Whitfield B. Growdon

Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson's disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity.

A mutation in the α-synuclein gene has recently been linked to some cases of familial Parkinsons disease (PD). We characterized the expression of this presynaptic protein in the midbrain, striatum, and temporal cortex of control, PD, and dementia with Lewy bodies (DLB) brain. Control brain showed punctate pericellular immunostaining. PD brain demonstrated α-synuclein immunoreactivity in nigral Lewy bodies, pale bodies and abnormal aeurites. Rare neuronal soma in PD brain were immunoreactive for α-synuclein. DLB cases demonstrated these findings as well as α-synuclein immunoreactivity in cortical Lewy bodies and CA2-3 neurites. These results suggest that, even in sporadic cases, there is an early and direct role for α-synuclein in the pathogenesis of PD and the neuropathologically related disorder DLB.

Clinicopathologic correlates in temporal cortex in dementia with Lewy bodies

Objective: To address the relationship between dementia and neuropathologic findings in dementia with Lewy bodies (DLB) in comparison with AD. Methods: We evaluated the clinical presentation of autopsy-confirmed DLB in comparison with AD according to new Consortium on DLB criteria and compared the two conditions using quantitative neuropathologic techniques. This clinicopathologic series included 81 individuals with AD, 20 with DLB (7 “pure” DLB and 13 “DLB/AD”), and 33 controls. We counted number of LB, neurons, senile plaques (SP), and neurofibrillary tangles (NFT) in a high order association cortex, the superior temporal sulcus (STS), using stereologic counting techniques. Results: The sensitivity and specificity of Consortium on DLB clinical criteria in this series for dementia, hallucinations, and parkinsonism are 53% and 83%, respectively, at the patient’s initial visit and 90% and 68%, respectively, if data from all clinic visits are considered. In pathologically confirmed DLB brains, LB formation in an association cortical area does not significantly correlate with duration of illness, neuronal loss, or concomitant AD-type pathology. Unlike AD, there is no significant neuronal loss in the STS of DLB brains unless there is concomitant AD pathology (neuritic SP and NFT). Conclusions: The evaluation of new Consortium on DLB criteria in this series highlights their utility and applicability in clinicopathologic studies but suggests that sensitivity and specificity, especially at the time of the first clinical evaluation, are modest. The lack of a relationship of LB formation to the amount of Alzheimer-type changes in this series suggests that DLB is a distinct pathology rather than a variant of AD.

Low risk of relapse after achieving undetectable hCG levels in women with partial molar pregnancy

OBJECTIVE: Complete hydatidiform molar pregnancies occur in approximately 1 of 1,000 conceptions. After uterine evacuation of the trophoblastic tissue, women are followed up with serial serum human chorionic gonadotropin (hCG) measurements. Patients are considered to have attained remission when their hCG level spontaneously declines to an undetectable level and remains there during a 6-month follow-up period. This standard effectively detects all disease recurrence; however, it is resource intensive, delays child bearing, and is subject to significant noncompliance. Our objective was to determine the risk of disease recurrence after hCG spontaneously declines to undetectable levels. METHODS: We used a database from the New England Trophoblastic Disease Center to analyze hCG levels in patients with complete molar pregnancies. RESULTS: Among 1,029 women with complete molar pregnancy and complete data, 15% developed persistent gestational trophoblastic neoplasia. The rate of persistent neoplasm among those whose hCG level fell spontaneously to undetectable levels was 0.2% (2/876, 95% confidence interval 0–0.8%). No women developed persistent gestational trophoblastic neoplasia after their hCG level fell to undetectable levels using an assay with a sensitivity of 5 mIU/mL (n = 82, 95% confidence interval 0–4.5%). CONCLUSION: Based on our experience with women with complete hydatidiform molar pregnancies whose hCG values spontaneously fell to undetectable levels after molar evacuation, we conclude that the risk of recurrent neoplasm after hCG levels fall to less than 5 mIU/mL approaches zero. LEVEL OF EVIDENCE: II-2

Tumor size, depth of invasion, and histologic grade as prognostic factors of lymph node involvement in endometrial cancer: A SEER analysis

OBJECTIVES The objective of this investigation was to evaluate the risk of nodal metastasis in patients with endometrial cancer, using the Mayo criteria, in a population-based analysis. MATERIALS AND METHODS Data from the SEER registry was reviewed for endometrial cancer cases diagnosed between 1988 and 2010. Patients were considered at low-risk for nodal metastasis if their tumors were histologic grade 1 or 2, myometrial invasion was less than 50%, and tumor size equal to or less than 2 cm. Patients not meeting these criteria were considered at high-risk for nodal involvement. RESULTS The final study group consisted of 19,329 women with surgically staged endometrial cancer. Of these, 1035 (5.3%) had lymph node involvement. Based on Mayo criteria, 4095 (21.1%) patients were found to be at low-risk and 15,234 (78.9%) at high-risk for nodal metastasis. Low-risk features were associated with a 1.4% risk for lymph node metastasis, compared to 6.4% in patients with high-risk features (p<0.001). When myometrial invasion was removed from the analysis, low-risk pathologic features were associated with a 2.4% risk of lymph node metastasis, compared to 10.4% in patients with high-risk features (p<0.001). CONCLUSIONS In a population-based analysis, women with low-risk endometrial cancer, as defined by the Mayo criteria, have a low rate of lymph node metastasis.

