Edgar G. Fischer

A phase II evaluation of lapatinib in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: A gynecologic oncology group study☆

OBJECTIVE Activation and dimerization of the ERBB family play a role in the pathogenesis and progression of ovarian cancer. We conducted a phase II trial to evaluate the activity and tolerability of lapatinib in patients with recurrent or persistent epithelial ovarian cancer (EOC) and to explore the clinical value of expression levels of epidermal growth factor receptors (EGFR), phosphorylated EGFR, HER-2/neu, and Ki-67, and the presence of EGFR mutations. METHODS Eligible patients had recurrent or persistent EOC or primary peritoneal carcinoma, measurable disease, and up to 2 prior chemotherapy regimens for recurrent disease. Patients were treated with lapatinib 1500 mg/day. The primary endpoint of efficacy was 6-month progression free survival (PFS). RESULTS Twenty-five of 28 patients were eligible and evaluable for analysis of efficacy and toxicity. Two (8.0%) were alive and progression-free at 6 months. No objective responses were observed. There were 1 grade 4 toxicity (fatigue) and few grade 3 toxicities. Associations between Ki-67 with prior platinum-free interval, PFS, and a polymorphism in EGFR were suggested. CONCLUSIONS Lapatinib has minimal activity in recurrent ovarian cancer. Ki-67 expression may be associated with prior PFS and a polymorphism in EGFR exon 20 (2361G>A, Q787Q).

Lapatinib and potential prognostic value of EGFR mutations in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer

OBJECTIVE A phase II trial was performed to evaluate the efficacy and safety of the tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and HER2, lapatinib, and to explore EGFR, HER2 (EGFR2), phosphorylated ERK MAP kinase (pERK), and Ki67 expression, as well as EGFR mutations in persistent/recurrent endometrial cancer (EC). METHODS Women with histologically-confirmed, measurable, persistent/recurrent EC following one or two prior regimens were eligible and treated with 1500 mg oral lapatinib daily until progression or severe toxicity. A 2-stage group sequential design was used to evaluate the regimen with 6 month PFS as the primary endpoint. The trial had a 10% type I error rate with 90% power. EGFR, HER2, pERK, and Ki67 were evaluated by immunohistochemistry (IHC) from hysterectomy specimens, pre-treatment biopsies, and post-treatment biopsies (when available). Exons 18-21 of EGFR were sequenced. RESULTS Three patients of 30 evaluable had PFS ≥6 months, one had a partial response, seven had stable disease, 21 had progressive disease and one was indeterminate. Three mutations in EGFR were identified. Two of these, L688F and K754E, were not associated with response or PFS. However, a newly identified mutation in exon 18, E690K, occurred in the patient with a partial response and progression-free survival extending past six months. CONCLUSION While lapatinib has limited activity in unselected cases, the identification of a previously unreported mutation in EGFR (E690K) with a response suggests that lapatinib may be beneficial in some cases of EC.

Fabry disease: a morphologic study of 11 cases

Fabry disease is a metabolic disorder caused by the genetic deficiency of alpha-galactosidase A. Deposition of glycosphingolipids in podocytes, endothelial cells, and other cell types leads to formation of myelin-like inclusions, which are the hallmark of the disease. In most untreated males, the disorder progresses to end-stage kidney disease. Fabry disease is rare, and no renal biopsy series focusing on pathologic findings has been published in the past 25 years. We retrieved kidney biopsies diagnosed with Fabry disease from our files, and reviewed clinical data as well as the light and electron microscopy. In total, 11 patients were identified: six male subjects aged 17–43 years and five female subjects aged 30–73 years. On average, male patients presented more than 10 years earlier then female patients. A total of 10 patients had proteinuria, two with the nephrotic syndrome. Four male and three female patients had decreased renal function. Light microscopy showed vacuolization of the podocyte cytoplasm and variable glomerular sclerosis. Older patients and males had more advanced glomerular and interstitial sclerosis, but three of the five female patients also had advanced renal disease. Electron microscopy showed the characteristic myelin-like inclusions most prominently in the podocyte cytoplasm. Seven patients also had podocyte foot process effacement. A second type of deposit, unexpected and conspicuous, was identified in three males, and found to be associated with glomerular basement membrane duplications. These deposits were composed of layered membrane-like material, and therefore morphologically distinct from myelin-like inclusions. They probably represent remnants of damaged endothelial cells.

