pyramidal neurons, which has been mainly attributed to a disinhibition of pyramidal neurons via activating Gαi subunit to suppress the presynaptic release of GABA in hippocampal interneurons. In contrast, the potential role of MOR in hippocampal astrocytes, the most abundant cell type in the brain, has remained unexplored. Here, we determine the cellular and subcellular distribution of MOR in different cell types of the hippocampus by utilizing MOR-mCherry mice and two different antibodies against MOR. Consistent with previous findings, we demonstrate that MOR expression in the CA1 pyramidal layer is co-localized with axon terminals from GABAergic inhibitory neurons but not with soma of pyramidal neurons. More importantly, we demonstrate that MOR is highly expressed in CA1 hippocampal astrocytes. The ultrastructural analysis further demonstrates that the astrocytic MOR is localized in soma and processes, but not in microdomains near synapses. Lastly, we demonstrate that astrocytes in ventral tegmental area and nucleus accumbens also express MOR. Our results provide the unprecedented evidence for the presence of MOR in astrocytes, implicating potential roles of astrocytic MOR in addictive behaviors.

A Case of von Hippel-Lindau Disease with Colorectal Adenocarcinoma, Renal Cell Carcinoma and Hemangioblastomas / Journal of the Korean Cancer Association, 대한암학회지

von Hippel-Lindau (VHL) disease is an autosomal dominant inherited tumor syndrome associated with mutations of the VHL tumor suppressor gene located on chromosome 3p25. The loss of functional VHL protein contributes to tumorigenesis. This condition is characterized by development of benign and malignant tumors in the central nervous system (CNS) and the internal organs, including kidney, adrenal gland, and pancreas. We herein describe the case of a 74-year-old man carrying the VHL gene mutation who was affected by simultaneous colorectal adenocarcinoma, renal clear cell carcinoma, and hemangioblastomas of CNS.

Exponential Rise in Prostate-Specific Antigen (PSA) during Anti-Androgen Withdrawal Predicts PSA Flare after Docetaxel Chemotherapy in Patients with Castration-Resistant Prostate Cancer

PURPOSE: To investigate the relationship between rising patterns of prostate-specific antigen (PSA) before chemotherapy and PSA flare during the early phase of chemotherapy in patients with castration-resistant prostate cancer (CRPC). MATERIALS AND METHODS: This study included 55 patients with CRPC who received chemotherapy and in whom pre-treatment or post-treatment PSA levels could be serially obtained. The baseline parameters included age, performance, Gleason score, PSA level, and disease extent. PSA doubling time was calculated using the different intervals: the conventional interval from the second hormone manipulation following the nadir until anti-androgen withdrawal (PSADT1), the interval from the initial rise after anti-androgen withdrawal to the start of chemotherapy (PSADT2), and the interval from the nadir until the start of chemotherapy (PSADT3). The PSA growth patterns were analyzed using the ratio of PSADT2 to PSADT1. RESULTS: There were two growth patterns of PSA doubling time: 22 patients (40.0%) had a steady pattern with a more prolonged PSADT2 than PSADT1, while 33 (60.0%) had an accelerating pattern with a shorter PSADT2 than PSADT1. During three cycles of chemotherapy, PSA flare occurred in 11 patients (20.0%); of these patients, 3 were among 33 (9.1%) patients with an accelerating PSA growth pattern and 8 were among 22 patients (36.4%) with a steady PSA growth pattern (p=0.019). Multivariate analysis showed that only PSA growth pattern was an independent predictor of PSA flare (p=0.034). CONCLUSION: An exponential rise in PSA during anti-androgen withdrawal is a significant predictor for PSA flare during chemotherapy in CRPC patients.

