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  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 1 ( 2015-01-01), p. 203-215
    Abstract: Metastatic cases of breast cancer pose the primary challenge in clinical management of this disease, demanding the identification of effective therapeutic strategies that remain wanting. In this study, we report that elevated levels of α-tubulin acetylation are a sufficient cause of metastatic potential in breast cancer. In suspended cell culture conditions, metastatic breast cancer cells exhibited high α-tubulin acetylation levels that extended along microtentacle (McTN) protrusions. Mutation of the acetylation site on α-tubulin and enzymatic modulation of this posttranslational modification exerted a significant impact on McTN frequency and the reattachment of suspended tumor cells. Reducing α-tubulin acetylation significantly inhibited migration but did not affect proliferation. In an analysis of more than 140 matched primary and metastatic tumors from patients, we found that acetylation was maintained and in many cases increased in lymph node metastases compared with primary tumors. Proteomic analysis of an independent cohort of more than 390 patient specimens further documented the relationship between increased α-tubulin acetylation and the aggressive behaviors of basal-like breast cancers, with a trend toward increased risk of disease progression and death in patients with high-intensity α-tubulin acetylation in primary tumors. Taken together, our results identify a tight correlation between acetylated α-tubulin levels and aggressive metastatic behavior in breast cancer, with potential implications for the definition of a simple prognostic biomarker in patients with breast cancer. Cancer Res; 75(1); 203–15. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 10572-10572
    Abstract: 10572 Background: Mammography is currently used in the surveillance of breast cancer survivors, who are at increased risk of developing ipsilateral and contralateral breast cancers regardless of age at diagnosis or time since diagnosis. Several prospective studies have shown the utility of breast MRI in other high risk populations; however, little data exists on the use of MRI for surveillance of breast cancer survivors. We aimed to compare the outcome of surveillance breast MRI vs. mammography in this population. Methods: We identified women 〈 65 with non-metastatic breast cancer or DCIS with at least one MRI performed at our center 〉 11 months after initial diagnosis, along with a mammogram done within 6 months of the MRI. We compared the outcome of MRI and mammography in terms of biopsies performed as well as in detection of new cancers. Results: Of 512 consecutive charts reviewed, 204 patients met inclusion criteria, 105 (51.4%) of whom were African-American. The average number of MRIs per patient was 2.3 (range 2-7), with a total of 474 MRIs performed between 2005 and 2011. MRI resulted in BIRADS scores of 1 or 2 in 73.5% of studies vs. 84.4% for mammography. There were 19 biopsies performed due to MRI findings alone, 7 done due to mammographic findings alone, and 6 biopsies done based on abnormalities seen on both MRI and mammography. There were 7 malignancies identified based on an abnormal MRI, 3 seen on both MRI and mammography, and none identified via mammography alone. The malignancies identified via MRI alone included 1 patient with DCIS, 5 with stage I disease, and 1 with isolated lung metastases. Of the 10 recurrences detected, 5 (50%) were in African Americans. Two patients developed interval cancers within 6 months of normal screening MRI and mammography. Sensitivity and specificity for MRI were 83.3% (95% CI 0.51-0.97) and 92.2% (95% CI 0.87-0.95), vs. 25% (95% CI 0.05-0.57) and 94.8% (95% CI 0.90-0.97) for mammography. Positive and negative predictive values were 40% and 98.9% for MRI vs. 25% and 95.2% for mammography. Conclusions: Gadolinium-enhanced breast MRI is a useful surveillance modality in breast cancer survivors 〈 age 65. Prospective studies are needed in this population.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
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  • 3
    Online Resource
    Online Resource
    American Society for Microbiology ; 2001
    In:  Antimicrobial Agents and Chemotherapy Vol. 45, No. 10 ( 2001-10), p. 2723-2732
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 45, No. 10 ( 2001-10), p. 2723-2732