A phase II evaluation of gefitinib in the treatment of persistent or recurrent endometrial cancer: A Gynecologic Oncology Group study ☆

BACKGROUND A phase II trial was performed to evaluate the efficacy and safety of gefitinib in patients with persistent/recurrent endometrial cancer. METHODS Women with histologically confirmed persistent/recurrent endometrial cancer were treated with 500mg oral gefitinib daily until progression or severe toxicity, with progression-free survival (PFS) at six months as the primary endpoint. Tumor expression of total epidermal growth factor receptor (EGFR), estrogen receptor (ER), progesterone receptor A (PRA) and B (PRB), Ki67, pEGFR and activated extracellular signal-regulated kinase (pERK) were examined pre- and post-treatment. EGFR was sequenced, and serum concentrations of soluble EGFR (sEGFR) at baseline also were examined. RESULTS Of 29 patients enrolled, 26 were evaluable for efficacy and toxicity. Four patients experienced PFS ≥6 months, and one had a complete response which was not associated with an EGFR mutation. The concentration of sEGFR in pretreatment serum was positively correlated with overall survival (OS), but not with responsiveness to gefitinib in this small patient cohort. Expression of tumor biomarkers was not associated with PFS or OS. Co-expression of ER with PRA in primary and recurrent tumors, and pEGFR with pERK in primary tumors was observed. CONCLUSIONS This treatment regimen was tolerable but lacked sufficient efficacy to warrant further evaluation in this setting. The possible association between serum sEGFR concentrations and OS, and temporal changes in expression of pEGFR and pERK and the documented CR of one patient are interesting and warrant additional investigation.

Perinuclear dot-like cytokeratin 20 staining in small cell neuroendocrine carcinoma of the ovary (pulmonary-type).

Primary ovarian small cell carcinomas are rare tumors that are subclassified into the hypercalcemic (HT) and the pulmonary type (PT), and each tumor type has different clinicopathologic characteristics. However, overlapping morphologic features can make the distinction between these lesions difficult. The PT small cell carcinoma is very rare, with only one series and a few case reports published. The authors report two additional cases of this entity and also report for the first time the immunohistochemical finding of perinuclear dot-like staining with cytokeratin 20. This staining pattern has been reported only for Merkel cell carcinoma and salivary gland small cell carcinoma. The authors suggest that the punctate CK20 staining is a useful tool in the diagnostic distinction of PT small cell carcinoma from HT small cell carcinoma, from other primary ovarian tumors such as granulosa cell tumors, and from metastatic neuroendocrine tumors originating at primary sites such as the lung. Since the authors’ conclusions are based on two cases of this rare entity, additional cases will need to be studied in the future.

Early growth response 1 and fatty acid synthase expression is altered in tumor adjacent prostate tissue and indicates field cancerization

Field cancerization denotes the occurrence of molecular alterations in histologically normal tissues adjacent to tumors. In prostate cancer, identification of field cancerization has several potential clinical applications. However, prostate field cancerization remains ill defined. Our previous work has shown up‐regulated mRNA of the transcription factor early growth response 1 (EGR‐1) and the lipogenic enzyme fatty acid synthase (FAS) in tissues adjacent to prostate cancer.

Organ-wide telomeric status in diseased and disease-free prostatic tissues

Telomere attrition occurs early in the development of prostatic adenocarcinoma. However, little is known about either telomere status in benign prostatic hyperplasia (BPH), or the spatial and organ‐wide distribution of potential telomere aberrations throughout all areas of prostatic glands affected by cancer or BPH.

Cholesterol Granulomas of the Lungs Associated With Microangiopathic Hemolytic Anemia and Thrombocytopenia in Pulmonary Hypertension

Cholesterol granulomas unrelated to endogenous lipoid pneumonia, pulmonary alveolar proteinosis, or cholesterol pneumonia are a rare finding during pneumectomy or autopsy. They have been occasionally reported in association with pulmonary hypertension. We report a case where these lesions were associated with long-standing pulmonary hypertension and microangiopathic hemolytic anemia and thrombocytopenia. Plexiform lesions were present in the pulmonary vasculature secondary to pulmonary hypertension, causing hemolysis and thrombocytopenia. We suggest that destruction of red blood cells and platelets could provide membrane lipids that are taken up by phagocytic cells, which promotes the formation of these cholesterol deposits.