Ca2+ Entry is Required for Mechanical Stimulation-induced ATP Release from Astrocyte

Astrocytes and neurons are inseparable partners in the brain. Neurotransmitters released from neurons activate corresponding G protein-coupled receptors (GPCR) expressed in astrocytes, resulting in release of gliotransmitters such as glutamate, D-serine, and ATP. These gliotransmitters in turn influence neuronal excitability and synaptic activities. Among these gliotransmitters, ATP regulates the level of network excitability and is critically involved in sleep homeostasis and astrocytic Ca2+ oscillations. ATP is known to be released from astrocytes by Ca2+-dependent manner. However, the precise source of Ca2+, whether it is Ca2+ entry from outside of cell or from the intracellular store, is still not clear yet. Here, we performed sniffer patch to detect ATP release from astrocyte by using various stimulation. We found that ATP was not released from astrocyte when Ca2+ was released from intracellular stores by activation of Galpha(q)-coupled GPCR including PAR1, P2YR, and B2R. More importantly, mechanical stimulation (MS)-induced ATP release from astrocyte was eliminated when external Ca2+ was omitted. Our results suggest that Ca2+ entry, but not release from intracellular Ca2+ store, is critical for MS-induced ATP release from astrocyte.

Familial Prostate Cancer in Three Brothers

We treated a family of 3 brothers with prostate cancer, which is the first report of familial prostate cancer in Korea. Prostate cancer was diagnosed in the first brother with a prostate-specific antigen (PSA) level of 12.70 ng/ml of at the age of 68 years. He underwent a radical retropubic prostatectomy (RRP); the cancer was pathologically staged to T2cN1Mo. He received adjuvant hormonal therapy postoperatively. Three years later, prostate cancer was diagnosed in the third brother at the age of 61 years with a high PSA level of 4.45 ng/ml. He underwent RRP, which revealed the pathological stage to be T2cN0M0. Three months later, the second brother, who had visited our hospital for lower urinary tract symptoms and for a PSA screening test was diagnosed with prostate cancer at the age of 60 years (PSA level of 3.96 ng/ml). He also underwent RRP, and his cancer was staged pathologically as T2cN0M0.

Management of BCG Failures in Non-Muscle-Invasive Bladder Cancer

PURPOSE: Bacillus Calmette-Guerin (BCG) intravesical therapy is the standard treatment in high-risk patients with non-muscle-invasive bladder cancer, but a significant number of patients experience recurrence after BCG therapy. Although several treatment options are available for recurrence after BCG therapy, the optimal treatment strategy is still controversial. We reviewed current and promising treatment options after BCG failure. MATERIALS AND METHODS: search of published literature using PubMed and meeting abstracts was performed. RESULTS: BCG failures are further subdefined as BCG refractory, BCG resistant, BCG relapsing, and BCG intolerance. Several predictors for BCG response have been studied, but prediction or stratification before therapy seems to be difficult in clinical practice. Novel biomarkers associated with immunologic mechanisms appear to be promising to predict BCG failure. Radical cystectomy is the standard treatment for BCG-refractory disease, but the timing of cystectomy is controversial. BCG maintenance or combination with interferon-alpha is a promising therapy for BCG resistance or relapse. Some salvage therapies or device-assisted instillations have been also promising, but the efficacy and safety of these novel therapies should be confirmed by large prospective studies before their clinical use in BCG failure. CONCLUSIONS: Patients with BCG failure are not a homogeneous group and need to be stratified. Radical cystectomy should be performed without delay in patients with BCG-refractory status, but salvage intravesical therapies may be an alternative in cases without true refractory status. Although BCG and interferon intravesical therapy is promising, more efficient salvage therapy after BCG failure is required.

Single Institutional Experience of Bladder-Preserving Trimodality Treatment for Muscle-Invasive Bladder Cancer

The authors designed this study to determine the clinical effectiveness of trimodality treatment, i.e., transurethral resection of a bladder tumor (TURBT) and concurrent chemoradiotherapy (CRT). Twenty patients with a muscle-invasive bladder cancer were treated by TURBT followed by concurrent cisplatin (75 mg/m(2) day), administered on weeks 1 and 4 of radiotherapy. According to residual tumor status after TURBT, patients were classified into patients with a complete TURBT group and incomplete TURBT group. Response to treatment was evaluated by restaging TURBT at 4 weeks after completing CRT (post-CRT). Fifteen patients (75%) achieved complete remission (CR) at restaging; 10 patients (50%) remained continuously free of tumor recurrence. Disease-specific and overall survivals were 51.1% and 38.6% at 5 yr post-CRT, respectively. Of 16 patients in the complete TURBT group, 14 patients (87.5%) achieved CR, which was significantly different from that observed in the incomplete TURBT group, in which only 1 (25%) of 4 patients achieved CR (p=0.032). Five- year disease-specific and overall survivals were 71.6% and 53.5%, respectively. Ten patients (90.9%) maintained their own bladder among the 11 surviving patients. Trimodality treatment was found to be an effective treatment in patients who underwent complete TURBT for a muscle-invasive bladder cancer.

