Hugh A.G. Fisher

High-dose carboplatin and etoposide with autologous bone marrow transplantation in refractory germ cell cancer: an Eastern Cooperative Oncology Group protocol.

PURPOSE A phase II trial was undertaken to assess the feasibility, toxicity, and efficacy of high-dose carboplatin and etoposide with autologous bone marrow transplantation in patients with relapsed or refractory germ cell tumors. PATIENTS AND METHODS Forty patients with recurrent germ cell cancer received carboplatin 500 mg/m2 and etoposide 400 mg/m2 given at 7, 5, and 3 days before marrow infusion. Autologous marrow infusion (day 0) was accomplished using one half of the bone marrow harvested before chemotherapy. Patients who achieved a complete or partial response with the first cycle of treatment received a second identical cycle of chemotherapy followed by infusion of the remaining cryopreserved bone marrow. RESULTS Objective responses were obtained in 17 of the 38 patients (45%) assessable for response, including eight partial and nine complete remissions. Five of these patients remain in continuous complete remission with minimal follow-up of 1 year. Toxicity encountered was primarily hematologic, and five patients (13%) died of treatment-related complications. Significant toxicities often seen with high-dose cisplatin (ototoxicity, neurotoxicity, and renal toxicity) were manageable in this regimen of high-dose carboplatin. CONCLUSIONS This trial confirms the curative potential of high-dose carboplatin and etoposide in highly refractory germ cell cancer.

Expression of Nuclear Factor-κB and IκBα Proteins in Prostatic Adenocarcinomas: Correlation of Nuclear Factor-κB Immunoreactivity with Disease Recurrence

Purpose: The nuclear transcription factor nuclear factor-κB (NFκB) and its inhibitor, IκB, regulate the transcription of various genes involved in cell proliferation, adhesion, and survival. The NFκB transcription factor complex plays a role in cancer development and progression through its influence on apoptosis. More recently, NFκB has been shown to be activated in human and androgen-independent prostate cancer cells. To our knowledge, this is the first study demonstrating the prognostic significance of NFκB immunoreactivity in prostate adenocarcinomas (PACs). Experimental Design: Using prostatectomy specimens, we performed immunohistochemical staining for NFκB and IκBα (Santa Cruz Biotechnology) on formalin-fixed, paraffin-embedded sections obtained from 136 patients with PAC. Cytoplasmic and nuclear immunoreactivity was scored for intensity and distribution, and results were correlated with preoperative serum prostate-specific antigen, tumor grade, stage, DNA ploidy (Feulgen spectroscopy), and biochemical disease recurrence. Results: Forty-nine percent of PACs overexpressed cytoplasmic NFκB, and 63% showed decreased IκB expression. Cytoplasmic NFκB overexpression correlated with advanced tumor stage (P = 0.048), aneuploidy (P = 0.022), and biochemical disease recurrence (P = 0.001). When we compared the means for the NFκB-positive and -negative subgroups, NFκB overexpression correlated with preoperative serum prostate-specific antigen (P = 0.04) and DNA index (P = 0.05). Fifteen percent of PACs expressed nuclear NFκB, which correlated with high tumor grade (P = 0.001) and advanced stage (P = 0.05). Decreased IκBα expression correlated with high tumor grade (P = 0.015). On multivariate analysis, tumor stage (P = 0.043) and NFκB overexpression (P = 0.006) were independent predictors of biochemical recurrence. Conclusion: These results support a role for NFκB pathway proteins in the tumorigenesis of PACs. The findings are also consistent with reported experimental studies suggesting a new strategy of combined chemotherapy and specific NFκB blockade in decreasing the rate of disease relapse.PURPOSE The nuclear transcription factor nuclear factor-kappa B (NF kappa B) and its inhibitor, I kappa B, regulate the transcription of various genes involved in cell proliferation, adhesion, and survival. The NF kappa B transcription factor complex plays a role in cancer development and progression through its influence on apoptosis. More recently, NF kappa B has been shown to be activated in human and androgen-independent prostate cancer cells. To our knowledge, this is the first study demonstrating the prognostic significance of NF kappa B immunoreactivity in prostate adenocarcinomas (PACs). EXPERIMENTAL DESIGN Using prostatectomy specimens, we performed immunohistochemical staining for NF kappa B and I kappa B alpha (Santa Cruz Biotechnology) on formalin-fixed, paraffin-embedded sections obtained from 136 patients with PAC. Cytoplasmic and nuclear immunoreactivity was scored for intensity and distribution, and results were correlated with preoperative serum prostate-specific antigen, tumor grade, stage, DNA ploidy (Feulgen spectroscopy), and biochemical disease recurrence. RESULTS Forty-nine percent of PACs overexpressed cytoplasmic NF kappa B, and 63% showed decreased I kappa B expression. Cytoplasmic NF kappa B overexpression correlated with advanced tumor stage (P = 0.048), aneuploidy (P = 0.022), and biochemical disease recurrence (P = 0.001). When we compared the means for the NF kappa B-positive and -negative subgroups, NF kappa B overexpression correlated with preoperative serum prostate-specific antigen (P = 0.04) and DNA index (P = 0.05). Fifteen percent of PACs expressed nuclear NF kappa B, which correlated with high tumor grade (P = 0.001) and advanced stage (P = 0.05). Decreased I kappa B alpha expression correlated with high tumor grade (P = 0.015). On multivariate analysis, tumor stage (P = 0.043) and NF kappa B overexpression (P = 0.006) were independent predictors of biochemical recurrence. CONCLUSION These results support a role for NF kappa B pathway proteins in the tumorigenesis of PACs. The findings are also consistent with reported experimental studies suggesting a new strategy of combined chemotherapy and specific NF kappa B blockade in decreasing the rate of disease relapse.

