James M. McKiernan

Protocol for the Examination of Specimens From Patients With Carcinoma of the Prostate Gland

Authors John R. Srigley, MD, FCAP* Department of Laboratory Medicine, Credit Valley Hospital, Mississauga, Ontario, Canada Peter A. Humphrey, MD, PhD, FCAP* Department of Pathology, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, Missouri Mahul B. Amin, MD, FCAP* Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California Sam S. Chang, MD Department of Urologic Surgery, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee Lars Egevad, MD Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden Jonathan I. Epstein, MD Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland David J. Grignon, MD Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana James M. McKiernan, MD Columbia University College of Physicians and Surgeons, New York, New York Rodolfo Montironi, MD, FRCPath Institute of Pathological Anatomy and Histopathology, University of Ancona School of Medicine, Ancona, Italy Andrew A. Renshaw, MD Department of Pathology, Baptist Hospital of Miami, Miami, Florida Victor E. Reuter, MD Pathology Department, Memorial Sloan-Kettering Cancer Center, New York, New York Thomas M. Wheeler, MD, FCAP Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas Ming Zhou, MD, PhD, FCAP† Department of Pathology, New York University Langone Medical Center, New York, New York For the Members of the Cancer Committee, College of American Pathologists

Dysregulation of Circulating MicroRNAs and Prediction of Aggressive Prostate Cancer

It is becoming increasingly evident that microRNAs (miRNAs) are associated with the development and progression of prostate cancer (PCa).

The Cost of Treatment of Skeletal-Related Events in Patients with Bone Metastases from Lung Cancer

Purpose: Patients with bone metastases from lung cancer often experience skeletal-related events (SREs) including pathological fracture, spinal cord compression, hypercalcemia or pain requiring surgery, radiotherapy or opioid analgesics. These complications result in impaired mobility and reduced quality of life and have a significant negative impact on survival. The economic consequences of SREs in patients with lung cancer have not been examined. Methods: We conducted a retrospective analysis using a large US health insurance claims database to estimate the incidence and costs of treatment of SREs in patients with bone metastases of lung cancer treated in a naturalistic setting. Study subjects had ≧2 encounters with a diagnosis of primary lung cancer and ≧2 encounters with a diagnosis of metastases to bone. SREs were identified based on the occurrence on or after the date of first diagnosis of bone metastases, of (1) ≧1 encounter with a diagnosis of pathological fracture, spinal cord compression or hypercalcemia, (2) ≧1 bone surgery or radiotherapy procedure, or (3) the initiation of opioid analgesic therapy. Survival and costs of SRE-related care in patients with SREs were estimated using Kaplan-Meier methods. Results: We identified 534 patients with lung cancer and bone metastases, including 295 (55%) with ≧1 SRE. Radiotherapy (68%) and fracture (35%) were the most common SREs. Median survival after the first identified SRE was 4.1 months (95% confidence interval: 3.6–5.5 months). The estimated lifetime SRE-related cost per patient was USD 11,979 (95% confidence interval: USD 10,193–13,766). Radiotherapy accounted for the greatest proportion of cost (61%) by SRE type. Conclusion: The economic burden of SREs in patients with bone metastases of lung cancer is substantial. Intravenous bisphosphonates, such as zoledronic acid, which have been shown to prevent these events, may reduce these costs.

A First in Human Phase 1 Study of CG0070, a GM-CSF Expressing Oncolytic Adenovirus, for the Treatment of Nonmuscle Invasive Bladder Cancer

PURPOSE We assessed the safety, pharmacokinetics and anticancer activity of intravesical CG0070, a cancer selective, replication competent adenovirus, for the treatment of nonmuscle invasive bladder cancer. MATERIALS AND METHODS A total of 35 patients received single or multiple (every 28 days × 3 or weekly × 6) intravesical infusions of CG0070 at 1 of 4 dose levels (1 × 10(12), 3 × 10(12), 1 × 10(13) or 3 × 10(13) viral particles). Response to treatment was based on cystoscopic assessment and biopsy or urine cytology. Urine and plasma CG0070, and granulocyte-monocyte colony-stimulating factor were measured in all patients. A subset of 18 patients was assessed for retinoblastoma phosphorylation status. RESULTS Grade 1-2 bladder toxicities were the most common adverse events observed. A maximum tolerated dose was not reached. High levels of granulocyte-monocyte colony-stimulating factor were detected in urine after administration in all patients. Virus replication was suggested based on an increase in urine CG0070 genomes between days 2 and 5 in 58.3% of tested patients (7 of 12). The complete response rate and median duration of the complete response across cohorts was 48.6% and 10.4 months, respectively. In the multidose cohorts the complete response rate for the combined groups (every 28 days and weekly × 6) was 63.6% (14 of 22 patients). In an exploratory, retrospective assessment patients with borderline or high retinoblastoma phosphorylation who received the multidose schedules had an 81.8% complete response rate (9 of 11). CONCLUSIONS Intravesical CG0070 was associated with a tolerable safety profile and antibladder cancer activity. Granulocyte-monocyte colony-stimulating factor transgene expression and CG0070 replication were also suggested.

