tbuckley/cabot-search huggingface dataset:
Genome Engineering Using Adeno-associated Virus: Basic and Clinical Research Applications
Authors: Thomas Gaj, Benjamin E Epstein, David V Schaffer
Journal: Molecular Therapy (2015)

In addition to their broad potential for therapeutic gene delivery, adeno-associated virus (AAV) vectors possess the innate ability to stimulate homologous recombination in mammalian cells at high efficiencies. This process--referred to as AAV-mediated gene targeting--has enabled the introduction of a diverse array of genomic modifications both in vitro and in vivo. With the recent emergence of targeted nucleases, AAV-mediated genome engineering is poised for clinical translation. Here, we review key properties of AAV vectors that underscore its unique utility in genome editing. We highlight the broad range of genome engineering applications facilitated by this technology and discuss the strong potential for unifying AAV with targeted nucleases for next-generation gene therapy.
Serum proangiogenic factors in patients with testicular germ cell tumors
Authors: A. L. Boutis, N. Diamantopoulos, D. Mouratidou, C. Andreadis, G. Galaktidou, K. Papazisis, E. Lalla, A. Kortsaris
Journal: Journal of Clinical Oncology (2008)

16050 Background: Angiogenesis has an established role in the initiation and maintenance of carcinogenesis, as well as a certain role in the establishment of metastatic foci. The role of angiogenesis in testicular germ cell tumors, although obvious, is not fully elucidated. The present study aims to clarify the role of serum proangiogenic factors in patients with testicular germ cell tumors. Methods: We measured serum basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), platelet derived growth factor BB (PDGF-BB) and angiopoietin-2 (Ang-2), using solid phase Elisa in 50 patients (mean age 32,3±9,1 years) with testicular cancer who underwent chemotherapy and in 16 healthy male, age-matched (mean age 31,8±7,12 years) controls. Three serum samples were obtained from patients with testicular cancer: prior to chemotherapy (baseline), before cycle 3, and 9–14 months after the completion of chemotherapy. One serum sample was obtained from controls. Informed consent was taken before the obtainment of the samples. Results: Baseline mean serum bFGF, VEGF, PDGF-BB, and Ang-2 were 666,5 ±550pg/ml, 228,3±181pg/ml, 10623,8pg/ml, 4089,82±3312pg/ml in patients and 1153,6±967pg/ml, 158,9±137pg/ml, 8726,1±4318pg/ml, 2647,2±1186pg/ml in controls (p=0,1, p=0,8, p=0,3 and p=0,013). Mean serum values 1 year after the completion of chemotherapy were 310,8±298pg/ml, 139±127pg/ml, 7500±3726pg/ml and 6275±5600pg/ml (p=0,044, p=0,198, p<0,001, p=0,008). As we can see, there was a trend toward normalization of proangiogenic factors values, especially for PDGF-BB and Ang-2, and there was a difference between patients and controls for Ang-2. Ang-2 was also statistically significant different between good (n=8) and intermediate-bad prognostic groups (n=42) (mean values 3413±2100 and 5291±3200, p=0,03). Conclusions: These results support the notion about the role of proangiogenic factors in germ cell carcinogenesis. Especially angiopoietin-2 seems to play a significant role, as it was the only factor with statistically significant difference between patients and controls and the only factor with difference between the various prognostic groups. Further study of angiopoietin-2 and its role in germ cell tumors is warranted. No significant financial relationships to disclose.
Clinical outcomes of male choriocarcinoma: A case series
Authors: B. L. Cho, C. J. Moore, B. Hayes-Lattin, S. Daneshmand, C. R. Nichols
Journal: Journal of Clinical Oncology (2008)

