Timothy A. Jennings

ENDO-RECTAL COIL MAGNETIC RESONANCE IMAGING IN CLINICALLY LOCALIZED PROSTATE CANCER: IS IT ACCURATE?

PURPOSE We assessed the staging accuracy of endo-rectal coil magnetic resonance imaging (MRI) in patients with clinically localized prostate cancer. MATERIALS AND METHODS In a prospective study 56 consecutive patients underwent endo-rectal coil MRI before scheduled surgery. The ability of MRI to identify tumor involvement of the periprostatic soft tissue, seminal vesicles and pelvic lymph nodes was assessed by comparison with final pathological stage. RESULTS Specificity of MRI was relatively high (84% for periprostatic soft tissue, 93% for seminal vesicles and 91% for pelvic lymph nodes) and sensitivity was low (22, 23 and 0%, respectively). Accuracy was 64% for identification of periprostatic soft tissue invasion, 77% for seminal vesicle invasion and 86% for pelvic lymph node metastases. Had we excluded from surgery patients with MRI evidence of extraprostatic disease our organ confined disease rate would have improved by 16.6%. However, this improvement would have been obtained at the expense of incorrectly excluding from surgery 21% of our patients with pathologically organ confined disease because of false-positive MRI predictions. CONCLUSIONS Endo-rectal coil MRI is not sufficiently accurate to influence the treatment of patients with clinically localized prostate cancer. Therefore, we advise against routine use of this imaging modality in staging such cases.

Phase II trial of taxol in salivary gland malignancies (E1394): a trial of the Eastern Cooperative Oncology Group.

Malignant tumors of the salivary glands make up approximately 5% of head and neck cancers. The Eastern Cooperative Oncology Group (ECOG) initiated a phase II evaluation of paclitaxel in patients with locally recurrent or metastatic salivary gland malignancies.

Biomarker-based prediction of response to therapy for colorectal cancer: current perspective.

The diagnosis and management of colorectal cancer (CRC) has been impacted by the discovery and validation of a wide variety of biomarkers designed to facilitate a personalized approach for the treatment of the disease. Recently, CRC has been reclassified based on molecular analyses of various genes and proteins capable of separating morphologic types of tumors into molecular categories. At the same time, a number of new prognostic and predictive single genes and proteins have been discovered that are designed to reflect sensitivity and/or resistance to existing therapies. Multigene predictors have also been developed to predict the risk of relapse for intermediate-stage CRC after completion of surgical extirpation. More recently, a number of biomarkers tested by a variety of methods have been proposed as specific predictors of chemotherapy and radiotherapy response. Other markers have been successfully used to predict toxic effects of standard therapies. In this review, a series of novel biomarkers are considered and compared with standard-of-care markers for their potential use as pharmacogenomic and pharmacogenetic predictors of disease outcome.

Association of p53 immunoreactivity with high gleason tumor grade in prostatic adenocarcinoma

To determine whether p53 immunoreactivity correlates with the Gleason tumor grade in primary adenocarcinoma of the prostate we analyzed 107 consecutive surgical specimens (78 radical prostatectomies and 29 transurethral resections). A hematoxylin-eosin-stained slide from a representative block of each tumor was examined, and primary and secondary Gleason scores were assigned in each case. Additional paraffin sections from the same block were stained immunohistochemically for p53 expression using the monoclonal antibody clone DO-1, a mouse IgG2a directed against a denaturation-resistant epitope of p53. Four of 54 (7.4%) low-grade tumors (combined Gleason score of 6 and below) and 11 of 53 (20.8%) high-grade tumors (combined Gleason score of 7 and above) revealed strong nuclear positivity for p53. When evaluated using only the primary Gleason score, none of 23 (0%) Gleason grade 2 tumors and 15 of 84 (17.9%) Gleason grade 3 or higher tumors were positive. These data demonstrate a positive association between p53 immunoreactivity and higher Gleason grade tumors (P = .04 for the combined score, P = .02 for primary score only). In addition, we noted occasional p53-positive nuclei in basal cells of benign glandular acini in regions flanking tumor. Focally positive nuclear staining also was demonstrated in basal cells from nine of 25 prostate glands exhibiting benign prostatic hyperplasia with no tumor. These results suggest that p53 overexpression might be associated with the known proliferative capacity of basal cells in benign hyperplastic prostate glands, and that mutations of p53 might play a role in the pathogenesis of a subset of high-grade prostate adenocarcinomas.

