tbuckley/cabot-search huggingface dataset:
Preclinical Models Provide Scientific Justification and Translational Relevance for Moving Novel Therapeutics into Clinical Trials for Pediatric Cancer
Authors: David M. Langenau, Alejandro Sweet-Cordero, Robert J. Wechsler-Reya, Michael A. Dyer
Journal: Cancer Research (2015)

Despite improvements in survival rates for children with cancer since the 1960s, progress for many pediatric malignancies has slowed over the past two decades. With the recent advances in our understanding of the genomic landscape of pediatric cancer, there is now enthusiasm for individualized cancer therapy based on genomic profiling of patients' tumors. However, several obstacles to effective personalized cancer therapy remain. For example, relatively little data from prospective clinical trials demonstrate the selective efficacy of molecular-targeted therapeutics based on somatic mutations in the patient's tumor. In this commentary, we discuss recent advances in preclinical testing for pediatric cancer and provide recommendations for providing scientific justification and translational relevance for novel therapeutic combinations for childhood cancer. Establishing rigorous criteria for defining and validating druggable mutations will be essential for the success of ongoing and future clinical genomic trials for pediatric malignancies.
A phase III trial of exemestane plus bevacizumab maintenance therapy in patients with metastatic breast cancer after first-line taxane and bevacizumab: a GINECO group study
Authors: O. Trédan, P. Follana, I. Moullet, C. Cropet, S. Trager-Maury, J. Dauba, S. Lavau-Denes, V. Diéras, D. Béal-Ardisson, M. Gouttebel, H. Orfeuvre, L. Stefani, C. Jouannaud, F. Bürki, T. Petit, E. Guardiola, C. Becuwe, E. Blot, E. Pujade-Lauraine, T. Bachelot
Journal: Annals of Oncology (2016)
Neoadjuvant chemotherapy with high-dose ifosfamide, doxorubicin and cisplatin in nonmetastatic osteosarcoma of the extremity
Authors: I. Kudawara, M. Ieguchi, Y. Aoki, N. Naka, N. Araki, H. Nakanishi, A. Matsumine, A. Myoui, T. Ueda, H. Yoshikawa
Journal: Journal of Clinical Oncology (2004)

9039 Background: Doxorubicin (DOX), cisplatin (CDDP) and methotrexate (MTX) are active agents for the treatment of osteosarcoma (OS). Neoadjuvant chemotherapy including these multi-agents has been established. However, ifosfamide (IFM) is mainly used in poor responders to adjuvant chemotherapy. Patients and methods: From 1997 to 2000, 26 patients (pts) with newly diagnosed, previously untreated nonmetastatic (stage IIB) OS of extremities received the OOS-D protocol. There were 16 males and 10 females. The median age was 17 (range 9 –59). Tumor locations: femur in 15, tibia in 7, fibula in 2, humerus in 1 and ulna in 1. Cycles 1 and 3 consisted of DOX 90 mg/m2 and CDDP 120 mg/m2. Cycles 2 and 4 consisted of continuous infusions of IFM12–15 g /m2. Local wide excision was scheduled after 4 courses of chemotherapy. All pts received limb-saving operations: prosthetic replacement in 21, resection in 1 and intraoperative extracorporeal autogenous irradiated bone grafts in 4. Two cycles of postoperative chemotherapy consisted of DOX + CDDP, IFM and HD-MTX (10–12 g/m2). Results: With a median follow up of 54 months (range, 12 –73 months), 20 pts were continuously disease free, in 3 there was no evidence of disease after pulmonary metastasectomy, 2 were alive with disease and 1 died of disease. Local recurrence was seen in 1. Histologic good responses were seen in 63%. The 3- year event-free survival rate for pts was 84%; overall survival was 96%. The 5-year event-free survival rate for pts was 79%; overall survival was 96%. These results are better than those achieved with our previous protocol (OOS-C). Conclusion: This study demonstrates good survival with the IFM-containing neoadjuvant protocol. No significant financial relationships to disclose.
Abstract 3231: An orthotopic xenograft model of sarcoma metastasis demonstrates essential role of tumor microenvironment for metastasis
Authors: Seth D. Goldstein, Masanori Hayashi, Catherine M. Albert, Kyle W. Jackson, David M. Loeb
Journal: Cancer Research (2015)