16128 Background: Pure choriocarcinoma is a very rare entity and is the most aggressive subtype of nonseminomatous germ cell tumor. Extensive metastatic disease, marked HCG elevations, and rapid disease progression and death are commonly seen. There is limited published data regarding specific treatment outcomes in this group of patients (pts). Methods: We identified 14 cases of pure choriocarcinoma treated by a single primary oncologist between 1998 and 2007. Retrospective chart review with descriptive statistical analysis was performed. Results: The median age was 28 years (range 12–51). Six pts had testis pure choriocarcinoma and eight pts had choriocarcinoma syndrome. According to the International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic classification system, ten pts were poor prognosis at diagnosis and four pts were intermediate prognosis. Four pts who underwent standard initial chemotherapy followed by surgical resection of all residual masses are alive at +3, +6, +7, and +120 months. Three pts with choriocarcinoma syndrome and one pt with primary testis choriocarcinoma were absolute cisplatin refractory and died within 3–6 months of diagnosis. Two pts underwent high dose chemotherapy with stem cell transplant (HDCT) as 2nd line treatment and four pts received HDCT as 3rd line treatment. Four of the six pts died of disease at a median of 10.5 months after transplant (range 3–16). Of three pts with cisplatin refractory disease prior to HDCT all died within 11 months of transplant. One pt is currently alive with disease, and one pt has received the first of planned tandem cycles. With a median follow-up of 8 months (range 4–192), five pts are alive without disease, one is alive with disease, and eight pts have died. Conclusions: Choriocarcinoma remains a significant therapeutic challenge. In our series, HDCT did not benefit patients with cisplatin refractory disease. Patients who are able to undergo complete resection of residual masses after standard chemotherapy appear to have better outcomes although follow up is brief thus far. Novel strategies are needed in this high risk, often cisplatin refractory population. No significant financial relationships to disclose.
Accurate classification of metastatic brain tumors using a novel microRNA-based test.
Authors: W. C. Mueller, D. Jaeger, Y. Spector, S. Rosenwald, T. B. Edmonston, A. Chajut
Journal: Journal of Clinical Oncology (2010)

e21044 Background: Identification of the tissue-of-origin (ToO) of a brain metastatic tumor is vital to its management. Carcinoma of unknown primary (CUP) is common in oncology, representing 4-6% of all invasive malignancies. A qRT-PCR-based test that measures the expression of 48 microRNAs was employed to identify the ToO of metastatic tumors of known origin as well as of CUP cases resected from brain or spine. Methods: A microRNA-based qRT-PCR diagnostic assay to identify the ToO of metastatic tumors was tested on 2 cohorts of resected brain and spinal metastatic lesions. The first cohort included 104 resected tumors with known origin (“reference diagnosis”), previously classified based on the patient's clinical history and pathological data. The second cohort included 57 tumors that had been originally diagnosed as CUP, for some of which additional clinical and pathological data was gathered following the original diagnosis. The majority of the samples were processed successfully (3 samples/cohort failed QA). Results: In this blinded study, the test predictions correctly identified the reference diagnosis of the samples with the known origin in 84% of the 89 cases (excluding prostate samples). In the second cohort, for 6 cases out of the 54 true CUP patients the diagnosis of the origin remained unknown clinically and after full pathological review. In 81% out of the remaining 48 CUP cases, the test prediction was in agreement with the diagnosis which was later confirmed clinically or with pathological data. In 19% out of the remaining CUP cases, the test results showed some discordance with the pathology or with clinical data. Additional clinical and pathological analysis of the CUP cases is currently ongoing. Conclusions: In a cohort of brain and spinal metastases, a previously developed qRT-PCR test based on the expression profile of 48 microRNAs allowed accurate identification of ToO in most of the cases. The high accuracy of this test in identifying the ToO of metastasis of unknown primary has been validated by this study and demonstrates its clinical utility. The test was also able to suggest origins in cases in which the pathological review was insufficient, suggesting additional clinical utility in those hard-to-resolve cases. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Rosetta Genomics Rosetta Genomics Rosetta Genomics
Dental health of long-term survivors of childhood cancer: The childhood cancer survivor study (CCSS)
Authors: S. C. Kaste, S. Baker, P. Goodman, W. Leisenring, M. Stovall, R. Hayashi, M. Yeazel, M. M. Hudson, C. Sklar, L. L. Robison
Journal: Journal of Clinical Oncology (2007)

