Gary L. Keeney

Retrospective review of 208 patients with leiomyosarcoma of the uterus: prognostic indicators, surgical management, and adjuvant therapy☆

Abstract Objective We evaluated the predictive value of several proposed prognostic indicators and the effect of surgical management and adjuvant therapy on clinical outcome associated with leiomyosarcoma (LMS) of the uterus. Methods A medical record search of patients treated at Mayo Clinic from 1976 through 1999 was performed using the International Classification of Diseases, Ninth Revision codes for LMS and malignant neoplasm of the uterus. Study inclusion criteria included confirmation of the diagnosis of LMS of the uterus by a pathologist at our institution. Survival curves were generated using the Kaplan–Meier method. Multivariate analysis was performed using the Cox proportional hazards model. A case-control investigation was also performed. Results A total of 208 patients met study requirements. The median follow-up for survivors was 7.7 years. Multivariate analysis showed that high grade, advanced stage, and oophorectomy were associated with significantly worse disease-specific survival. Case-control investigations suggested that ovarian preservation does not adversely affect survival and that adjuvant pelvic radiation therapy does not significantly improve survival. An LMS risk-assessment index that was generated is highly predictive of survival. Conclusions Tumor grade and stage (using modified criteria for endometrial cancer) appear to be valid prognostic indicators for LMS of the uterus. Ovarian preservation may be considered in premenopausal patients with early-stage leiomyosarcoma of the uterus. Additionally, adjuvant therapy does not appear to significantly affect survival. Finally, our highly predictive LMS risk-assessment index may be useful for counseling patients.

Folate receptor alpha as a tumor target in epithelial ovarian cancer.

OBJECTIVES Folate receptor alpha (FRalpha) is a folate-binding protein overexpressed on ovarian and several other epithelial malignancies that can be used as a target for imaging and therapeutic strategies. The goal of this study is to improve historical data that lack specific information about FRalpha expression in rare histological subtypes, primary disease versus metastatic foci, and recurrent disease. METHODS FRalpha expression was analyzed by immunohistochemistry on 186 primary and 27 recurrent ovarian tumors, including 24 pairs of samples obtained from the same individuals at diagnosis and at secondary debulking surgery. For 20 of the 186 primaries, simultaneous metastatic foci were also analyzed. FRalpha staining was analyzed in light of disease morphology, stage, grade, debulking status, and time from diagnosis to recurrence and death. RESULTS FRalpha expression was apparent in 134 of 186 (72%) primary and 22 of 27 (81.5%) recurrent ovarian tumors. In 21 of 24 (87.5%) matched specimens, recurrent tumors reflected the FRalpha status detected at diagnosis. Metastatic foci were similar to primary tumors in FRalpha staining. FRalpha status was not associated with time to recurrence or overall survival in either univariate or multivariable analyses. CONCLUSION FRalpha expression occurs frequently, especially in the common high-grade, high-stage serous tumors that are most likely to recur. New findings from this study show that FRalpha expression is maintained on metastatic foci and recurrent tumors, suggesting that novel folate-targeted therapies may hold promise for the majority of women with either newly diagnosed or recurrent ovarian cancer.

HER-2/neu expression: A major prognostic factor in endometrial cancer☆

The HER-2/neu oncogene encodes for a specific cell-surface glycoprotein similar to the human growth factor receptor. An analysis of 247 patients with endometrial cancer treated between 1979 and 1983 was performed using an immunoperoxidase technique on paraffin-embedded tissue samples to detect HER-2/neu overexpression. Specimens were graded blindly with regard to HER-2/neu staining intensity. Overexpression of HER-2/neu was identified as strong in 37 patients (15%), mild in 144 (58%), and none in 66 (27%). The 5-year progression-free survival was 56% for the strong, 83% for the mild, and 95% for the nonstaining groups. The strong (P < 0.0001) and the mild (P = 0.028) staining groups were distinct from the nonstaining group in predicting progression-free survival. Likewise, strong overexpression was associated with a poor (51%) overall survival (P < 0.0001). Multivariate analysis revealed that intense overexpression had independent significance in predicting progression-free (P = 0.0003) and overall survival (P < 0.0001). In stage I patients (203), the 5-year progression-free survival was 62% for the strong and 97% for the nonstaining groups (P = 0.0007). This retained independent significance when subjected to multivariate analysis (P = 0.0017). Other significant stage I prognostic factors in multivariate analysis included DNA ploidy, histologic subtype, and histologic grade but not depth of invasion.

