tbuckley/cabot-search huggingface dataset:
369. AAV9 Mediated Correction of Iduronate-2-Sulfatase Deficiency in the Central Nervous System of Mucopolysaccharidosis Type II Mice
Authors: Kanut Laoharawee, Kelly M. Podetz-Pedersen, Kelley Kitto, Lucy Vulchanova, Carolyn Fairbanks, Karen Kozarsky, Walter C. Low, R. Scott McIvor
Journal: Molecular Therapy (2015)

Mucopolysaccharidosis type II (MPS II; Hunter Syndrome) is an X-linked inherited lysosomal storage disease caused by deficiency of iduronate-2-sulfatase (IDS) and subsequent accumulation of glycosaminoglycans (GAGs) dermatan and heparan sulphate. Affected individuals exhibit a range in severity of manifestations such as organomegaly, skeletal dysplasias, cardiopulmonary obstruction, neurocognitive deficit, and shortened life expectancy. There is no cure for MPS II at the moment. Current standard of care is enzyme therapy (ELAPSRASE; idursulfase), which is used to manage disease progression. As hematopoetic stem cell transplantation (HSCT) has not shown neurologic benefit for MPS II, there is currently no clinical recourse for patients exhibiting neurologic manifestations of this disease, and new therapies are desperately needed. We have been developing the use of AAV9 vectors for delivery of the human IDS gene into the central nervous system of MPS II mice to restore IDS levels in the brain and prevent the emergence of neurocognitive deficits in the treated animals. A series of CBA-regulated vectors were generated that encode human IDS with or without the human sulfatase modifying factor-1 (SUMF-1), required for activation of the sulfatase active site. Intrathecal (IT) administration of these vectors into IDS positive mice (NOD.SCID and C57BL/6) did not result in a significant increase in IDS levels in the brains or in the organs of treated mice when compared to untreated animals. However, plasma showed higher enzyme levels in the intrathecally treated C57BL/6 mice than in untreated animals that persisted for at least 6 weeks post injection. There was no evidence for diminished activity that would be associated with immune response against human IDS protein. In contrast to the IT administered mice, MPS II mice administered AAV9-IDS vector intracerebroventricularly exhibited two- to four-fold higher levels of IDS enzyme activity in all portions of the brain in comparison with untreated, unaffected littermates. The ICV treated animals also showed lower levels of tissue GAG in the brain than untreated MPS II animals and similar levels as their wild-type littermates. IDS activity in the plasma of ICV treated mice was also significantly higher than that of wild type mice with no sign of immune response at least 6 weeks post administration. These results show the potential therapeutic benefit of AAV9-mediated IDS gene delivery to the CNS through the cerebrospinal fluid to address neurological manifestations of MPS II, Hunter syndrome.
Impact of socioeconomic status on melanoma clinical presentation and prognosis in non-White melanoma patients.
Authors: L. G. Wich, M. W. Ma, R. S. Berman, A. C. Pavlick, R. L. Shapiro, G. Miller, U. Sarpel, L. S. Price, J. D. Goldberg, I. Osman
Journal: Journal of Clinical Oncology (2010)

e16543 Background: Advanced presentation and poor prognosis have been noted for non-white compared to non-Hispanic white melanoma patients. Socioeconomic status (SES) is thought to explain this disparity, at least in part. However, the association between SES and clinical presentation in non-white melanoma patients has not yet been defined. Methods: Demographic, race and insurance information, tumor characteristics, and follow-up data were retrieved for melanoma patients who presented to Bellevue Hospital Center, a public hospital, and the New York University Cancer Institute (NYUCI), a private academic medical center, for treatment of melanoma between 1998 and 2009. We used these data in conjunction with information from the U.S. Census Bureau (median household income, level of education) to determine patients' SES. We focused our analyses on non-white patients. Three groups of melanoma patients were compared: Bellevue Hispanic, Bellevue other race (includes Asian, Black, and other race), and NYUCI non-white. Continuous variables (age at diagnosis, income, educational level, primary tumor thickness) were analyzed using the Kruskal-Wallis test. Discrete variables (gender, clinical stage at presentation, primary anatomic site) were evaluated using the Chi- Square test. Results: 50/119 (42%) melanoma patients presenting for treatment at Bellevue were non-white (32 Hispanic, 18 other race), whereas only 27/1296 (2%) accrued at NYUCI were identified as non-white. NYUCI non-white patients were significantly more likely to have a higher median household income (p = 0.05), a higher level of education (p = 0.04), and an earlier clinical stage at presentation (p = 0.02) compared to either group of non-white Bellevue patients. At last follow-up, 78% of NYUCI non-white patients showed no evidence of disease, compared to 59% and 50% of Bellevue Hispanic and other race patients, respectively. Conclusions: Our data suggest thatnon-white melanoma patients with higherSES present at an earlier stage with better outcome. Increased screening efforts in areas of low SES are therefore warranted to improve early diagnosis of melanoma. No significant financial relationships to disclose.
<i>EGFR</i> and <i>K-RAS</i> gene status evaluation in anal canal squamous cell carcinoma
Authors: N. Van Damme, N. Van Roy, F. Speleman, A. Bols, J. Van Dorpe, P. Pauwels, M. Peeters
Journal: Journal of Clinical Oncology (2008)