Abstract Sarcoma metastasis is a multi-step process that includes migration, intravasation into the circulation, extravasation and invasion to distant tissue, and distant tumor growth, and because commonly used xenograft models do not account for every step in the process, we sought to develop a novel metastasis model system. Our technique involves implanting small fragments of patient-derived xenografts into either the tibia or gastrocnemius muscle of NOD/SCID/IL-2Rγ knock-out mice and amputating the affected limb when the tumor reaches at least 1 cm in diameter. Mice are then followed for the development of distant metastases. We found that Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma xenografts all undergo distant metastasis when implanted in an orthotopic location, but do not metastasize after subcutaneous implantation, even when the subcutaneous tumor is excised and mice are observed long-term post-excision. We also investigated whether the difference in metastatic potential is related to cell intrinsic or cell extrinsic factors. Analysis by immunofluorescence revealed that tumors are infiltrated by macrophages regardless of site of implantation, but that the polarization of these macrophages differs. We also found differences in expression of arginase and NOS2 based on site of xenograft implantation. Thus, we have demonstrated that sarcoma patient-derived xenografts undergo spontaneous distant metastasis when implanted in an orthotopic location, but not when implanted in a heterotopic location, highlighting the essential role of the tumor microenvironment in determining metastatic potential. This model has significant benefits compared with the more commonly used tail vein injection model of metastasis, which bypasses the requirements for local invasion and vascular intravasation, processes that are amenable to study using our model. We have begun to use this model to investigate the mechanisms by which tumor microenvironment influences metastasis, and also are using this model for preclinical drug evaluation to determine a therapy's effect not only on growth of the primary tumor, but also on development of metastasis. Citation Format: Seth D. Goldstein, Masanori Hayashi, Catherine M. Albert, Kyle W. Jackson, David M. Loeb. An orthotopic xenograft model of sarcoma metastasis demonstrates essential role of tumor microenvironment for metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3231. doi:10.1158/1538-7445.AM2015-3231
A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1)
Authors: H. Bonnefoi, T. Grellety, O. Tredan, M. Saghatchian, F. Dalenc, A. Mailliez, T. L'Haridon, P. Cottu, S. Abadie-Lacourtoisie, B. You, M. Mousseau, J. Dauba, F. Del Piano, I. Desmoulins, F. Coussy, N. Madranges, J. Grenier, F.C. Bidard, C. Proudhon, G. MacGrogan, C. Orsini, M. Pulido, A. Gonçalves
Journal: Annals of Oncology (2016)
Mitomycin (M) in combination with cisplatin (P) or vinorelbine (V) and erythropoietin (Epo) in patients with in field relapse after radiation therapy of non-small cell lung cancer: A phase II study of the AIO
Authors: F. Griesinger, I. Stenger, C. Tomala, U. Olgemoeller, W. Koerber, B. Fischer, M. Sebastian, T. Overbeck
Journal: Journal of Clinical Oncology (2007)

18208 Background: Therapy for in radiation field relapse of NSCLC is challenging. Tumors are regularly resistant to chemotherapy, most likely due to a high proportion of hypoxic tumor. Mitomycin (M) is effective in hypoxic environment. However, in outer regions of the tumor, normoxic conditions might exist. Therefore, a combination of M and cytotoxic agents (cisplatin (P) and vinorelbine (V)) which are effective under normoxic conditions as well as Epo which decreases tumor hypoxia might represent an effective way to treat in radiation field relapses. Therefore, this approach was investigated in a multicenter phase II trial. Patients and Methods: 12 patients with a progressing symptomatic relapse within the radiation field have been enrolled in the study as of yet: 12 male, 0 female, 8 squamous cell, 4 adenocarcinoma, 5 stage IIIB, 7 stage IV, median age 63 y. Pts were to receive 4 cycles M 8 mg/m 2 d1 and V 25 mg/m 2 d1, 8 q22 days in case of P pretreatment, or M 8 mg/m 2 and P 40 mg/m 2 d1,8 q22 days in case of no P pre-treatment. Epo 40.000 IE s.c. q7 days was administered to maintain Hb levels between 12 and 13.0 g%. Response (WHO criteria), time to progression, survival and toxicities, Hb values, as well as quality of life (not shown) were evaluated. Results: A median of 2 cycles were administered (1–4). Stable disease was observed in 7/12 evaluable patients (58%, 95% CI 28–84%). Median time to progression was 2.3 months (1.0–2.9 months), median survival was 3.8 months (2.9–6.2 months). Grade 3/4 toxicities were: dyspnea 1/12, loss of appetite 1/12, leukocytopenia 4/12, lymphocytopenia 1/12, neutropenia 3/12, nausea 1/12. Median Hb levels were maintained above 12 g%. Discussion: Cinical benefit was observed in 58% of patients with in radiation field relapse. To the knowledge of the authors, this is the first study specifically addressing the efficacy of chemotherapy for in radiation field relapses of NSCLC. M in combination with P or V and Epo results in similar response rates as second line chemotherapy for chemotherapy pretreated relapses. These results warrant further studies in NSCLC relapsing within radiation fields. No significant financial relationships to disclose.
DNA repair biomarker alterations in breast cancer relevant to adjuvant chemotherapy treatment decisions.
Authors: K. M. Sprott, X. Wang, W. Pierceall, J. Kutok, T. Heikkinen, P. Heikkila, J. Bartek, D. T. Weaver, C. Blomqvist, H. Nevanlinna
Journal: Journal of Clinical Oncology (2010)