9017 Background: This study describes the frequencies of and risk factors for altered oral health and dental development in pediatric patients who have survived childhood cancer. Methods: We identified 8,522 participants and 2,831 siblings in the CCSS with information on dental health. Dental outcomes of treatment and socioeconomic-demographic (SED) data, were analyzed using univariate and multivariate logistic regression models to estimate odds ratios (OR). Results: Survivors included 4,249 females (49.9%), 7,367 white non-Hispanic (86.5%). Median age at cancer diagnosis, 6.8y (range, 0–20 y); time from diagnosis to interview, 31.4 y (range, 17–54 y). Overall, 30% of survivors self-reported ≥ 1 oral-dental abnormality: microdontia (10%), hypodontia (8%), &gt; 5 caries (55%), root stunting (6%), enamel hypoplasia (13%), gingivitis (7%). Compared to siblings, survivors were at increased risk of ≥ 1 oral-dental abnormalities when adjusted for SED (OR = 2.0, p&lt;0.001). Increased risk of abnormalities was associated with being female (p&lt;0.001) or white non-Hispanic (p=0.001), having an income &lt; $20K (p=0.001) or lower education (p=0.004), and lack of health insurance (p=0.02). Patients with central nervous system tumors, neuroblastoma and soft tissue sarcoma had highest risk of abnormality (all P-values &lt; 0.001). In multivariate models adjusted for SED, radiation dose to jaw, and exposure to increasing doses of alkylating agents increased risk of oral-dental abnormalities (radiation dose = 20 Gy OR = 5.6, p &lt; 0.001; alkylating agent score OR=1.6, p&lt;0.0001). Conclusions: Childhood cancer therapy results in adverse long- term oral-dental sequelae and is associated with specific treatment factors. No significant financial relationships to disclose.
Abstract 12569: Intrathoracic Impedance Change Reflects Reverse Left Ventricular Remodeling in Response to Cardiac Resynchronization Therapy in Chronic Heart Failure
Authors: Shinya Yamada, Hitoshi Suzuki, Hironori Uekita, Yoshiyuki Kamiyama, Syuuichi Saitou, Yasuchika Takeishi
Journal: Circulation (2010)

Background: Intrathoracic impedance monitoring has been reported to be useful for prediction of worsening chronic heart failure. However, it is not revealed the relation between changes in intratho...
Contraception in premenopausal breast cancer patients on tamoxifen: Have you advised?
Authors: S. Ramamurthy, R. Willis, D. Lee
Journal: Journal of Clinical Oncology (2011)

e11558 Background: Studies in women taking tamoxifen have confirmed that ovulation does occur and they can continue to menstruate during treatment. Therefore premenopausal women (PMW) taking tamoxifen are potentially at risk for pregnancy and must be counselled about barrier contraception. The risks of tamoxifen causing congenital malformations or late teratogenic manifestations in adulthood are unknown. In our center we treat hormone receptor positive breast cancer in PMW with tamoxifen. It is used in both adjuvant and palliative settings. It is a well-recognized good clinical practice to provide relevant information about the benefits and side effects of treatment to patients prior to its commencement. We undertook an audit to investigate if the issue of contraception was addressed with premenopausal breast cancer patients (PMBCP) prior to starting of tamoxifen by their oncologist. Methods: A retrospective review of 50 case notes of PMBCP was carried out. A search was conducted to find out if the clinician starting tamoxifen had advised these patients regarding contraception. Printed information and/or verbal advice given, provided they were recorded in notes, were taken as positive evidence. All patients who received tamoxifen for breast cancer in our audit had hormone receptor positive disease confirmed on histology. Results: See table. Conclusions: In PMBCP taking tamoxifen, the issue of contraception is often not discussed and/or is poorly documented. This has potential ethical and legal implications for clinician in charge should a pregnancy occur during the treatment tenure. Recorded (%) Not recorded (%) Menstrual history 35 (70) 15 (30) Parity 18 (36) 32 (64) Contraceptive advice given 8 (16) 42 (84) Method of contraception discussed 2 (4) 48 (96)
Significance of CA 27.29 (MUC 1 glycoprotein) levels in patients with breast cancer
Authors: V. Ghai, H. A. Harvey, K. K. Abbi, A. Barochia, C. Bhardwaj, L. M. Demers
Journal: Journal of Clinical Oncology (2009)

