Cancer cells and stem cells share a number of biological characteristics including abundant amounts of decondensed chromatin. However, the molecular correlates and the factors involved in altering chromatin structure in cancer cells are not well known. Here, we report that less differentiated stem-like cells in the basal compartment of human and mouse prostate contain lower levels of the polycomb heterochromatin marker H3K27me3 than more differentiated luminal cells. This link to differentiated normal cells is also found in a number of other human and rodent tissues characterized by hierarchical differentiation. In addition to MYC's traditional role as a gene-specific transcription factor, recent studies indicate that MYC also affects global chromatin structure where it is required to maintain "open" or active chromatin. We now demonstrate that in both MYC-driven prostate cancers in mice and human prostate cancers, global levels of H3K27me3 are reduced in prostatic intraepithelial neoplasia and invasive adenocarcinoma lesions. Moreover, decreased levels of H3K27me3 correlate with increased markers of disease aggressiveness (eg, Gleason score and pathological stage). In vitro, experimentally forced reductions in MYC levels result in increased global levels of H3K27me3. These findings suggest that increased levels of decondensed chromatin in both normal progenitor cells and cancer cells are associated with global loss of H3K27me3, which is linked to MYC overexpression.
INTRODUCTION AND OBJECTIVE: To evaluate the detection of clinically significant prostate cancer (CSPCa) by systematic (SB) and target biopsy (TB) in men with Prostate Imaging Reporting and Data System - PIRADS 5; and the need for SB in this population. METHODS: We identified consecutive patients with PIRADS 5 lesion on multiparametric MRI (mpMRI; 3T, T2W, DWI, ADC, DCE) undergoing prostate biopsy (PBx) for suspicion of PCa, from our PBx database (IRB# HS-13–00663). Patients underwent mpMRI followed by 12-core SB and at least two TB cores per PIRADS 5 lesion. All MRIs were re-reviewed by an experienced radiologist. PBx were performed by an expert urologist using an MRI-transrectal ultrasound fusion system (Koelis). Each core-biopsy was labeled individually and interpreted according to ISUP Grade Group (GG) standards. Men with prior treatment for PCa or poor-quality MRI were excluded. The positive predictive value (PPV) of PIRADS 5 on MRI for CSPCa (GG ≥2) detection on PBx was analyzed. PSA density (PSAD) was calculated by dividing PSA by prostate volume on MRI. RESULTS: A total of 124 patients met inclusion criteria. The median (IQR) age, PSAD, number of positive cores, cancer core length and percent were: 69Y (64-75), 0.23ng/ml/cc (0.13-0.36), 7 (5-9), 12mm (9-15) and 90% (70-95), respectively. The CSPCa detection rate for SB+TB, TB and SB was: 88%, 82% and 65%, respectively. SB added 6% CSPCa detection to TB. The PPV for SB + TB of PIRADS 5 for any GG PCa and for CSPCa was 95% and 88%. Only 6 (6/124 = 5%) patients were not diagnosed with PCa on PBx: 2 with granuloma, 2 HGPIN, 1 focal inflammation, 1 benign prostatic tissue, but with metastatic PCa on pelvic lymph node biopsy. Considering only patients with PSAD>0.15ng/ml/cc (N = 86; 68% of the entire cohort), the CSPCa detection rate for SB+TB, TB and SB was: 95%, 92% and 72%. SB added 3% CSPCa detection to TB. Three (3/86=3.5%) patients with PSAD>0.15ng/ml/cc were diagnosed with CSPCa only on SB, and GG 1 PCa on TB. Had they been diagnosed with GG 1 on TB alone; these patients would not meet criteria for active surveillance because of high PSA or large cancer volume. The PPV for SB + TB of PIRADS 5 for any GG PCa and for CSPCa in men with PSAD>0.15ng/ml/cc was 98% and 95%, respectively. CONCLUSIONS: PIRADS 5 on mpMRI showed high positive predictive value for CSPCa on prostate biopsy. In those with PSAD>0.15ng/ml/cc, systematic biopsy marginally increased CSPCa, but not overall PCa detection in comparison to target biopsy alone. Systematic biopsy didn’t affect patients’ management and could be omitted on this population. Source of Funding: This study was funded in part by the R01 grant CA205058-01 from the National Institutes of Health/ National Cancer Institute (M.C.S, I.S.G. and A.L.A.).
Permanent prostate brachytherapy is frequently performed worldwide, and many studies have demonstrated its favorable outcomes. Implant seeds used in this procedure contain a precise amount of radionuclide and are completely sealed. Because these seeds are not manufactured in Japan, they are expensive (6300 yen per seed) and therefore need careful management as a radioisotope. The proper implantation technique requires considerable procedure time, good dosimetric outcomes and simple radioactive isotope management. To evaluate the modified hybrid interactive technique based on these considerations, we assessed 313 patients who underwent hybrid interactive brachytherapy without additional external beam radiotherapy. We evaluated the duration of the procedure, dosimetric factors and the total number of excess seeds. The dosimetric results from computed tomography on Day 30 of follow-up were: 172 Gy (range 130-194 Gy) for pD90, 97.8% (83.5-100%) for pV100, 54.6% (27.5-82.4%) for pV150, 164 Gy (120-220 Gy) for uD90, 194 Gy (126-245 Gy) for uD30, 210 Gy (156-290 Gy) for uD5, 0.02 ml (0-1.2 ml) for rV100 and 0 ml (0-0.2 ml) for rV150. The number of excess seeds was determined by subtracting the number of implanted seeds from the expected number of seeds calculated from previously proposed nomograms. As per our method, nine excess seeds were used for two patients, whereas using the nomograms, the number of excess seeds was approximately eight per patient. Our modified hybrid interactive technique reduced the number of excess seeds while maintaining treatment quality.
A 75-year-old man with a history of chronic kidney disease (CKD) visited our emergency room after the sudden onset of severe right lower abdominal pain and nausea. Computed tomography (CT) showed right perirenal hematoma and renal tumor, which was diagnosed as a spontaneous rupture of the right renal tumor. It was difficult to correctly diagnose the tumor as benign or malignant with magnetic resonance imaging (MRI). Because of CKD, a shunt was implanted, and dynamic enhanced CT was performed. Dynamic enhanced CT showed a slightly enhanced area of the tumor, and it was diagnosed as renal cell carcinoma (RCC). Radical nephrectomy was performed, and he has not experienced recurrence within 7 months after the surgery. Pathological diagnosis was papillary renal carcinoma. Spontaneous renal hemorrhage is relatively uncommon, but the most common cause of spontaneous renal hemorrhage is renal cell carcinoma (26.1%). CT is useful for diagnosis, but it is not highly accurate. Therefore, it is necessary to discuss surgical indication carefully.