Lack of independent associations of apolipoprotein E promoter and intron 1 polymorphisms with Alzheimer's disease

Several studies have demonstrated genetic associations between Alzheimers disease (AD) and polymorphisms in the promoter/enhancer regions of the apolipoprotein E (APOE) gene. These studies raise the possibility that APOE transcription control may be involved in altered risks for AD. We evaluated polymorphic sites in the intron-1 enhancer element (IE-1G/C) and in the APOE promoter (-219G/T). For the IE-1 polymorphism, we analyzed 433 individuals (183 AD and 250 controls), and found a strong linkage between the IE-1G allele and APOE-epsilon4. When we controlled for this linkage using log-linear model analysis, we found no independent association between the IE-1 polymorphism and AD. For the -219 polymorphism, we analyzed 475 individuals (168 AD cases, 234 controls, and 73 cases of cerebral amyloid angiopathy (CAA)). We found strong linkages between the -219G allele and APOE-epsilon2 and between the -219 T allele and APOE-epsilon4. Controlling for these linkages, we found no independent association between the -219 polymorphism and AD or CAA. Thus, our studies do not support independent associations between AD and either the IE-1 or the -219 polymorphisms.

Decreased survival in EGFR gene amplified vulvar carcinoma

OBJECTIVE We undertook an extensive molecular characterization of the epidermal growth factor receptor (EGFR) gene in vulvar squamous cell carcinomas to investigate EGFR mutation and/or genomic amplification and its association with EGFR protein expression, high-risk human papillomavirus (HPV) status and clinical outcome. METHODS A cohort of 51 vulvar cancer patients distributed across all FIGO stages was selected for immunohistochemistry (IHC) and fluorescence in situ hybridization. EGFR expression and gene amplification were correlated with high-risk HPV status, EGFR mutational status and clinical prognostic variables. Fishers exact tests, Kaplan-Meier survival estimates and a Cox proportional-hazards model were utilized. RESULTS EGFR gene amplification and chromosome 7 high polysomy were observed in 12% and 6% of cases, respectively. IHC of malignant tissue with 3+ staining demonstrated 100% sensitivity and 79% specificity to detect EGFR gene amplification, yielding a 39% positive predictive value. Decreased survival (p<0.025) was observed in patients with gene amplification, and was associated with a more statistically robust 3.3 hazard ratio (p<0.005) in the Cox proportional-hazards model that controlled for age at diagnosis, stage and lymph node metastasis. Univariate analysis confirmed that EGFR gene amplification was associated with the absence of high-risk HPV (p<0.001). Common activating EGFR gene mutations were not identified. CONCLUSION A subset of patients with vulvar squamous cell carcinoma was identified with EGFR gene amplification that was HPV-independent and associated with poor prognosis. Given the association of EGFR amplification with response to targeted therapy in other tumor types, these patients may be candidates for therapeutic strategies that target the EGFR pathway.

Phase II trial of erlotinib in women with squamous cell carcinoma of the vulva

OBJECTIVE To evaluate the efficacy and toxicity of erlotinib in the management of squamous cell carcinoma (SCC) of the vulva. METHODS Patients with vulvar lesions amenable to surgery or chemoradiation (cohort 1) or those with metastatic measurable disease (cohort 2) received erlotinib 150 mg daily. Patients were monitored for toxicity. Responses were determined by digital photography or RECIST 1.1. Cohort 1 underwent pre and post treatment biopsies. EGFR immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH), and mutational analysis were performed. RESULTS 41 patients were enrolled: 17 in cohort 1 and 24 in cohort 2. Notable grade 3 or 4 toxicities included allergic reaction (1), diarrhea/electrolyte abnormalities (3), ischemic colitis (1), and renal failure (3) and electrolyte abnormalities (n=2). Mean number of cycles for cohort 2 was 3.3. Overall clinical benefit rate was 67.5% with 11 (27.5%) partial responses (PR), 16 (40.0%) stable disease (SD), and 7 (17.5%) progressive disease. Responses were of short duration. All pre and post treatment biopsies exhibited 2-3+ EGFR staining. 5 of 14 patients (35%) were found to have EGFR amplification (n=3) or high polysomy/trisomy (n=2). These five patients had either a PR (n=3) or SD (n=2). Gain of function mutations were not been identified. CONCLUSIONS This is the first reported controlled trial evaluating erlotinib for the management of vulvar carcinoma. Toxicities were acceptable given the lack of treatment options for these patients. Given the observed clinical benefits erlotinib may represent one of the most active agents available to treat vulvar SCC.