e11579 Background: ASCO guidelines do not support the use of CA 15–3 and CA 27.29 for monitoring patients for recurrence after primary breast cancer therapy. However, several well-designed studies have shown that an increase in CA 15–3 or CA 27.29 after primary and/or adjuvant therapy can predict recurrence an average of 5 to 6 months before other symptoms or tests. We wanted to assess the significance of measuring the tumor marker (CA 27.29 levels) to monitor the clinical progress of breast cancer. Methods: After IRB approval, we conducted a retrospective chart review of 392 patients with breast cancer who had regular monitoring of CA 27.29 levels following the diagnosis of breast cancer. A total of 2671 values of CA 27.29 were evaluated from our institution over the past 5 years (2003–2008). Patient CA 27.29 levels were correlated with clinical progression of the disease (diagnostic imaging and history and physical examinations). Results: Out of 330 patients with Stage I, II, and III after treatment with adjuvant therapy, 316 had no evidence of disease (NED) and had normal levels(&lt;38) of CA 27.29. Out of the14 patients with clinical evidence of disease recurrence, 3 had persistently elevated levels. Of the 62 patients with stage IV breast cancer following cheomotherapy, 29 patients had clinical progression of disease with 20 (69%) patients showing increasing levels. Out of the 33 patients with no evidence of progression of disease only 4(12%) had increasing levels. Conclusions: Our trend analysis concludes that a normal CA 27.29 level in patients with Stage I, II, and III, after adjuvant treatment, correlates well with clinically NED status and might be of reassuring benefit to the patients. However, increasing levels of CA27.29 in metastatic disease correlate well with clinical progression of the disease. A large multicenter prospective study is warranted to further assess the role of CA 27.29 for disease monitoring in locally advanced and metastatic breast cancer. No significant financial relationships to disclose.
KRAS mutations in colorectal cancer patients in Italy: Results from the KRAS aKtive program.
Authors: A. Marchetti, C. Pinto, G. L. Taddei, G. Troncone, A. Russo, G. Fontanini, L. M. Larocca, M. Mottolese, G. Giannini, L. Ruco, E. Roz, A. Scarpa, G. Calabrese, B. Bortesi, S. Vaccarella, A. Cossu, V. Ludovini, N. Normanno
Journal: Journal of Clinical Oncology (2011)