A High Frequency of Activating Extracellular Domain ERBB2 (HER2) mutation in Micropapillary Urothelial Carcinoma

Purpose: Micropapillary urothelial carcinoma (MPUC) is a rare and aggressive form of bladder cancer. We conducted genomic analyses [next-generation sequencing (NGS)] of MPUC and non-micropapillary urothelial bladder carcinomas (non-MPUC) to characterize the genomic landscape and identify targeted treatment options. Experimental Design: DNA was extracted from 40 μm of formalin-fixed paraffin-embedded sections from 15 MPUC and 64 non-MPUC tumors. Sequencing (NGS) was performed on hybridization-captured, adaptor ligation–based libraries to high coverage for 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The results were evaluated for all classes of genomic alteration. Results: Mutations in the extracellular domain of ERBB2 were identified in 6 of 15 (40%) of MPUC: S310F (four cases), S310Y (one case), and R157W (one case). All six cases of MPUC with ERBB2 mutation were negative for ERBB2 amplification and Erbb2 overexpression. In contrast, 6 of 64 (9.4%) non-MPUC harbored an ERBB2 alteration, including base substitution (three cases), amplification (two cases), and gene fusion (one case), which is higher than the 2 of 159 (1.3%) protein-changing ERBB2 mutations reported for urinary tract cancer in COSMIC. The enrichment of ERBB2 alterations in MPUC compared with non-MPUC is significant both between this series (P < 0.0084) and for all types of urinary tract cancer in COSMIC (P < 0.001). Conclusions: NGS of MPUC revealed a high incidence of mutation in the extracellular domain of ERBB2, a gene for which there are five approved targeted therapies. NGS can identify genomic alteration, which inform treatment options for the majority of MPUC patients. Clin Cancer Res; 20(1); 68–75. ©2013 AACR.

Prediction of pathologic stage and postprostatectomy disease recurrence by dna ploidy analysis of initial needle biopsy specimens of prostate cancer

Background. DNA ploidy determination of carcinomas in radical prostatectomy specimens has shown significant correlation with patient outcome, but the predictive value of ploidy status of cancers obtained by transrectal ultrasound‐guided needle biopsies has not been studied extensively.

Needle biopsy DNA ploidy status predicts grade shifting in prostate cancer.

DNA ploidy analysis of prostate needle biopsy specimens was performed to determine whether ploidy status could predict tumor grade shifting at radical prostatectomy. The paired needle biopsy and radical prostatectomy specimens from 111 randomly selected men with prostate cancer were obtained from the surgical pathology files of the Albany Medical Center Hospital. The original tumor grades were assigned by a staff of 12 surgical pathologists according to the Gleason system. Tumors with original Gleason scores < or = 6 were classified as low grade, and tumors with scores of > or = 7 were considered high grade. DNA ploidy analysis was performed on the needle biopsy specimens using the CAS 200 image analyzer (Becton Dickinson Immunocytometry Systems, Mountain View, CA, USA) on Feulgen stained 5-microm tissue sections. There were 88 diploid and 23 nondiploid cases. Thirty-eight of 111 (34%) of cases had grade shifting from needle biopsy to radical prostatectomy specimens. Of 89 low-grade needle biopsy cases, 28 (31%) were upgraded at radical prostatectomy. Of 22 high-grade needle biopsy cases, 10 (45%) were downgraded to low grade at radical prostatectomy. Of the 28 low-grade needle biopsy specimens that were upgraded at radical prostatectomy, 19 (68%) featured an aneuploid histogram and 9 (32%) were diploid. Nineteen of 28 (68%) of aneuploid low-grade tumors on needle biopsy became high-grade at radical prostatectomy. Nine of 10 (90%) diploid high-grade tumors at needle biopsy became low-grade at radical prostatectomy. Of the 38 cases in which ploidy and grade were incongruous, 28 (74%) had grade shifting. In a multivariate regression analysis, a high-grade Gleason score on radical prostatectomy specimens correlated significantly with needle biopsy ploidy (p = 0.0001) but not with needle biopsy grade (p = 0.15). The sensitivity of the needle biopsy grade in the detection of high-grade tumors on radical prostatectomy was 30%, and the specificity was 86%. The sensitivity of ploidy status in the prediction of high grade at radical prostatectomy was 78%, and the specificity was 96%. With a prostate-specific antigen (PSA) level of >0.4 ng/ml as the indicator of post-radical prostatectomy disease recurrence on a subset of 106 patients, on univariate analysis, disease recurrence was predicted by needle biopsy ploidy (p = 0.001) and radical prostatectomy grade (p = 0.04) but not by needle biopsy grade (p = 0.39). On multivariate analysis, needle biopsy DNA ploidy status independently predicted disease recurrence (p = 0.002), whereas needle biopsy and prostatectomy grade did not. These results indicate that DNA ploidy analysis of needle biopsy specimens of prostate cancer predicts grade shifting, that it is a more sensitive and specific indicator of final tumor grade at radical prostatectomy than is the original needle biopsy grade, and that ploidy status independently predicts postoperative disease recurrence.