Docetaxel Chemotherapy of Korean Patients with Hormone-refractory Prostate Cancer: Comparative Analysis between 1st-line and 2nd-line Docetaxel

PURPOSE: This study was undertaken to investigate the outcomes associated with docetaxel treatment of Korean patients with hormone-refractory prostate cancer (HRPC) and to compare its clinical efficacies in 1st and 2nd-line settings. PATIENTS AND METHODS: This study was retrospectively performed and included 47 patients with HRPC. The 1st-line group consisted of 19 patients who had not undergone prior chemotherapy, and the 2nd-line group consisted of 28 patients who underwent prior chemotherapy. All patients were treated with 75mg/m2 IV docetaxel every 3 weeks and 5mg of prednisone twice daily with a continuous androgen blockade. RESULTS: Of 47 study subjects, 14 patients (29.8%) had > or = 50% PSA decline from baseline. PSA response was more common in the 1st-line group, but this was not statistically different (42.1% vs. 21.4%, p = 0.114). After a median follow up of 11 months (range, 6-24 months), the 1st-line group showed a longer time to PSA progression (4 vs. 2 months, p = 0.015) and survival (17 vs. 10 months, p = 0.037) than the 2nd-line group. In terms of toxicities, no difference was apparent between the 2 groups. CONCLUSION: In a 1st-line setting, docetaxel is an effective and tolerable agent for Korean HRPC patients, and that its efficacy is limited, although 2nd-line docetaxel is tolerable.

Epidermal Growth Factor Receptor as Predicting Factor on Biochemical Recurrence after Radical Prostatectomy: A Prospective Study / 대한비뇨기과학회지

PURPOSE: We investigated epidermal growth factor receptor(EGFR) expression in prostate cancer(PCa) and their potential role as predicting factor on biochemical recurrence(BCR). MATERIALS AND METHODS: Between February 2005 and February 2007, EGFR expression were prospectively evaluated in a consecutive series of 88 PCa patients with the following characteristics: 66 patients treated with retropubic radical prostatectomy(RRP); 22 patients treated with neoadjuvant hormonal therapy followed by RRP. The relationship between EGFR expression and several clinicopathologic parameters were evaluated. The probability of BCR-free survival was determined using the Kaplan-Meier method. RESULTS: EGFR expression, was evaluated by immunohistochemistry, was found in 31 of 88(35.2%) patients. 8 of 31 EGFR-positive patients(25.8%) had BCR, whereas only 5 of 57 EGFR-negative patients(8.8%) had BCR (p=0.031) during a median follow-up of 21 months. Among several variables, high serum prostate-specific antigen values(>or=20), extraprostatic extension, seminal vesicle invasion, and EGFR expression were the significant predictors of BCR on univariate analysis. But, multivariate analysis showed that no variable was significant predictor of BCR. EGFR-negative patients had a significantly longer mean BCR-free survival time than EGFR-positive patients(p=0.027). CONCLUSIONS: EGFR expression could be an potential predicting factor on BCR following RRP.

Analysis of Changes in the Total Lymphocyte and Eosinophil Count during Immunotherapy for Metastatic Renal Cell Carcinoma: Correlation with Response and Survival