Histologic effects of Medroxyprogesterone Acetate on endometrioid endometrial adenocarcinoma: a Gynecologic Oncology Group study

Progestins have been used in the treatment of recurrent endometrial adenocarcinoma for almost 50 yr. Some endometrial carcinomas respond to hormonal therapy, but the mechanism of action remains incompletely known. We wished to determine the efficacy of progestins to induce a histologic response in endometrioid carcinomas and explore its effects on histologic and immunohistochemical measures of growth and cell death. The Gynecologic Oncology Group initiated a study of 75 women with endometrioid endometrial adenocarcinoma, 59 of whom received the progestin, medroxyprogesterone acetate for 21 to 24 d immediately before hysterectomy and had available slides. Initial biopsies and hysterectomies were hematoxylin and eosin-stained and immunostained for estrogen receptor (ER) and progesterone receptor (PR), progesterone receptor-&bgr; (PRB), Bcl-2, Ki-67, and cleaved caspase-3 (Casp3). A histologic response was defined subjectively, following which specific histologic measurements and semiquantitative scores of immunohistologic variables of initial biopsies were compared with posttreatment slides. Only 1 complete histologic response was seen, but 37 tumors (63%) had a partial histologic response. Specific histologic changes included the following: a decrease in the nuclear grade, the number of mitotic figures, nucleoli, and mean gland cellularity, and acquisition of more abundant eosinophilic cytoplasm, squamous metaplasia, and secretion. The tumors that displayed a subjectively defined histologic response following treatment differed initially from those that did not only with respect to initial nuclear grade and the mitotic index. Statistically significant differences in the specific histologic features in carcinomas of responders versus nonresponders following treatment were found only with respect to acquisition of pale eosinophilic cytoplasm and luminal secretion. More than 90% of tumors were initially ER positive and 76% were PR positive. The initial presence of ER or PR was not related to subjective histologic response. PR and PRB were significantly downregulated following progestin therapy, as were Ki-67 and Bcl-2. However, ER and Casp3 did not change significantly. Tumors that displayed a histologic response had significantly lower pretreatment levels of Ki-67. Mean Ki-67 and Bcl-2 decreases following medroxyprogesterone acetate were greater in histologic responders than nonresponders, but not decreases in ER, PR, PRB, and Casp3. The histologic response in the tumors and their stroma differed quantitatively and qualitatively from that of the adjacent benign endometrium, where decidual change accompanied luminal secretion and secretory exhaustion of glands. Three weeks of medroxyprogesterone acetate therapy induces partial histologic responses in most endometrioid adenocarcinomas. Previously suggested features of histologic response do not capture the entire spectrum of changes seen. Downregulation of ER, PR, PRB, Ki-67, and Bcl-2 occurs without a significant change in Casp3. These alterations suggest that progestins act by differentiation of neoplastic cells with diminished proliferation rather than tumor cell death. As stromal decidualization was confined to areas surrounding benign glands, a paracrine effect may be involved in complete response to progestins.

Prostate Field Cancerization: Deregulated Expression of Macrophage Inhibitory Cytokine 1 (MIC-1) and Platelet Derived Growth Factor A (PDGF-A) in Tumor Adjacent Tissue

Prostate field cancerization denotes molecular alterations in histologically normal tissues adjacent to tumors. Such alterations include deregulated protein expression, as we have previously shown for the key transcription factor early growth response 1 (EGR-1) and the lipogenic enzyme fatty acid synthase (FAS). Here we add the two secreted factors macrophage inhibitory cytokine 1 (MIC-1) and platelet derived growth factor A (PDGF-A) to the growing list of protein markers of prostate field cancerization. Expression of MIC-1 and PDGF-A was measured quantitatively by immunofluorescence and comprehensively analyzed using two methods of signal capture and several groupings of data generated in human cancerous (n = 25), histologically normal adjacent (n = 22), and disease-free (n = 6) prostate tissues. A total of 208 digitized images were analyzed. MIC-1 and PDGF-A expression in tumor tissues were elevated 7.1x to 23.4x and 1.7x to 3.7x compared to disease-free tissues, respectively (p<0.0001 to p = 0.08 and p<0.01 to p = 0.23, respectively). In support of field cancerization, MIC-1 and PDGF-A expression in adjacent tissues were elevated 7.4x to 38.4x and 1.4x to 2.7x, respectively (p<0.0001 to p<0.05 and p<0.05 to p = 0.51, respectively). Also, MIC-1 and PDGF-A expression were similar in tumor and adjacent tissues (0.3x to 1.0x; p<0.001 to p = 0.98 for MIC-1; 0.9x to 2.6x; p<0.01 to p = 1.00 for PDGF-A). All analyses indicated a high level of inter- and intra-tissue heterogeneity across all types of tissues (mean coefficient of variation of 86.0%). Our data shows that MIC-1 and PDGF-A expression is elevated in both prostate tumors and structurally intact adjacent tissues when compared to disease-free specimens, defining field cancerization. These secreted factors could promote tumorigenesis in histologically normal tissues and lead to tumor multifocality. Among several clinical applications, they could also be exploited as indicators of disease in false negative biopsies, identify areas of repeat biopsy, and add molecular information to surgical margins.