    Abstract: The orally administered neuraminidase (NA) inhibitor RWJ-270201 was tested in parallel with zanamivir and oseltamivir against a panel of avian influenza viruses for inhibition of NA activity and replication in tissue culture. The agents were then tested for protection of mice against lethal H5N1 and H9N2 virus infection. In vitro, RWJ-270201 was highly effective against all nine NA subtypes. NA inhibition by RWJ-270201 (50% inhibitory concentration, 0.9 to 4.3 nM) was superior to that by zanamivir and oseltamivir carboxylate. RWJ-270201 inhibited the replication of avian influenza viruses of both Eurasian and American lineages in MDCK cells (50% effective concentration, 0.5 to 11.8 μM). Mice given 10 mg of RWJ-270201 per kg of body weight per day were completely protected against lethal challenge with influenza A/Hong Kong/156/97 (H5N1) and A/quail/Hong Kong/G1/97 (H9N2) viruses. Both RWJ-270201 and oseltamivir significantly reduced virus titers in mouse lungs at daily dosages of 1.0 and 10 mg/kg and prevented the spread of virus to the brain. When treatment began 48 h after exposure to H5N1 virus, 10 mg of RWJ-270201/kg/day protected 50% of mice from death. These results suggest that RWJ-270201 is at least as effective as either zanamivir or oseltamivir against avian influenza viruses and may be of potential clinical use for treatment of emerging influenza viruses that may be transmitted from birds to humans.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
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    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2001
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
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  • 4
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 10, No. 24 ( 2004-12-15), p. 8301-8308
    Abstract: Purpose: Inosine monophosphate dehydrogenase (IMPDH) inhibitors have been used to induce leukemia blast cell differentiation but have not been tested in multiple myeloma for activity. Currently, available IMPDH inhibitor, mycophenolate mofetil (MMF), which is known as an immunosuppressant, was shown to induce apoptosis in myeloma cell lines. On the basis of our preclinical studies, we designed a clinical study to test our hypothesis that MMF has antimyeloma activity. Experimental Design: A Phase I MMF dose escalation study was conducted in relapsed and refractory myeloma patients who had documented disease progression by myeloma markers or bone marrow plasmacytosis to determine the maximum tolerated dose, toxicities, and efficacy of the drug. To assess the activity of IMPDH inhibition in the myeloma cells of patients, we measured intracellular nucleotide triphosphate levels by high-performance liquid chromatography-based analysis and examined the correlation with clinical response. Results: Among the 11 study patients, MMF was generally well tolerated and was administered up to a maximum dose of 5g/day. The most common toxicity was grade 1 fatigue (n = 4, 36%). One patient had a partial response (3g/day), four patients had stable disease, and six patients had progression of disease. There was a statistically significant difference in the intracellular dGTP level changes between the stable disease/partial response group versus progression of disease. Conclusions: MMF at 1 to 5 g/day daily dose is well tolerated by patients with relapsed and refractory multiple myeloma patients. Positive correlation between clinical response and depletion of intracellular dGTP level was shown. Future drug development to target this enzyme maybe useful in treating myelomas.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2004
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  • 5
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 6051-6051
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 6051-6051
    Abstract: 6051 Background: Despite overall decline in cancer mortality, African Americans suffer from higher mortality in most cancer types including cancers of the head and neck. These differences likely result from a complex interplay of clinical and non-clinical factors. We aim to estimate disparities in overall survival across racial groups in HNSCC in the United States. Methods: This study used SEER-Medicare linked database. We identified all patients aged 66 years or older diagnosed with HNSCC as their first cancer from 1992 to 2011. We excluded those in HMO, diagnosed by death certificate or autopsy, non-SCC, unknown race, and missing month and/or year of diagnosis. Further exclusions included metastatic disease, salivary gland cancers, receiving no treatment in the first 180 days, and unknown stage. Analytic data set included oropharynx, oral cavity, nasopharynx, hypopharynx, and larynx. Primary treatment was defined as any treatment modality received within 180 days after diagnosis. Overall survival (OS) parameters were estimated across ethnic groups by the Cox regression model stratified by site and stage of cancer at diagnosis, adjusted for clinical and demographic characteristics, and propensity score weighted. Results: Our study population included 15, 