The aims of this study were to analyze lymphocyte and eosinophil counts in consecutive peripheral blood samples taken during immunotherapy for metastatic renal cell carcinoma (mRCC) and to correlate the findings with objective response and survival. A total of 40 patients with mRCC who received immunotherapy with interleukin-2, interferon-alpha, and 5-fluorouracil were analyzed. Objective responses were observed in 14 patients, including 2 (5%) who showed a complete response (CR) and 12 (30%) who showed a partial response (PR). Eleven patients (27%) achieved stable disease (SD), and 15 patients (38%) had progressive disease (PD). Changes from baseline in the total lymphocyte counts were significantly higher in the responding patients (CR+PR+SD) than in the non-responding patients (PD) (p=0.017), but no difference was seen in the total eosinophil counts (p=0.275). Univariate analysis identified the Eastern Cooperative Oncology Group (ECOG) performance status (p=0.017), the presence of a primary renal tumor (p<0.001) and the peripheral lymphocyte counts at week 4 (p=0.034) as prognostic factors, but a low ECOG performance status (p=0.003) and the presence of a primary renal tumor (p=0.001) were identified as independent poor prognostic factors by multivariate analysis. This study provides further evidence that changes in blood lymphocyte counts may serve as an objective indicator of objective responses.

Estramustine Phosphate Based Chemotherapy for Hormone Refractory Prostate Cancer / 대한비뇨기과학회지

PURPOSE: We wanted to evaluate the efficacy and side effects of estramustine monotherapy and estramustine plus etoposide or dexamethasone combined therapies for patients with hormone refractory prostate cancer(HRPC). MATERIALS AND METHODS: Between 2000 and 2004, 33 patients who were diagnosed with HRPC and treated with estramustine-based chemotherapy were evaluated. Eleven patients had oral estramustine monotherapy(group 1), 12 patients had oral estramustine plus oral etoposide(group 2), and finally 10 patients had oral estramustine plus oral dexamethasone(group 3). The prostate-specific antigen(PSA) response, progression-free survival and disease-specific survival were evaluated. RESULTS: The median patient age was 71 years and the median PSA was 97.3ng/ml. The median follow-up period was 17 months(range: 5-47). The overall response rate was 45.5%, and the response rate for each group was 36.4% for group 1, 41.7% for group 2 and 70.0% for group 3, respectively. The median time to progression(TTP) was 5 months(range: 1-16) overall and it was 5 months, 5.5 months and 5 months in groups 1, 2 and 3, respectively. Regarding the response rate, progression-free survival and disease specific survival, there were no statistically significant differences between the three groups(p>0.05). The most common hematologic complication was anemia that occurred in 28 patients and deep vein thrombosis occurred in 2. Severe toxicities(>or=grade 3) occurred in only 2 patients. CONCLUSIONS: Estramustine phosphate showed over a 45% response rates with less morbidities. Estramustine-based chemotherapy can be considered as an option for the treatment of HRPC. However, larger randomized controlled trials for regimens combined with other efficacious agents are necessary to elucidate the efficacy of chemotherapy for HRPC.

Adult's Wilms' Tumor Mimicking Renal Pelvis Tumor / 대한비뇨기과학회지

Wilms' tumor is a rare malignant renal tumor in adults and it usually presents as a parenchymal mass that resembles renal cell carcinoma. The authors observed one case of adults Wilms' tumor developing in the renal pelvis and the initial diagnosis was renal pelvis tumor. The patient underwent radical nephroureterectomy with bladder cuff excision and adjuvant chemotherapy with the combination of vincristine and actinomycin. The patient has remained healthy and was without evidence of tumor recurrence on a follow-up CT scan at 18 months postoperatively.

Partial Nephrectomy using Parenchymal Compression without Renal Pedicle Clamping / 대한비뇨기과학회지

PURPOSE: The hemostasis and closure of the collecting system are still problems to be overcome during a partial nephrectomy. Herein, our initial experience of a parenchymal compression technique, without clamping of the renal pedicle during an open partial nephrectomy, is reported. MATERIALS AND METHODS: Between May 2000 and August 2005, 10 patients underwent an open partial nephrectomy, without pedicle clamping, for a renal mass. The open partial nephrectomy was performed under regional ischemia, which was achieved by parenchymal compression using a long curved vascular clamp. Several parameters were retrospectively assessed, including the tumor size, location, pathology, estimated blood loss, preoperative and postoperative serum creatinine, complications, and tumor recurrence. RESULTS: The mean mass size was 23.8mm, ranging between 12 and 55mm, and the tumors were located in the upper, mid and lower poles in 2, 3 and 4 cases, respectively. Pathological examinations revealed renal cell carcinomas in 6, an angiomyolipoma in 1, and complicated renal cysts in 3 patients. In all the patients with renal cell carcinoma, the frozen and permanent sections analyses confirmed negative margins. There were no differences between the preoperative and postoperative creatinine levels, with no significant complications observed, including urinary leak and bleeding, during the recovery period. No patient developed a local recurrence or distant metastasis during the mean follow-up period of 17.2 months. CONCLUSIONS: This technique is simple, and can be easily practiced by any urological surgeon, without concerns relating to the ischemic time and complications. It is suggested that the regional parenchymal compression is an efficient technique for hemostasis and repair of the collecting system during an open partial nephrectomy.

