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ABSTRACT: To evaluate the efficacy and toxicity of erlotinib in the management of squamous cell carcinoma (SCC) of the vulva.
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.
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.
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.
Gynecologic Oncology 06/2012; 127(1):141-6. · 3.89 Impact Factor
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ABSTRACT: To determine the outcomes in patients with Stage I uterine clear cell carcinoma (UCCC) treated with and without adjuvant therapy, and to compare the outcomes in these patients to that of matched controls, patients with Stage I, grade 3, endometrioid adenocarcinoma of the endometrium (EC).
Patients with FIGO Stage I UCCC who underwent comprehensive surgical staging between January 1996 and January 2007 were identified. Cases (UCCC) were matched by age, stage, adjuvant therapy, and year of diagnosis to controls consisting of patients with grade 3 EC. Recurrence and survival were analyzed using the Kaplan-Meier method.
25 patients with Stage I UCCC were identified of whom 13 (52%) received no adjuvant therapy and 12 (48%) received adjuvant radiation therapy (XRT). The 5-year disease-free survival and overall survival rates for the observation and the XRT groups were 78% and 75%, (p = 0.7) and 85% and 82% (p = 0.1), respectively. When compared to controls, the 5-year disease-free survival rates and overall survival rates of patients with Stage I UCCC were not significantly different, 77% vs 75% (p = 0.8) and 84% vs 88% (p = 0.5), respectively.
In patients with Stage I UCCC tumors there was no clear benefit to adjuvant radiation given the absence of improvement in recurrence risk or any survival benefit. These data question the benefit of radiation therapy in UCCC patients with disease confined to the uterus.
European journal of gynaecological oncology 01/2010; 31(3):284-7. · 0.47 Impact Factor
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ABSTRACT: Central nervous system metastasis from gynecological malignancy is a rare phenomenon that has been described in the past 30 years. The objective of this study is to analyze the treatment modalities and prognostic factors for brain metastases from gynecological tumors that predict prolonged survival. A retrospective chart and pathology review of 47 patients diagnosed with a gynecological tumor with brain metastasis in 1994-2004 was performed. Thirty patients had undergone initial diagnosis and treatment at our institution, and 17 patients were referred following primary treatment at an outside institution. Adjusted Chi-square, Kaplan-Meier survival estimates, log-rank tests, and Cox regression analysis were utilized for statistical analysis of the total cohort. Of the 3146 patients with newly diagnosed gynecological cancer in this 10-year period, 30 developed brain metastasis demonstrating an incidence of 0.95%. Overall median survival from the time of diagnosis of brain metastasis was 7.5 months (95% CI 4-15, range 9 days-64 months) and 40% survival at 1 year. Multivariate analysis revealed evidence of extracranial disease at time of metastasis diagnosis predicted decreased survival (hazard ratio 6.207), while papillary serous histology (hazard ratio 0.42), and use of any chemotherapy (hazard ratio 0.24) predicted longer survival. No other patient or tumor characteristics were found to be independent prognostic indicators affecting survival. Despite the ominous prognosis associated with the development of brain metastasis, these retrospective data suggest that multimodal therapy with whole brain radiation therapy, chemotherapy, and surgical resection of metastases in selected patients without evidence of extracranial and with solitary or multiple lesions can prolong survival.
International Journal of Gynecological Cancer 02/2008; 18(2):262-8. · 1.65 Impact Factor
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ABSTRACT: To address the relationship between dementia and neuropathologic findings in dementia with Lewy bodies (DLB) in comparison with AD.
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.
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).
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.