547 patients. Median OS was 3.5 years (95% CI: 3.4-3.7) across all ethnic groups. African Americans (AA) had inferior outcome with median OS of 2.0 years (95% CI: 1.9-2.3) compared to 3.7 years (95% CI: 3.6-3.8) for Caucasian Americans (CA) (p 〈 0.0001). This difference was seen despite AA patients receiving comparable treatments and presenting at similar stage of disease, except for cancers of the oral cavity where AA were more likely to present with advanced disease (67% versus 47%; P 〈 0.001). The difference was most pronounced in the oropharynx where median OS was 1.9 years (95% CI: 1.7-2.1) for AA and 3.8 years (95% CI: 3.5-4.1) in CA (P 〈 0.0001). AA also had consistently worse OS over time from 1992 to 2011. This study clearly demonstrated AA have inferior outcomes despite similar treatments, comorbidities, age at diagnosis, stage at presentation, tumor location, year of diagnosis and sex. Conclusions: The current study demonstrates inferior overall survival for African American head and neck cancer patients independent of primary site and treatment modalities.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 6
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 6075-6075
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 6075-6075
    Abstract: 6075 Background: Using concurrent chemoradiation (CRT) to treat oropharyngeal cancer (OPC) has increased since 2000. However, there is limited information regarding the cost-effectiveness of CRT compared to radiation alone (RT) especially given the approval of cetuximab (cetux) in 2006. We conducted a cost-effectiveness analysis of 1) platinum-based CRT compared to RT and 2) cetuximab plus RT (cetux+RT) compared to RT to determine the value of CRT over time. Methods: In this retrospective cohort study, we identified non-metastatic OPC patients aged 66 years or older diagnosed between 2000-2011 using the linked Surveillance, Epidemiology and End Results -Medicare dataset. We defined two cohorts based on the diagnosis period: 2000-2005 (Cohort I) and 2006-2011 (Cohort II). Cetux+RT was identified in Cohort II only. We matched the platinum-based CRT and cetux+RT groups to the RT groups using propensity score models that included age, race, marital status, income, Charlson Comorbidity Index and stage at diagnosis. The outcomes were incremental cost, incremental life-year gained (LYG) and incremental cost-effectiveness ratio (ICER) during the 3 years after diagnosis. Costs were estimated from the Medicare perspective and using 2017 USD. Results: 2,646 OPC patients were eligible for the study. The estimated parameters with the corresponding 95% confidence intervals (CI) are shown in the table. Conclusions: From 2000-2005, platinum-based CRT was a cost-effective option compared to RT. From 2006-2011 and compared to RT, platinum-based CRT provided a survival benefit at higher costs while cetux+RT patients incurred higher costs with no survival benefit. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. 555-555
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
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  • 8
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2008
    In:  Cancer Research Vol. 68, No. 9 ( 2008-05-01), p. 3516-3522
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 68, No. 9 ( 2008-05-01), p. 3516-3522
    Abstract: Although the aromatase inhibitor anastrozole has been shown to be very effective in the treatment of hormone-dependent postmenopausal breast cancer, some patients with advanced disease will develop resistance to treatment. To investigate therapeutic strategies to overcome resistance to anastrozole treatment, we have used an intratumoral aromatase model that simulates postmenopausal breast cancer patients with estrogen-dependent tumors. Growth of the tumors in the mice was inhibited by both anastrozole and fulvestrant compared with the control tumors. Nevertheless, tumors had doubled in size at 5 weeks of treatment. We therefore investigated whether switching the original treatments to anastrozole or fulvestrant alone or the combination of anastrozole plus fulvestrant would reduce tumor growth. The results showed that the best strategy to reverse the insensitivity to anastrozole or fulvestrant is to combine the two agents. Additionally, the tumors treated with anastrozole plus fulvestrant from the beginning had only just doubled their size after 14 weeks of treatment, whereas the anastrozole and fulvestrant treatments alone resulted in 9- and 12-fold increases in tumor size, respectively, in the same time period. Anastrozole plus fulvestrant from the beginning or in sequence was associated with down-regulation of signaling proteins involved in the development of hormonal resistance such as insulin-like growth factor type I receptor β, mitogen-activated protein kinase (MAPK), p-MAPK, AKT, mammalian target of rapamycin (mTOR), p-mTOR, and estrogen receptor α compared with tumors treated with anastrozole or fulvestrant alone. These results suggest that blocking the estrogen receptor and aromatase may delay or reverse the development of resistance to aromatase inhibitors in advanced breast cancer patients. [Cancer Res 2008;68(9):3516–22]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. e19565-e19565