15569 Background: Mutations affecting the epidermal growth factor receptor (EGFR) gene and the K-RAS gene have been identified in a variety of human solid tumours and have been validated as promising therapeutic targets. Approximately 85% of non small-cell lung cancer patients, who responded to gefinitib or erlotinib, have somatic mutations in the EGFR gene (exons 18–21) and for metastatic colorectal cancer patients, wild-type K-RAS is required for responsiveness to panitumumab. In squamous cell carcinoma of the anal canal however, the EGFR and K-RAS gene status has not systematically been investigated. Patients and Methods: In this study, 30 primary squamous cell carcinomas of the anal canal were investigated. The panel consisted of twenty men and 10 women with a median age of 60.5 years (range: 34–86 years). The formalin-fixed paraffin embedded tissues were immunohistochemically (ICH) examined for EGFR expression (Zymed Laboratories) and analysed by fluorescence in situ hybridisation (FISH) for EGFR gene copy numbers. Furthermore, EGFR and K-RAS mutation analysis was performed on DNA isolated from formalin-fixed paraffin embedded tissues. EGFR mutation analysis was carried out using exons 18 through 21 specific primers. For K-RAS, exon 2 was analysed for the presence of mutations. Results: EGFR immunoreactivity was detected in 27 of 29 (93%) tumours. One tumour yielded no conclusive results. Nineteen (65%) cases exhibited a moderate (2+) or strong (3+) staining intensity. FISH results were not interpretable in 18 (60%) cases. Of the remaining 12 cases, none showed EGFR gene amplification. Mutation analysis was performed on 20 samples, but no mutations could be identified in the kinase domain of the EGFR gene nor in the K-RAS gene. Conclusion: In our panel of squamous cell carcinoma of the anal canal, all samples showed a strong EGFR protein expression as evaluated by IHC. However, no EGFR gene amplification nor EGFR and K-RAS mutation could be identified. No significant financial relationships to disclose.
Discovery of a new phospho-HER2+/FISH- molecular subtype of human breast cancer by functional pathway mapping
Authors: J. Wulfkuhle, M. Pierobon, J. Laird, V. Espina, I. L. Liotta, L. Esserman, E. Petricoin
Journal: Journal of Clinical Oncology (2009)