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.

HER-2/neu gene amplification status in prostate cancer by fluorescence in situ hybridization

HER-2/neu expression has been established as a prognostic factor in breast and other cancers. In prostate cancer (PC), a similar predictive role has been hindered by variable immunohistochemical (IHC) results. The authors studied DNA amplification of the HER-2/neu gene on 4-microm sections obtained from 62 formalin-fixed, paraffin-embedded PCs by fluorescence in situ hybridization (FISH). The results were compared with HER-2/neu protein expression as determined by IHC and correlated by logistic regression analysis with Gleason tumor grade, DNA ploidy, serum prostate specific antigen (PSA), and pathological stage. The HER-2/neu gene was localized using the Oncor (Gaithersburg, MD) digoxigenin-labeled unique sequence probe. Amplified PCs had at least 20 malignant cells, with 5 or more copies of the sequence. Amplification of HER-2/neu correlated with Gleason score (P = .0001). The mean Gleason score of unamplified tumors was 5.7 and that of amplified tumors was 7.5. Nondiploid tumors had a significantly greater rate of HER-2/neu amplification compared with diploid tumors (P = .0003). Of the 62 cases evaluated by IHC and FISH, 18 cases (29%) were overexpressed by IHC, and 27 cases (44%) were amplified by FISH. A trend for similar HER-2/neu status in each PC by the two methods did not reach statistical significance (P = .23). HER-2/neu amplification by FISH was associated with advanced pathological stage; however, this relationship reached only near-statistical significance (P = .06). There was no correlation of HER-2/neu amplification by FISH with patient age or preoperative serum PSA levels. The authors conclude that HER-2/neu gene amplification status can be determined by FISH on archival prostate cancer specimens, significantly correlates with high tumor grade and nondiploid DNA content, and is more frequently encountered in tumors with advanced pathological stage. Also, FISH is more sensitive than IHC for detection of abnormalities in the HER-2/neu gene, and further studies should be undertaken to determine whether a FISH-based HER-2/neu detection method may prove of importance in the prediction of prognosis and planning of therapy in prostate cancer patients.