Phase I Trial of Intraperitoneal Administration of an Oncolytic Measles Virus Strain Engineered to Express Carcinoembryonic Antigen for Recurrent Ovarian Cancer

Edmonston vaccine strains of measles virus (MV) have shown significant antitumor activity in preclinical models of ovarian cancer. We engineered MV to express the marker peptide carcinoembryonic antigen (MV-CEA virus) to also permit real-time monitoring of viral gene expression in tumors in the clinical setting. Patients with Taxol and platinum-refractory recurrent ovarian cancer and normal CEA levels were eligible for this phase I trial. Twenty-one patients were treated with MV-CEA i.p. every 4 weeks for up to 6 cycles at seven different dose levels (10(3)-10(9) TCID(50)). We observed no dose-limiting toxicity, treatment-induced immunosuppression, development of anti-CEA antibodies, increase in anti-MV antibody titers, or virus shedding in urine or saliva. Dose-dependent CEA elevation in peritoneal fluid and serum was observed. Immunohistochemical analysis of patient tumor specimens revealed overexpression of measles receptor CD46 in 13 of 15 patients. Best objective response was dose-dependent disease stabilization in 14 of 21 patients with a median duration of 92.5 days (range, 54-277 days). Five patients had significant decreases in CA-125 levels. Median survival of patients on study was 12.15 months (range, 1.3-38.4 months), comparing favorably to an expected median survival of 6 months in this patient population. Our findings indicate that i.p. administration of MV-CEA is well tolerated and results in dose-dependent biological activity in a cohort of heavily pretreated recurrent ovarian cancer patients.

Folate receptor overexpression is associated with poor outcome in breast cancer

The high affinity folate receptor is a membrane‐associated glycoprotein that is preferentially expressed in cancers of epithelial origin and rarely expressed in normal cells. We examined its expression pattern in breast cancer, utilizing a tissue microarray containing samples from 63 invasive breast cancers from women with divergent clinical outcomes. Thirty‐three women comprised the poor outcome group with a median time to recurrence of 1.9 years. Thirty women, the good outcome group, were free of recurrence for a minimum of 7 years after diagnosis. The intensity of folate receptor staining was strongly correlated with outcome. There were two summary categories of staining intensity: weak (n = 42) or strong (n = 21). In the strong staining group, 17 of 21 women (81%) have recurred and their median survival is 2.4 years. In the weak staining group, 16 of 42 women (38%) have recurred. Their median survival is not estimable. After adjustment for tumor size, nodal status, ER status, adjuvant therapy, histology and tumor grade, strong staining for the folate receptor remained significantly associated with poor outcome, p < 0.001. Our work requires validation in a larger cohort, but supports the possibility of using folate receptor‐targeted approaches in the management of breast cancer.

Prognostic significance of p53 immunostaining in epithelial ovarian cancer.

PURPOSE To evaluate the prognostic significance of p53 expression in epithelial ovarian cancer, including a subset of stage I patients, and to look for correlations between p53 expression and other disease parameters, including stage, grade, age, histologic subtype, second-look results, ploidy, and percent S phase. PATIENTS AND METHODS We analyzed p53 expression in 284 patients with epithelial ovarian cancer using immunohistochemical techniques in paraffin-embedded specimens. There were 36 patients with stage I disease, 20 with stage II disease, 186 with stage III disease, and 42 with stage IV disease. RESULTS p53 immunoreactivity was present in 177 cases (62%). p53 expression was associated with grade 3 to 4 disease (P = .003). The following factors were associated with a decrease in overall survival in a univarate analysis: stage III or IV disease (P = .0001), grade 3 or 4 disease (P = .0001), age above the median (P = .0002), and p53 reactivity (P = .04). In a multivariate analysis, stage, grade, and age retained independent prognostic significance. In the subset of 36 stage I patients, p53 positively approached statistical significance (P = .10) as a negative prognostic factor in a univariate analysis. CONCLUSION Abnormalities of p53 expression occur commonly in epithelial ovarian cancer. Although associated with decreased survival in a univariate analysis, this biologic marker did not retain independent prognostic significance in a multivariate analysis. p53 expression should be studied in a larger cohort of early-stage patients, where accurate prognostic information is needed to direct therapy.

Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study

BACKGROUND Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival. METHODS 12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (≥50%). Associations with disease-specific survival were assessed. FINDINGS 2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21-0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55-0·91; p=0·0080), but weak PR expression was not (1·02, 0·89-1·18; p=0·74). INTERPRETATION PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer. FUNDING Carraresi Foundation and others.

Papillary serous carcinoma of the peritoneum. A review of 33 cases treated with platin-based chemotherapy

Thirty‐three patients were identified who had papillary serous carcinoma of the peritoneum (PSCP). The gross operative specimens, histopathologic condition, and treatment records were reviewed. The median age at presentation was 60 years (age range, 22 to 78 years). Abdominal pain and distention were the most common presenting symptoms. All patients had a total abdominal hysterectomy and bilateral salpingo‐oophorectomy, and all but two had debulking surgery. All patients had disease involving the omentum, the abdominal and pelvic peritoneum, and the surface of the ovaries, but none had intrinsic disease of the ovaries. Eight patients had disease outside of the abdominal cavity. Seven of these patients had malignant pleural effusions. All patients received platin‐based chemotherapy. Sixteen patients underwent second‐look laparotomy, two had no evidence of disease, and one had microscopic disease only. The median survival time for all patients was 17 months. Three patients are alive 6 to 7 years after the initial diagnosis. In conclusion, longterm survival can be achieved in some PSCP patients by debulking surgery and platin‐based chemotherapy.

Seroma-associated primary anaplastic large-cell lymphoma adjacent to breast implants: an indolent T-cell lymphoproliferative disorder.

Non-Hodgkin lymphomas of the breast are rare, encompassing approximately 0.04–0.5% of all malignant breast tumors, and the vast majority are B-cell lymphomas. In contrast, lymphomas of T-cell phenotype have been rarely reported and some of these have been in close proximity to a breast implant. In our consultation practice, we have identified four patients with primary T-cell anaplastic large-cell lymphoma presenting adjacent to silicone or saline breast implants. All patients presented with seroma and neoplastic cells were identified in suspension in the serous fluid without solid tissue invasion. Three patients had no evidence of systemic disease (stage 1E), and one patient was not staged. The mean age of the patients was 46 years (range, 34–59 years). In all patients, the neoplastic cells had a T-cell phenotype, expressed CD30, cytotoxic granule-associated proteins, EMA and clusterin, and were anaplastic lymphoma kinase-1-negative. Clonal T-cell receptor γ-chain gene rearrangements were identified in three patients. All patients underwent capsulectomy with removal of the implant. One patient subsequently received chemotherapy and radiation therapy, and another was treated with radiation alone. The third patient received no further therapy and the fourth patient has been recently diagnosed. After a mean time of 13 months (range, 9–20 months), all three patients with follow-up were alive and well without any recurrence or systemic disease. Although the follow-up time was relatively short, our series and other reported cases suggest that primary anaplastic large-cell lymphoma adjacent to breast implants is an indolent T-cell lymphoproliferative disorder.

Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity

Resistance to chemotherapy presents a serious challenge in the successful treatment of various cancers and is mainly responsible for mortality associated with disseminated cancers. Here we show that expression of HtrA1, which is frequently downregulated in ovarian cancer, influences tumor response to chemotherapy by modulating chemotherapy-induced cytotoxicity. Downregulation of HtrA1 attenuated cisplatin- and paclitaxel-induced cytotoxicity, while forced expression of HtrA1 enhanced cisplatin- and paclitaxel-induced cytotoxicity. HtrA1 expression was upregulated by both cisplatin and paclitaxel treatment. This upregulation resulted in limited autoproteolysis and activation of HtrA1. Active HtrA1 induces cell death in a serine protease-dependent manner. The potential role of HtrA1 as a predictive factor of clinical response to chemotherapy was assessed in both ovarian and gastric cancer patients receiving cisplatin-based regimens. Patients with ovarian or gastric tumors expressing higher levels of HtrA1 showed a higher response rate compared with those with lower levels of HtrA1 expression. These findings uncover what we believe to be a novel pathway by which serine protease HtrA1 mediates paclitaxel- and cisplatin-induced cytotoxicity and suggest that loss of HtrA1 in ovarian and gastric cancers may contribute to in vivo chemoresistance.