11009 Background: Effective treatment of breast cancer through the targeting of the HER2 protein in human breast cancer represents a major advance in oncology, yet the identification of responders has relied on non-quantitative methods (IHC) that measure the erbB2 protein or indirect genomic analysis (FISH) of the erbB2 gene that cannot predict protein pathway activation status. We utilized a new quantitative protein microarray assay to measure total and phosphorylated HER2 in the context of broad-scale EGFR signal pathway mapping in order to generate a new molecular characterization scheme for human breast cancer. Methods: Pure tumor epithelium from 149 frozen pre-treatment human breast cancer tissue specimens (from the I-SPY TRIAL: CALGB 150007/150012, ACRIN 6657) were procured via Laser Capture Microdissection and protein pathway mapping was performed using Reverse Phase Protein Microarrays (RPMA) whereby the activation of 40 key signaling proteins was quantitatively measured at once. Results: While phospho-HER2 and total HER2 as measured by RPMA had excellent concordance with FISH (95%) and IHC (94%), of the 63 cases where both clinical FISH and IHC status of c-erbB2 were known, we discovered that 5/45 (11%) of the FISH-/IHC- cases had phosphorylated HER2 levels as high or higher than the FISH+/IHC positive patients. These results were confirmed and validated by independent analysis with quantitative Western Blot using a separate biopsy specimen from the same patients. Conclusions: A new molecular phenotype of human breast cancer has been identified whereby total levels of HER2 are low yet levels of the phosphorlyated receptor are very high. This molecular phenotype is not detectable by FISH analysis nor by measurement of the total HER2 protein itself. Given the central importance of phosphorylation on effective signal transduction of the EGFR family, we are planning to determine the clinical significance of this finding by retrospective analysis of banked material with outcome, and a prospective clinical trial in I-SPY 2. Support: ACRIN U01 CA079778 ; CALGB CA31964, CA33601; NCI SPORE CA58207. [Table: see text]
Carboxyl- and amino-functionalized polystyrene nanoparticles differentially affect the polarization profile of M1 and M2 macrophage subsets
Authors: Ann-Kathrin Fuchs, Tatiana Syrovets, Karina A. Haas, Cornelia Loos, Anna Musyanovych, Volker Mailänder, Katharina Landfester, Thomas Simmet
Journal: Biomaterials (2016)
Early discontinuation of tamoxifen and aromatase inhibitors (AIs) by postmenopausal women with early-stage breast cancer.
Authors: J. A. Charlson, T. Hedin, R. Sparapani, C. Guo, A. Nattinger
Journal: Journal of Clinical Oncology (2010)

524 Background: In women with early stage, hormone responsive breast cancer, compliance with adjuvant endocrine therapy is important for optimal outcomes. Prior studies, focused mostly on tamoxifen, have suggested suboptimal compliance, but compliance to AI therapy is little studied. We studied rates and predictors of nonpersistence in women aged 65 years and older who were treated with tamoxifen and/or AIs. Methods: A series of four telephone surveys were administered to community-dwelling women (age 65 to 89 years, median age 72) residing in 4 large states, who had initial treatment for early-stage breast cancer in 2003. The surveys, administered from 2005 to 2008, assessed demographic, socioeconomic and health factors, along with cancer treatment details, including use of adjuvant endocrine therapy. Nonpersistence was defined as a gap in adjuvant endocrine therapy of more than 60 days. Medication stop, start and switch dates were determined from survey responses. Cox proportional hazards models were used to identify patient and treatment factors that predicted nonpersistence. Results: In our cohort of 1,402 women, 55% were initially prescribed AIs, 45% tamoxifen. With median followup 59 months, 325 women (23%) discontinued treatment early (prior to 5 years). Among the 325 nonpersistent subjects, 27% discontinued therapy in the first year. Age over 80 years predicted non-persistence, risk ratio (RR) of 1.61 (p < 0.05), with a trend toward nonpersistence in women over 75 – RR 1.36 (p = 0.07). Patients in the lowest quartile of income (< $15K) had higher risk of nonpersistence (p = 0.002). Initial endocrine therapy (tamoxifen vs. AIs) was not predictive of nonpersistence. However, patients on AI's at censoring had lower nonpersistence risk, of borderline statistical significance (RR 0.80, p = 0.06). Race, marital status, education, stage, comorbidity, and type of surgery were not predictive of nonpersistence. Conclusions: Our study shows that noncompliance with standard adjuvant endocrine therapy is common in the current treatment environment. Older age and lowest income levels are associated with non-persistence. Women on AIs may be at less risk for nonpersistence. No significant financial relationships to disclose.
Preliminary results of docetaxel (T) and trastuzumab (H) combination administered every 21 days in metastatic breast cancer (MBC) and HER-2 over-expression patients (P)
Authors: I. Tusquets, M. Ramos, M. Gil, P. Sánchez-Rovira, J. R. Mel, A. Duque, L. García-Estévez, A. Velasco
Journal: Journal of Clinical Oncology (2006)