e14000 Background: The Italian Association of Medical Oncology (AIOM) and the Italian Society of Surgical Pathology and Cytopathologyy (SIAPEC) collaborated to promote a national program (KRAS aKtive) to support the activity of oncologists and pathologists involved in the management of metastatic colorectal cancer patients who need the assessment of the mutational status of the KRAS gene. Methods: The KRAS aKtive program was specifically devised to facilitate the exchange of biologic material, clinicopathological data and diagnostic reports within a network of oncologist, pathologists and pathology/molecular biology reference laboratories throughout Italy, connected through the site www.kras-aKtive.it. KRAS mutation analysis was performed by PCR-Sanger sequencing, real time PCR or other techniques. Data were collected in a common database. Results: Started on March 2009, the KRAS aKtive program has involved 407 oncologists, 125 pathologists, and 24 reference laboratories from 16 of the 21 Italian regions. A total of 2,589 KRAS mutation texts were performed. The majority of tests (1,967 cases, 78.1%) were conducted by sequencing. In 231 (9.2%) cases a real-time PCR assay was used, other detection techniques were used in 321 (12.7%) cases. The tests were informative in 97.3% of cases. KRAS mutations at codons 12-13 were detected in 940 cases (37.3%). The frequency of mutations detected by sequencing was lower than that observed by real-time PCR (35.7 and 48.1%, respectively). The frequency of the different type of mutations at codons 12 and 13 is reported in the table. Conclusions: The results of this large survey allow an accurate estimation of the actual prevalence of KRAS mutations and their types in caucasian colorectal cancer patients. Moreover, although the subset numbers are still insufficient to draw definitive conclusions, our data suggest that the frequency of mutations detected by real-time PCR amplification is higher than that obtained by sequencing. Program supported by Merck Italy. Mutation type Number % GGT->GTT G12V 226 24.04% GGT->GAT G12D 309 32.87% GGC->GAC G13D 186 19.79% GGT->TGT G12C 78 8.30% GGT->GCT G12A 49 5.21% GGT->AGT G12S 43 4.57% GGT->CGT G12R 14 1.49% Others 35 3.72% Total 940 100.00%
Xenografts of human hepatocellular carcinoma: A tool for screening drugs used in treatment of this disease
Authors: Thanh Hung Nguyen, Phuc Tien Do, Khee Chee Soo, Pierce Chow, Lawrence Panasci, Hung Huynh
Journal: Cancer Research (2005)

1985   Hepatocellular carcinoma (HCC) is a common malignancy in Asia and Africa. There is currently no successful treatment for HCC. In the present study, we report the establishment and characterisation of 6 lines of xenografts from primary human HCC tumours. They were classified into 1318 and 5-1318 series. The 1318 series (3 lines) was a trabecular type, grew rapidly in  SCID  mice and doubled its volume every 48 to 60 hrs. The 5-1318 series (3 lines) possessed a pseudoglandular pattern, grew relatively slowly in  SCID  mice and required approximately 8 to 10 days to double its tumour volume. Although 1318 and 5-1318 xenografts expressed androgen receptor, estrogen receptor alpha and progesterone receptor, their growth rate did not affected by either castration or sex steroid hormone supplementation. Systemic delivery of cisplatin, oxaliplatin, vitamin D analog EB1089 and EGF-R inhibitor Iressa to mice bearing 1318 or 5-1318 xenografts resulted in no growth suppression. Studying their protein profile revealed that growth behaviour of HCC xenografts was positively correlated with the levels of cdc-2. Target inhibition of cdc-2 activity by intraperitoneal delivery of 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) to mice bearing either 1318 or 5-1318 xenografts resulted in a significant growth inhibition. The results indicate that 1318 and 5-1318 xenografts are useful tools for screening drugs used in treatment of HCC and suggest a potential use of SarCNU in treatment of this fatal disease.
The Relative Bioavailability, Food Effect and Drug Interaction With Omeprazole Of Momelotinib Tablet Formulation
Authors: Yan Xin, Lixin Shao, Wei Deng, Amanda Shaffer, Pharm D, Dimitrios Stefanidis, Jeffrey Hemenway, Xiaoming Li, Susie Jun, Srini Ramanathan
Journal: Blood (2013)
Phase II study of FOLFIRI chemotherapy as first-line treatment for elderly patients (pts) with advanced gastric cancer (AGC).
Authors: Y. Becouarn, C. Bellera, R. Brunet, J. Legoux, L. Cany, J. Dauba, D. Smith, D. Auby, C. Mertens, M. Fonck
Journal: Journal of Clinical Oncology (2010)