Single luminal epithelial progenitors can generate prostate organoids in culture

The intrinsic ability to exhibit self-organizing morphogenetic properties in ex vivo culture may represent a general property of tissue stem cells. Here we show that single luminal stem/progenitor cells can generate prostate organoids in a three-dimensional culture system in the absence of stroma. Organoids generated from CARNs (castration-resistant Nkx3.1-expressing cells) or normal prostate epithelia exhibit tissue architecture containing luminal and basal cells, undergo long-term expansion in culture and exhibit functional androgen receptor signalling. Lineage-tracing demonstrates that luminal cells are favoured for organoid formation and generate basal cells in culture. Furthermore, tumour organoids can initiate from CARNs after oncogenic transformation and from mouse models of prostate cancer, and can facilitate analyses of drug response. Finally, we provide evidence supporting the feasibility of organoid studies of human prostate tissue. Our studies underscore the progenitor properties of luminal cells, and identify in vitro approaches for studying prostate biology.

Phase I Trial of Intravesical Docetaxel in the Management of Superficial Bladder Cancer Refractory to Standard Intravesical Therapy

Purpose Up to 50% of patients treated with intravesical agents for superficial bladder cancer will experience recurrence. Response rates to second-line intravesical therapies range from 20% to 40%. For these high-risk patients, novel agents are necessary to prevent recurrence. Docetaxel is a microtubule depolymerization inhibitor with unique physiochemical properties, making it an excellent candidate for investigation as an intravesical agent. Patients and Methods This phase I trial included patients with recurrent Ta, T1, and Tis transitional cell carcinoma who experienced treatment failure with at least one prior intravesical treatment. Docetaxel was administered as six weekly instillations at a starting dose of 5 mg, with a dose-escalation model used until a maximum tolerated dose (MTD) was achieved. Primary end points were dose-limiting toxicity (DLT) and MTD. Efficacy was evaluated by cystoscopy with biopsy, cytology, and computed tomography imaging. Results Eighteen patients (100%) completed the trial, and the distribution of stages included six patients with Tis, seven with Ta, and five with T1 disease. No grade 3 or 4 DLTs occurred in 108 infusions, and no patient had systemic absorption of docetaxel. Eight (44%) of 18 patients experienced grade 1 or 2 toxicities, with dysuria being the most common. Ten (56%) of 18 patients had no evidence of disease at their post-treatment cystoscopy and biopsy. None of the patients who experienced relapse had disease progression. Conclusion Intravesical docetaxel exhibited minimal toxicity and no systemic absorption in the first human intravesical clinical trial. This suggests that docetaxel is a safe agent for further evaluation of efficacy in a phase II trial.

Active surveillance for renal cortical neoplasms.

PURPOSE We retrospectively evaluated our single center experience with patients with renal cortical neoplasms who elected active surveillance. MATERIALS AND METHODS We retrospectively evaluated our urological oncology database between January 1993 and January 2009, identifying a total of 223 renal cortical neoplasms in 212 patients that were initially managed by active surveillance. We described patient and tumor characteristics, and assessed the differences between patients who remained on AS and those who underwent delayed intervention or progressed with metastasis. RESULTS Median patient age was 71 years at active surveillance initiation and the median Charlson comorbidity index was 3. Median tumor size was 2.8 cm (range 0.5 to 13.7) at study enrollment and 3.7 cm (range 0.9 to 14.1) at final assessment. The median growth rate in the entire cohort was 0.34 cm per year (range 0.29 to 2.3). Median followup was 35 months (range 6 to 137). Active surveillance failed in 15 patients (7%), of whom 4 (2%) progressed to metastasis and 11 (5%) required intervention. When comparing cases of failed active surveillance with those that continued, there were statistical differences in initial tumor size (2.61 vs 3.64 cm, p = 0.019), final tumor size (3.56 vs 5.17 cm, p = 0.001) and growth rate (0.34 vs 1.75, p = 0.001). There was no correlation between initial tumor size and growth rate (Pearsons coefficient r = 0.006, p = 0.932). A total of 14 patients died of another medical condition. Only 1 cancer related death (0.5%) was reported in the entire cohort. CONCLUSIONS Active surveillance for renal cortical neoplasms in select older patients with comorbidities is a reasonable treatment option. At 3-year followup we noted a 7% failure rate.