10670 Background: T combined with weekly H confers greater tumor response and survival compared to T monotherapy in P with Her-2 positive MBC. A recent report has demonstrated that H can be administered q3wks. The primary endpoint is to evaluate time to progression (TTP). Sencondary objectives are response rate, overall survival and safety profile. Methods: P cytologically or histologically confirmed of metastatic breast cancer, HER-2 positive (+++ by Herceptest, or FISH positive), age &gt; 18, ECOG PS ≤ 2, and adequate organ function, were included. Prior chemotherapy for MBC or adjuvant anthracycline-based regimen in the previous 6 months was not allowed. Treatment: T 100 mg/m 2 iv D1 q3wks for 6 cycles, H 8 mg/kg (cycle 1) and 6 mg/kg (consecutive cycles) iv D1, q3wks. P may receive H monotherapy until PD at the investigator criteria. Results: Over 41 analyzed P, median age was 57 years (29–75); ECOG PS 0–1 95% and ductal carcinoma 88%. Twenty five P received prior chemotherapy. Treatment: 217 cycles of TH (median 6) were administered. After that, 23 P received 189 cycles of H monotherapy (median 5, 1–32). During TH treatment median RDI was 97% for T and 96% for H, and it was 99% during H treatment. Over 33 P for efficacy analysis (2 consent withdrawal, 1 allergic reaction, 1 ongoing and 4 response not confirmed by RECIST criteria), 6 achieved CR and 12 PR, for an ORR of 54.6% (95% CI: 37.6–71.6). Median follow-up time was 11.8 m and median TTP was 8.8 m (95% CI, 1.9–15.6). All P were evaluable for safety. During TH treatment, grade III/IV neutropenia occurred in 16 cycles (7.4 %), 14 of them were febrile neutropenia episodes (6.5%). Other grade III/IV toxicities per cycle were: leucopenia (5.5%), hyperglycemia (2.3%), anorexia (2.3%) and skin (2.3%). During H monotherapy treatment, the only grade III-IV toxicities observed were, skin (1.6%), oedema (1.1%), nail disorders (0.5%) and malaise (4.3%). Six P (14.6%) dropped out due to cardiac toxicity: 5 had LVEF under 50% and one atrial fibrillation. Conclusions: Preliminary results suggest that TH q3wks followed by H as single agent, is an effective regimen for the treatment of P with Her2 positive MBC. No significant financial relationships to disclose.
Weekly high-dose erlotinib in patients with non-small cell lung cancer (NSCLC): A phase I/II study
Authors: D. T. Milton, V. A. Miller, C. G. Azzoli, M. Dunne, J. E. Gomez, R. Heelan, L. M. Krug, D. Ramies, N. A. Rizvi, M. G. Kris
Journal: Journal of Clinical Oncology (2004)

7085 Background: In preclinical studies, higher concentrations of the oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) erlotinib (Tarceva™) effectively inhibit MAPK and Akt, downstream components of the EGFR signaling pathway that may confer resistance to this agent. In BT-20 and MDA468 cells, the dose response curves for the inhibition of these kinases are steep (Akita et al. Semin. Oncol. 2003; 30: 15–24.). Notably, a prior Phase I study suggested these erlotinib concentrations can be attained clinically on a weekly schedule at doses less than 2000 mg (Karp et al. Proc ASCO 1999;40:#1499). We undertook this phase I/II study to explore high doses of erlotinib given once weekly. Methods: Patients with previously treated advanced NSCLC were enrolled in 3-patient cohorts, with no intrapatient escalation, at dose levels of 1200, 1600, and 2000 mg weekly. Six patients were planned for study at the 2000 mg dose level. Results: 11 patients have been enrolled to date. The first 2 dose levels (n=6) are completed. Pt characteristics: Female: 3; Karnofsky Performance Status median 80% (70–90%); age median 68 (54–76); prior chemotherapy median 2 (1–3). Toxicity (≥ Grade 2) by dose level 1200 mg: G2 rash (n=1), G2 diarrhea (n=1); 1600 mg : G2 diarrhea (n=1), G2 emesis (n=1). To date, all Grade 2 toxicities have resolved within one week of onset. Five additional patients have been enrolled at the 2000 mg dose level and are in their first month of treatment; none have experienced DLT to date. Conclusions: Weekly erlotinib at a dose of 1600 mg is tolerable for patients with advanced NSCLC refractory to initial chemotherapy. MTD has not yet been defined. The Phase II portion of the trial will commence after the MTD is identified. Supported, in part, by Genentech. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Inc. AstraZeneca; Genentech, Inc. Genentech, Inc. AstraZeneca Genentech, Inc.
Results of a phase I study of DTS-201, a peptidic prodrug of doxorubicin, in patients with solid tumors
Authors: J. Delord, P. Schöffski, E. Brain, H. Dumez, J. Robert, S. Faivre, V. Dubois, K. Vialatte, J. Deshayes, D. Ravel
Journal: Journal of Clinical Oncology (2007)