Neurology 01/2000; 53(9):2003-9. · 8.31 Impact Factor
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ABSTRACT: Although the APOE epsilon4 allele is a strong risk factor for Alzheimer's disease (AD), it is not deterministic, as many APOE epsilon3/4 individuals do not develop AD. It has been hypothesized that this incomplete penetrance is due, in part, to an imbalance of allele expression in heterozygous individuals. In this regard, Lambert et al. (1998) reported that AD individuals have a higher APOE epsilon4/total APOE ratio than non-demented control subjects. We tested this hypothesis using radioactive RT-PCR to quantitate APOE epsilon3 and epsilon4 allele expression levels in AD and non-AD brain samples from APOE epsilon3/4 individuals. Quantitative analyses of amplified products within the linear range of amplification (18-20 cycles) revealed no difference from the expected 1:1 ratio in genomic DNA and in cDNA from AD and control brains. Using high PCR cycle numbers (approximately 30), we observed an artificial elevation of the APOE epsilon3/total APOE ratio in both DNA and cDNA samples, possibly due to DNA heteroduplex formation. Our results do not support the hypothesis that allelic imbalance contributes to the risk of developing AD among APOE epsilon3/4 heterozygote individuals.
Neuroscience Letters 10/1999; 272(2):83-6. · 2.11 Impact Factor
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ABSTRACT: Several studies have demonstrated genetic associations between Alzheimer's 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.
Neuroscience Letters 10/1999; 272(3):155-8. · 2.11 Impact Factor
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T Gómez-Isla, W B Growdon,
M J McNamara,
D Nochlin,
T D Bird,
J C Arango,
F Lopera,
K S Kosik,
P L Lantos,
N J Cairns,
B T Hyman
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ABSTRACT: To assess the influence of the presenilin 1 (PS1) and 2 (PS2) mutations on amyloid deposition, neurofibrillary tangle (NFT) formation and neuronal loss, we performed stereologically based counts in a high-order association cortex, the superior temporal sulcus, of 30 familial Alzheimer's disease cases carrying 10 different PS1 and PS2 mutations, 51 sporadic Alzheimer's disease cases and 33 non-demented control subjects. All the PS1 and PS2 mutations assessed in this series led to enhanced deposition of total Abeta and Abeta(x-42/43) but not Abeta(x-40) senile plaques in the superior temporal sulcus when compared with brains from sporadic Alzheimer's disease patients. Some of the PS1 mutations studied (M139V, I143F, G209V, R269H, E280A), but not others, were also associated with faster rates of NFT formation and accelerated neuronal loss in the majority of the patients who harboured them when compared with sporadic Alzheimer's disease patients. In addition, our analysis showed that dramatic quantitative differences in clinical and neuropathological features can exist even among family members with the identical PS mutation. This suggests that further individual or pedigree genetic or epigenetic factors are likely to modulate PS phenotypes strongly.
Brain 10/1999; 122 ( Pt 9):1709-19. · 9.46 Impact Factor
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T Gómez-Isla,
W Wasco,
W P Pettingell,
S Gurubhagavatula,
S D Schmidt,
P D Jondro,
M McNamara,
L A Rodes,
T DiBlasi, W B Growdon,
P Seubert,
D Schenk,
J H Growdon,
B T Hyman,
R E Tanzi
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ABSTRACT: The prevalence of known mutations in presenilin genes (PS1 and PS2) causing early-onset familial Alzheimer's disease (FAD) was assessed in a population of 98 singleton early-onset AD cases, 29 early-onset FAD cases, and 15 late-onset FAD cases. None of the cases tested positive for the eight mutations initially reported, and none of these mutations were observed in 60 age-matched controls. A novel mutation (R269H) in PS1 was found in a single case of early-onset AD but not in any other AD or control case. Thus, the PS mutations tested are quite rare in early-onset AD. Amyloid beta protein (A beta) deposition was investigated in the temporal cortex of the R269H mutation case using end-specific monoclonal antibodies to detect the presence of A beta x-40 and A beta x-42 subspecies. Stereologically unbiased tangle and neuropil thread counts were obtained from the same region. R269H PS1 mutation was associated with early age of dementia onset, higher amounts of total A beta and A beta x-42, and increased neuronal cytoskeletal changes. Thus, if the changes observed on this case prove to be typical of PS1 mutations, PS1 mutations may impact both amyloid deposition and neurofibrillary pathology.
Annals of Neurology 07/1997; 41(6):809-13. · 11.09 Impact Factor