4150 Background: 58% of gastric cancers occur after 70 and 28% after 80. Trials demonstrated efficacy of FOLFIRI association in gastric cancer. Efficacy of this regimen in pts older than 70 with AGC and good physiological status has to be evaluated in terms of efficacy and toxicity. As few trials reported benefits of geriatric assessment, we assessed their prognostic impact. Methods: We investigated efficacy of bimonthly 48-h regimen with irinotecan, folinic acid and fluorouracil by conducting a multicenter two-stage phase 2 trial. Primary endpoint: 2-month objective response rate (ORR). Secondary endpoints: OS; PFS; toxicity; identification of geriatric parameters predicting chemotherapy-induced toxicity; 4 geriatric evaluations (baseline; after cycles 1 and 3; end of treatment) were realized evaluating cognitive function (MMSE), nutritional status (MNA), comorbidity (CIRS-G), mobility (get up and go), autonomy (ADL, IADL), quality of life (QLQ-C30), thymic function (GDS-15). Results: Since 2005, 43 elderly pts treatment-naïve were enrolled; median age 77.5 (70.4-86.9), 32 males ; 2-month ORR was 22.5% (1CR + 8PR); including stable disease lead to a 77.5% disease control rate. Median follow-up time was 34 months. Median OS was 10.5 months, 1-year OS rate 44%. Grade 3-4 adverse events were: haematologic toxicity (6), cardiac failure (4), diarrhea (2), nausea (2). Second-line treatment was proposed in 18 cases (43%); 5 pts underwent surgery. At baseline, 92.5% had good ADL score and 92.5% IADL, 12.5% had poor cognitive function (MMSE < 24/30), 28.2% were depressed (GDS15 > 6), 75% were at risk of malnutrition (MNA < 23.5), 2.9% had fall risk (get up and go > 20 seconds); 12.8% estimated poor quality of life (< 4). After 4 cycles, autonomy, cognitive functions and spirit were not significantly modified; only 59.5% were at risk of malnutrition. Prognostic impact of geriatric functions is currently being analyzed. Conclusions: Results suggest excellent disease control rate with limited treatment-induced toxicity and preserved geriatric functions. No significant financial relationships to disclose.
A phase I study of radiation therapy (RT) with concurrent oxaliplatin (OXL), cisplatin (P) and protacted infusion 5-fluorouracil (FU) for locally advanced esophageal (ES) or gastroesophageal (GEJ) carcinoma
Authors: R. Gallego, A. Cervantes, M. Pera, H. Manzano, R. Salazar, C. Conill, J. Maurel, X. Marfà, P. Gascón
Journal: Journal of Clinical Oncology (2004)

4243 Background: Concurrent chemoradiotherapy with P and FU is superior to RT alone for locally advanced ES and GEJ carcinoma (Herskovic NEJM 1992) but at the cost of substantial toxicity. OXL has demonstrated activity in gastrointestinal tumors and overcome mismatch repair cisplatin-resistance in vitro. This study was undertaken to assess toxicity in patients with ES and GEJ treated with RT, OXL, P and FU. Methods: OXL, P and FU in 96 hour protacted infusion were given to 19 patients in two cycles every 4 weeks during RT (50.4 Gy in 28 fractions), using escalating doses outlined in the table. Results: Patients characteristic: 17 male, 2 female. Median age: 59 years (range 42–75); PS 0;4, PS 1;15. Loss weight (<10%;12p,>10%; 7p).Grade 3–4 neutropenia occurred in three patients (one at dose level 3 and two at dose level 4) and grade 3–4 thrombocytopenia ocurred in 2 patients (one at level 3 and 1 at level 4). Non-hematological toxicity is shown in the table. The most common grade 3–4 toxicities were diarrhea (1p), mucositis (1p) and asthenia (1p). Dose level 3 was defined to be the maximum tolerated dose. 12/19 (63%) patients underway tumor resection with 2/19 pCR (10%). Conclusions: The 3rd level is feasible and well-tolerated. A phase II study in patients with resectable ES and GEJ is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi-Synthelabo S.A.