Role of promoter hypermethylation in Cisplatin treatment response of male germ cell tumors

BackgroundMale germ cell tumor (GCT) is a highly curable malignancy, which exhibits exquisite sensitivity to cisplatin treatment. The genetic pathway(s) that determine the chemotherapy sensitivity in GCT remain largely unknown.ResultsWe studied epigenetic changes in relation to cisplatin response by examining promoter hypermethylation in a cohort of resistant and sensitive GCTs. Here, we show that promoter hypermethylation of RASSF1A and HIC1 genes is associated with resistance. The promoter hypermethylation and/or the down-regulated expression of MGMT is seen in the majority of tumors. We hypothesize that these epigenetic alterations affecting MGMT play a major role in the exquisite sensitivity to cisplatin, characteristic of GCTs. We also demonstrate that cisplatin treatment induce de novo promoter hypermethylation in vivo. In addition, we show that the acquired cisplatin resistance in vitro alters the expression of specific genes and the highly resistant cells fail to reactivate gene expression after treatment to demethylating and histone deacetylase inhibiting agents.ConclusionsOur findings suggest that promoter hypermethylation of RASSF1A and HIC1 genes play a role in resistance of GCT, while the transcriptional inactivation of MGMT by epigenetic alterations confer exquisite sensitivity to cisplatin. These results also implicate defects in epigenetic pathways that regulate gene transcription in cisplatin resistant GCT.

THE INCREASING USE OF INTRAVESICAL THERAPIES FOR STAGE T1 BLADDER CANCER COINCIDES WITH DECREASING SURVIVAL AFTER CYSTECTOMY

Intravesical therapy (IVT), chemo and immunotherapy, has made conservative, bladder‐sparing strategies a viable option for managing patients with high grade T1 bladder cancer. However, many of these patients will have recurrence and occasionally progression, questioning delayed intervention. This study examines the patterns of use of IVT in high‐grade T1 bladder cancer and the subsequent impact on survival for patients ultimately proceeding to radical cystectomy (RC).

Five-year Analysis of a Multi-institutional Prospective Clinical Trial of Delayed Intervention and Surveillance for Small Renal Masses: The DISSRM Registry ☆

BACKGROUND A growing body of retrospective literature is emerging regarding active surveillance (AS) for patients with small renal masses (SRMs). There are limited prospective data evaluating the effectiveness of AS compared to primary intervention (PI). OBJECTIVE To determine the characteristics and clinical outcomes of patients who chose AS for management of their SRM. DESIGN, SETTING, AND PARTICIPANTS From 2009 to 2014, the multi-institutional Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry prospectively enrolled 497 patients with solid renal masses ≤4.0cm who chose PI or AS. INTERVENTION AS versus PI. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The registry was designed and powered as a noninferiority study based on historic recurrence rates for PI. Analyses were performed in an intention-to-treat manner. Primary outcomes were overall survival (OS) and cancer-specific survival (CSS). RESULTS AND LIMITATIONS Of the 497 patients enrolled, 274 (55%) chose PI and 223 (45%) chose AS, of whom 21 (9%) crossed over to delayed intervention. AS patients were older, had worse Eastern Cooperative Oncology Group scores, total comorbidities, and cardiovascular comorbidities, had smaller tumors, and more often had multiple and bilateral lesions. OS for PI and AS was 98% and 96% at 2 yr, and 92% and 75% at 5 yr, respectively (log rank, p=0.06). At 5 yr, CSS was 99% and 100% for PI and AS, respectively (p=0.3). AS was not predictive of OS or CSS in regression modeling with relatively short follow-up. CONCLUSIONS In a well-selected cohort with up to 5 yr of prospective follow-up, AS was not inferior to PI. PATIENT SUMMARY The current report is among the first prospective analyses of patients electing for active surveillance of a small renal mass. Discussion of active surveillance should become part of the standard discussion for management of small renal masses.