Decreased levels of CD44 protein and mRNA in prostate carcinoma: Correlation with tumor grade and ploidy

CD44, a transmembrane protein, is associated with cell‐cell and cell‐matrix interaction and with tumor growth and metastasis. Expression of both standard form and variant isoforms of CD44 protein has been associated with aggressive behavior and metastasis in various tumors, but has not been characterized in prostate adenocarcinoma (PAC).

Prognostic significance of matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 expression in prostate cancer.

Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading the structural support network for normal and malignant cells, promoting neoplastic cell invasion and metastasis. Tissue inhibitors of metalloproteinases (TIMPs) maintain connective tissue integrity by modulating MMP activity. Formalin-fixed paraffin-embedded tissue sections from 138 prostatic adenocarcinomas (PACs) were immunostained by a combined automated/manual method using monoclonal antibodies against MMP2 and TIMP2. Immunoreactivity was semiquantitatively scored based on stain intensity and distribution, and results were correlated with Gleason grade, pathologic stage, ploidy status, and disease recurrence. One hundred five of 138 (76%) and 113/138 (82%) PACs expressed MMP2 and TIMP2, respectively. Co-expression was observed in 94/138 (68%) of PACs (P = .01), correlated with advanced tumor stage (P = .05), and tended to be associated with disease recurrent cases (P = .07). TIMP2 expression individually correlated with advanced tumor stage (P = .04) and reached near significance with disease recurrence (P = .06). MMP2 expression was also more frequent in recurrent PACs, although this value did not reach statistical significance (P = .07). However, on multivariate analysis, only pathologic stage (P = .009) and ploidy status (P = .03) independently predicted disease recurrence. In conclusion, MMP2 and TIMP2 are co-expressed in a majority of PACs and correlate with prognostic variables. Interestingly, contrary to the previously documented anti-tumor effects of TIMPs, TIMP2 expression appears to have a tumor-promoting role in PACs and warrants further investigation.

Correlation of p34cdc2 cyclin-dependent kinase overexpression, CD44s downregulation, and HER-2/neu oncogene amplification with recurrence in prostatic adenocarcinomas.

PURPOSE To test whether p34cdc2 overexpression, CD44s downregulation, and HER-2/neu amplification correlate with disease recurrence after radical prostatectomy, and to evaluate a possible biologic association between p34cdc2 and HER-2/neu expression. MATERIALS AND METHODS Immunohistochemical (IHC) detection of both p34cdc2 cyclin-dependent kinase (CDK) and CD44s expression and fluorescence in situ hybridization (FISH)-based analysis of HER-2/neu gene status were performed on formalin-fixed, paraffin-embedded sections of 106 prostatic adenocarcinomas (PACs). Findings were correlated with Gleason grade, pathologic stage, DNA ploidy, and postsurgical biochemical disease recurrence. RESULTS CDK overexpression correlated with tumor grade (P = .001), DNA ploidy (P = .001), pathologic stage (P = .04), and disease recurrence (P = .01). CD44s downregulation correlated with grade (P = .03), ploidy (P = .01), and recurrence (P = .02). HER-2/neu amplification correlated with grade (P = .001), ploidy (P = .001), and recurrence (P = .01). On multivariate analysis, CDK overexpression independently predicted recurrence (P = .001) after prostatectomy. CDK expression correlated with HER-2/neu status with 32 of 65 (49%) tumors that overexpressed CDK and showed concomitant HER-2/neu amplification (P = .04). CONCLUSION This study showed that p34cdc2, CD44s, and HER-2/neu are variably expressed or amplified in prostatic carcinoma and that such alteration may affect tumor behavior. In addition, CDK overexpression and HER-2/neu amplification may be biologically related.

Localized lymphedema (elephantiasis): a case series and review of the literature

Background:  Lymphedema typically affects a whole limb. Rarely, lymphedema can present as a circumscribed plaque or an isolated skin tumor.

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.

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.