2547 Background: DTS-201 is a promising prodrug of doxorubicin (dox) designed to preferentially deliver the parent compound to tumor cells and to limit cardiotoxicity. Based on animal studies showing that DTS-201 was markedly safer and more active than conventional dox, a phase I trial was conducted to determine safety, pharmacokinetics and the recommended dose (RD) for phase II studies. Methods: DTS-201 was given as 1-hour infusion every 3 weeks. Four dose levels were tested: 80, 160, 250 and 400 mg/m 2 equivalent to 45 to 225 mg dox/m 2 . Toxicity was evaluated according to CTCAE v3.0 with specific attention to cardiotoxicity assessed by troponin I, echocardiography or cardio MUGA scan and 12-lead ECG. Results: Nineteen cancer patients (pts) with solid tumors (age range: 30–72 yrs) received DTS-201. Tolerance was good at 80 and 160 mg/m 2 . Three dose limiting toxicities (DLTs) were observed at cycle 1, one at 250 mg/m 2 (grade 3 diarrhea) and two at 400 mg/m 2 (one grade 3 vomiting and one grade 4 neutropenia = 5 days). Myelosuppression was the most common toxicity with 5 of the 6 pts treated at 400 mg/m 2 experiencing transient asymptomatic grade 3–4 neutropenia on day 15 that spontaneously resolved. Other adverse reactions included mild to moderate asthenia, alopecia, anorexia and nausea. Neither cardiotoxicity or dox unrelated toxicities were observed. Disease stabilization for more than 4 cycles was observed in three pts with prostate cancer, pleural mesothelioma or bronchoalveolar carcinoma at 250 and 400 mg/m 2 . The pt with prostate cancer treated at 250 mg/m 2 experienced a 60% decrease in serum PSA and a 23% reduction in lymph node size. The plasma AUCs and C max for DTS-201 and dox increased linearly with dose. At 400 mg/m 2 , the AUC of dox was within the range of values observed in pts receiving 60 mg/m 2 of conventional dox. However the C max of dox, observed at 1 to 1.5 hours following DTS-201 administration, was 20 to 25 times lower. Conclusion: DTS-201 was well tolerated up to 400 mg/m 2 , corresponding to 3.750-fold the standard dose of dox. This dose, with no evidence of cardiac toxicity, was proposed to be the RD for future phase II studies. Six additional pts will be treated at that dose level to better characterize safety. No significant financial relationships to disclose.
New Findings in Adult Opsoclonus-Myoclonus Syndrome
Authors: Jérôme Honnorat
Journal: JAMA Neurology (2016)

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Phase II study of DMXAA combined with carboplatin and paclitaxel in recurrent ovarian cancer
Authors: H. Gabra
Journal: Journal of Clinical Oncology (2006)

5032 Background: DMXAA (AS1404) is a small-molecule vascular disrupting agent, which in animal models shows additive or supra-additive effects with cytotoxics, including taxanes and platinum agents. This phase II study evaluated DMXAA in combination with carboplatin and paclitaxel in recurrent platinum-sensitive ovarian cancer patients with a progression-free interval of more than 6 months after response to platinum-based chemotherapy. Methods: Patients had first diagnosed disease FIGO stage Ic-IV, with presence of recurrent disease confirmed by imaging. Patients were randomised 1:1 to receive up to 6 cycles of carboplatin (AUC 6 mg/ml × min) and paclitaxel (175 mg/m 2 ) with or without DMXAA (1200 mg/m 2 ). Safety assessments included EKG, adverse events, laboratory screens and ophthalmic exam. Efficacy endpoints are objective response rates, time to progression, duration of response and stable disease, and median and 1-year survival. Results: 55 patients have been enrolled to date from a planned total of ∼70. Initial safety findings in the two arms are comparable. Preliminary investigator-assessed RECIST response data show the following unconfirmed outcomes: of 17 patients in the DMXAA arm, there are 10 with partial responses (PRs), 7 with stable disease (SD) and 0 with progressive disease (PD); of 14 patients in the control arm, there are 8 PRs, 6 SDs and 0 PDs. Conclusions: Initial safety findings suggest that addition of DMXAA to standard doses of carboplatin and paclitaxel did not add significantly to toxicity. Efficacy assessments are ongoing to determine the value of the triple combination in recurrent ovarian cancer. No significant financial relationships to disclose.