Comprehensive Genomic Profiling of Relapsed and Metastatic Adenoid Cystic Carcinomas by Next-generation Sequencing Reveals Potential New Routes to Targeted Therapies

Abstract:We hypothesized that next-generation sequencing could reveal actionable genomic alterations (GAs) and potentially expand treatment options for patients with advanced adenoid cystic carcinoma (ACC). Genomic profiling using next-generation sequencing was performed on hybridization-captured, adapter ligation libraries derived from 28 relapsed and metastatic formalin-fixed paraffin-embedded ACC. The 3230 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer were fully sequenced using the Illumina HiSeq 2000. All classes of GAs were evaluated. Actionable GAs were defined as those impacting targeted anticancer therapies on the market or in registered clinical trials. A total of 44 GAs were identified in the 28 ACC tumors, with 12 of 28 (42.9%) of tumors harboring at least 1 potentially actionable GA. The most common nonactionable GAs were identified in KD6MA (5 cases; 18%), ARID1A (4 cases; 14%), RUNX1 (2 cases; 7%), and MYC (2 cases; 7%). Actionable GAs included NOTCH1 (3 cases; 11%), MDM2 (2 cases; 7%), PDGFRA (2 cases; 7%), and CDKN2A/B (p16) (2 cases; 7%). Other potentially actionable GAs identified in a single case included: mutations in AKT1, BAP1, EGFR, and PIK3CA, homozygous deletion of FBXW7, and amplifications of CDK4, FGFR1, IGF1R, KDR, KIT, and MCL1. The frequency of GA in ACC is lower than that seen in the more common solid tumors. Comprehensive genomic profiling of ACC can identify actionable GAs in a subset of patients that could influence therapy for these difficult-to-treat progressive neoplasms.

Prostaglandin-endoperoxide H Synthase-2 Expression in Human Thyroid Epithelium EVIDENCE FOR CONSTITUTIVE EXPRESSION IN VIVO AND IN CULTURED KAT-50 CELLS

Prostaglandin-endoperoxide H synthase (PGHS) (EC1.14.99.1) expression was examined in human thyroid tissue and in KAT-50, a well differentiated human thyroid epithelial cell line. PGHS-1 is found constitutively expressed in most healthy tissues, whereas PGHS-2 is highly inducible and currently thought to be expressed, with few exceptions, only in diseased tissues. Surprisingly, PGHS-2 mRNA and protein were easily detected in normal thyroid tissue. KAT-50 cells express high levels of constitutive PGHS-2 mRNA and protein under basal culture conditions. Compounds usually associated with PGHS-2 induction, including interleukin-1β (IL-1β), phorbol 12-myristate 13-acetate, and serum transiently down-regulated PGHS-2 expression. Human PGHS-2 promoter constructs (−1840/+123 and −831/+123) fused to a luciferase reporter and transfected into untreated KAT-50 cells exhibited substantial activity. NS-398, a highly selective inhibitor of PGHS-2 could inhibit substantial basal prostaglandin E2 production. Exogenous IL-1 receptor antagonist or IL-1α neutralizing antibodies could attenuate constitutive PGHS-2 expression in KAT-50 cells, suggesting that endogenous IL-1α synthesis was driving PGHS-2 expression. Our findings suggest that normal thyroid epithelium expresses high constitutive levels of PGHS-2 in situ andin vitro and this enzyme is active in the generation of prostaglandin E2. Thus, unprovoked PGHS-2 expression might be considerably more widespread in healthy tissues than is currently believed.

Choriocarcinoma presenting as a cutaneous metastasis.

The rare presentation of choriocarcinoma as a cutaneous metastasis in a 23‐year‐old male is reported. Histological and immunohistochemical analysis of the biopsy material demonstrated two distinct cell populations, syncytiotrophoblasts and cytotrophoblasts, with syncytiotrophoblasts strongly positive for human chorionic gonadotropin antigen. Subsequent clinical evaluation revealed a testicular tumor with metastases to lungs, brain, liver and kidney and increased serum levels of human chorionic gonadotropin. The patient died shortly alter diagnosis due to complications of metastatic disease despite chemotherapy.