    Abstract: e19565 Background: OM is a common complication of high-dose melphalan in MM patients (pts). Proposed risk factors for OM in SCT include: low albumin and high serum creatinine (Cr) levels, both were evaluated in MM patients undergoing Mel/ASCT. (Grazziutti, ML, Bone Marrow Transplant 2006). Methods: This is a single center retrospective chart review of 214 sequentially treated MM pts who received Mel 200mg/m2 conditioning prior to SCT between January 2005-September 2011. Data collected included: demographics, Hgb, Cr, C-reactive protein and albumin on the day of SCT, length of hospital stay. OM assessment was graded as follows: Grade 1, no OM; Grade 2, mild OM; the pts maintained adequate oral intake; Grade 3, decreased oral intake and/or use of oral narcotics; Grade 4, severe OM needing intravenous narcotics. Results: The table below describes pt characteristics grouped by OM grade. Overall, 56 pts (27%) had grade 3/4 OM. Multivariate analysis of variance revealed no statistically significant correlation between OM grade and Hgb, Cr, albumin, CRP; the overall test’s p value = 0.55. There were no racial or gender differences with regard to grade of mucositis, the p-values range are 0.75 and 0.31, respectively (likelihood ratio chi-square test). Most interestingly, OM did not impact length of hospital stay. Conclusions: We did not establish any predictive risk factors for OM as previously described. Analysis of the impact of OM on MM response and event and overall survival will be presented. Studies of Mel pharmacogenetics may provide insight to patients' predisposition to OM. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 10
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 6536-6536
    Abstract: 6536 Background: For patients with primary untreated locally advanced head and neck squamous cell carcinoma (PULA-HNSCC), high dose once every 3 weeks cisplatin (HDC; 100 mg/m 2 ) added to curative radiotherapy (RT) prolongs survival, but is associated with severe toxicities. Concurrent chemoradiation (CRT) with low dose weekly cisplatin (LDC; 30-40 mg/m 2 ), carboplatin (C), or RT alone is often substituted for HDC. We estimated and compared overall survival (OS) and acquired toxicities among Medicare beneficiaries treated with CRT using HDC, LDC, C, or RT. Methods: Patients diagnosed from 2004-2011 with PULA-HNSCC (stages III-IVB AJCC 6 th and 7 th editions) of the oropharynx (OPC), hypopharynx (HP), or larynx (L) who received definitive RT or CRT were identified using the linked SEER-Medicare database. An analytic cohort of patients receiving CRT with HDC, LDC, or C was constructed using well-established eligibility criteria. OS was estimated and compared between patients grouped by treatment received utilizing a multivariable stratified propensity scores weighted Cox regression model, including demographic and disease characteristics. Toxicities were compared using exact common odds-ratio and Fisher’s tests. Results: We identified 1,335 patients that received RT: OPC (n = 731), HP (n = 174), or L (n = 430). Out of those, patients were treated with HDC (n = 264), LDC (n = 259), C (n = 353), or RT alone (n = 459). Median OS (years) was 5.61 (95% CI = 4.58-7.69) for HDC, 3.7 (95% CI = 3.1-4.79) for LDC, 3.1 (95% CI = 2.48-3.86) for C, and 1.36 (95% CI = 1.19-1.58) for RT, respectively. OS was significantly greater for HDC than for LDC (HR = 1.35, 95% CI = 1.06-1.72, p= 0.02), C (HR = 1.41, 95% CI = 1.12-1.76, p= 0.003), or RT (HR = 2.1, 95% CI = 1.68-2.61, p= 〈 0.001). Treatment with HDC compared to LDC was not associated with increased prevalence of dysphagia or neutropenia. HDC was associated with hearing loss when assessed at 9-12 months post-diagnosis ( p =0.03). Conclusions: In SEER-Medicare beneficiaries with PULA-HNSCC of the OPC, HP, or L, OS was significantly better for HDC than LDC when accounting for baseline clinical and demographic characteristics and propensity score weights. Toxicities were similar between regimens, except for an increased incidence of the late acute toxicity of hearing loss in HDC. A regimen of HDC improves OS, but needs to be carefully assessed against increased toxicity risk, with hearing loss in particular.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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