Spermatic Cord Metastasis of Esophageal Cancer, Mimicking as an Incarcerated Hernia / 대한비뇨기과학회지

Metastatic cancers in the spermatic cord are extremely rare. A 79-year-old man, who had undergone palliative chemotherapy and radiotherapy one year previously, due to inoperable esophageal cancer, visited our hospital suffering from right inguinal swelling. Ultrasonography showed echogenic lesions superior to the right testis, suspicious of a swollen bowel loop. An emergency exploration revealed no bowel content or mesentery, but with thickened of the spermatic cord and epididymis four times that of the contralateral side. Pathology confirmed a metastatic carcinoma, likely to have originated from the esophagus.

Changing Trends in the Management of Benign Prostatic Hyperplasia during Recent 5 Years / 대한비뇨기과학회지

PURPOSE: Benign prostatic hyperplasia (BPH) is not uncommon, and its prevalence is increasing; its treatment is also undergoing certain changes, which are quite different from previously used treatments. The purpose of this study was to investigate the trend in BPH treatment over the last 5 years, at the Yonsei Medical Center, with its clinical implications. Materials and Methods: A retrospective analysis was performed on patients diagnosed with BPH, and treated surgically and/or medically at our hospital, on an outpatient or inpatient basis, over the 5 year period from Jan 1998 to Nov 2002. The subjects were divided into surgically and medically treated groups. Prostate volume was measured by means of transrectal ultrasonography, and the proportion of the total number of BPH patients in each group identified. RESULTS: The mean age of the medically and surgically treated groups were 65.9 and 68.5 years, respectively, with no significant difference between the groups (p>0.05). The numbers of patients diagnosed and treated for BPH increased annually over the 5 years, and were 3,934, 5,318, 6,612, 8,466 and 9,457, respectively, and the numbers of transurethral prostate resection (TURP) performed were 241, 273, 288, 332 and 333, respectively. Although the absolute number of surgical treatments seem similar, the actual proportion; 6.1, 5.1, 4.3, 3.9 and 3.5%, respectively, showed significant decreases year-on-year (p0.05), the mean prostate volume in the surgically treated group for the 5 consecutive years were 37.1, 39.3, 44.2, 49.1 and 53.6cc, respectively, showing a significant increase (p<0.05). CONCLUSIONS: The number of BPH patients attending Yonsei Medical Center has rapidly increased over the last 5 years, with medical rather than surgical treatment becoming the primary treatment of BPH. However, despite the number of patients requiring surgical treatment appearing to have change little, the prostate volume of these patients has shown a tendency to increase.

Cystic Lymphangioma of the Kidney / 대한비뇨기과학회지

A lymphangioma is a benign tumor and predisposed to the neck and the axillary region. A lymphangioma of the kidney is a very rare and seen as multilocular cysts in imaging studies, and are difficult to differentiate from other malignant cystic diseases. A 53 year-old man was referred for known right renal cysts. Abdominal ultrasonography and computed tomography showed a 4.0x3.6cm multiloculated cystic mass in the right upper pole of the kidney and 2.3cm sized simple cyst in the ipsilateral mid pole. Malignant cystic diseases could not be excluded from the radiological studies. He underwent a radical nephrectomy. Gross examinations revealed a multilocular cyst protruding from the renal parenchyme. The multilocular cyst was located in the upper pole of the kidney, with another simple cyst in the mid pole. Microscopic examinations showed that attenuated flat to cuboidal cells paved the multilocular cyst, but no nephron was seen in the cystic wall. A distinct thick fibromuscular bundle represented a large lymphatic channel. These findings were compatible with a lymphangioma.