Tissue-specific signatures of activating PIK3CA and RAS mutations in carcinosarcomas of gynecologic origin

OBJECTIVES Gynecologic carcinosarcoma is an aggressive malignancy that requires more effective treatment approaches. However, therapeutic implications regarding the specific gynecologic site of origin and the admixture of carcinomatous and sarcomatous elements that define this tumor remain uncertain. Therefore, broad genotyping was performed to identify tissue-specific somatic mutational profiles that may help direct targeted therapies in this complex neoplasia. METHODS Genotyping was conducted on primary gynecologic carcinosarcomas arising from various disease sites (uterus, ovary, fallopian tube, vagina) and within isolated histological subcomponents. Nucleic acids extracted from diagnostic tissue were used in a genotyping platform that simultaneously queried >120 common mutations across 14 cancer genes. Mutational status was correlated with clinical variables using logistic regression and Kaplan-Meier survival estimates. RESULTS Cancer gene mutations were identified in 46% of the 52 patient cohort and include TP53 (23%), PIK3CA (19%), KRAS (15%), CTNNB1 (4%) and NRAS (2%). Mutation in a single gene was observed in 31% of patient samples, while synchronous mutations involving 2 and 3 genes were noted in 13% and 2% of samples, respectively. Comparative evaluation of the carcinomatous and sarcomatous elements within a tumor demonstrated a similar mutation signature. Mutations in PIK3CA, KRAS and NRAS were exclusive to tumors of uterine origin and age-adjusted Cox proportional hazards modeling associated advanced age, stage and TP53 mutations with decreased survival in the uterine subset. CONCLUSION While carcinosarcomas across gynecologic disease sites are histologically similar, therapeutically relevant mutations in the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways predominated in carcinosarcomas arising in the uterus.

Carcinosarcoma of the ovary: A case-control study

INTRODUCTION Carcinosarcoma of the ovary is a rare tumor with a grim prognosis. Chemotherapy for these tumors is chosen according to guidelines established for epithelial ovarian cancer (EOC). The purpose of this study is to compare response to chemotherapy and survival in patients with advanced stage carcinosarcoma of the ovary. METHODS We identified women with advanced carcinosarcoma of the ovary who underwent first-line platinum and taxane-based chemotherapy. Each case was matched to two women with serous EOC. Cases and controls were matched by age, stage, and year of diagnosis. The Kaplan-Meier method was used to generate overall survival (OS) data. Factors predictive of outcome were compared using the log-rank test and Cox proportional hazards model. RESULTS Fifty women treated with first line platinum and taxane-based chemotherapy had advanced carcinosarcoma of the ovary and were selected as cases. The response rates to chemotherapy for cases and controls were 62% and 83% (P=0.03), respectively. Median progression-free survival was 11 months (95% CI, 8 to 14 months) versus 16 months (95% CI, 12 to 21 months; P=0.02) and median overall survival was 24 months (95% CI, 18 to 29 months) versus 41 months (95% CI, 33 to 49 months; P=0.002) for cases and controls, respectively. CONCLUSION Patients with advanced carcinosarcoma of the ovary have a poorer response to platinum and taxane-based first-line chemotherapy and worse survival, compared to patients with serous EOC. Aggressive surgical treatment may play an important role. However, other alternative systemic therapeutic approaches should be sought for patients with carcinosarcoma of the ovary.

Evaluating methotrexate treatment in patients with low-risk postmolar gestational trophoblastic neoplasia

OBJECTIVE To identify clinical factors associated with requiring more than a single course of Methotrexate (MTX) to achieve remission among women with low-risk postmolar gestational trophoblastic neoplasia (GTN). METHODS We studied 150 women with persistent GTN after diagnosis of complete (n=110) or partial mole (n=40) to identify possible predictors of requiring additional treatment after a single treatment of methotrexate (MTX). All women had low-risk disease using FIGO and WHO scoring systems. RESULTS Seventy women (47%) required additional courses of chemotherapy, of whom 45 (64%) received chemotherapy other than MTX. Multivariate analysis revealed that complete mole histology, presence of metastasis, single day MTX infusion and any increase in serum beta human chorionic gonadotropin (beta-hCG) level 1 week after MTX therapy were independent predictors of requiring additional MTX or alternative chemotherapy. Dilatation and curettage (D+C) within 1 week after the diagnosis of persistence did not affect future chemotherapy requirements (p>0.64). Following complete mole, beta-hCG levels >2000 mIU/mL at 1 week post MTX were associated with a 89% risk of additional cycles chemotherapy including MTX and a 65% risk of alternative chemotherapy. CONCLUSIONS Metastatic disease, MTX infusion protocol and complete mole histology were independently associated with the need for additional chemotherapy after an initial course of MTX for women with low risk GTN. D+C at persistence did not alter the chemotherapy requirement. Elevated beta-hCG level at 1 week after the initial course of MTX was also an independent factor predicting the need for additional courses of MTX or alternative chemotherapy.