10634 Background: It is increasingly evident that DNA Repair pathways are important determinants, prognostically and predictively, in breast cancer outcomes. Although anthracycline-based therapies are standard-of-care in breast cancer, some patients may benefit from other available therapies. Based on the DNA-damaging mechanism of action of anthracyclines and radiation, we sought to discriminate the phenotypic tumor changes to DNA repair by investigating multiple DNA repair biomarkers. We utilized a digital pathology platform to explore the association of these biomarkers with chemotherapy outcome. Methods: Tumor from 1,491 breast cancer patient specimens collected at Helsinki University Central Hospital between 1997 and 2000 were formatted into Tissue Microarrays (TMAs). The FFPE samples included 6,392 cores with four 0.6mm diameter cores per patient. IHC was performed with antibodies against 6 DNA repair proteins: BRCA1, FANCD2, RAD51, PAR, XPF, and phosphoMapKapKinase2 (pMK2). Fifty or greater tumor cells per core were analyzed using a pattern recognition and image analysis platform. Nuclear plus/minus cytoplasmic intensity and quantity measurements were acquired for the markers. Results: Digital pathology platforms are a robust means to determine levels of protein biomarkers as evidenced by DNA repair analysis. Pattern recognition and manual pathologist selection of tumor zones for scoring achieved high similarity with R2 correlations of >0.96, allowing increased throughput of biomarker analysis. RAD51 and FANCD2 biomarkers had the greatest fraction of breast cancer patients with low score values with mean scores of 44 and 30 respectively (0-300 scale). For BRCA1, pMK2, and PAR, the scores were variable amongst breast cancer patients with mean scores of 119 (0-300 scale), 166 (0-300 scale), and 50 (0-100 scale). Statistical analysis with univariate and multimarker models for subtype definition and treatment associations to determine the prognostic and predictive significance of DNA repair biomarkers are to be presented. Conclusions: Significant DNA repair differences are evident in breast cancer, and may be important determinants of therapy selection. No significant financial relationships to disclose.
Carotid artery stenting is as effective as carotid endarterectomy, study shows
Authors: Susan Mayor
Journal: BMJ (2016)

Carotid artery stenting achieves a similarly low risk of death, stroke, and myocardial infarction (MI) to carotid endarterectomy in older patients with asymptomatic severe carotid stenosis, shows a randomised trial published in the New England Journal of Medicine that also showed similar rates of stroke and survival at five years.1

Carotid artery disease causes around 20% of strokes, and studies have shown that carotid endarterectomy can reduce the risk of stroke and death in people with severe carotid artery stenosis. Carotid artery stenting offers a …
A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy
Authors: J. O'Shaughnessy, K. L. Blackwell, H. Burstein, A. M. Storniolo, G. Sledge, J. Baselga, M. Koehler, S. Laabs, A. Florance, D. Roychowdhury
Journal: Journal of Clinical Oncology (2008)

1015 Background: Lapatinib (L) is an oral, small-molecule inhibitor of EGFR and HER2 with a mechanism of action distinct from that of trastuzumab (T). Preclinical data suggest synergy between L and T. We studied L alone and in combination with T in pts with HER2+ MBC who progressed on T. Methods: Eligible women had received prior anthracycline and taxane therapy, had MBC with measurable lesions or bone-only disease, and had progressed on prior T-containing therapy. Pts were stratified by hormone receptor status and visceral/nonvisceral disease, then randomized to receive either L (1,500 mg QD) or L (1,000 mg QD) plus T (2 mg/kg weekly after 4 mg/kg loading dose). If pts progressed on the L arm, they could cross over to the L+T arm. The primary endpoint was PFS (investigator assessment), and secondary endpoints were clinical benefit rate (CBR) at 24 wks, RR, and OS. Results: 296 pts were randomized. All pts had received prior T; the median number of prior chemotherapy regimens was 6. Combination therapy significantly improved PFS and CBR; RR and OS were similar in both arms (Table). Both treatment regimens were generally well tolerated. Grade 1/2 diarrhea was higher in the L+T arm (53% vs 41%); acneiform rash was more common in the L-alone arm, likely due to higher L dose. Asymptomatic decline in LVEF (> 20% and below LLN) occurred in 5% of pts in L+T arm and 2% of pts in L-alone arm. 1 death occurred due to cardiac toxicity in the L+T arm. Conclusions: This is the largest study of 2 targeted agents in HER2+ MBC and the first to demonstrate the synergy of L+T in a phase III setting. Improved clinical outcome was achieved with the combination of L+T in pts progressing on T-based therapy and without a substantial change in the side effect profile. The role of combined anti-HER2 therapy, in combination with chemotherapy, in less heavily pretreated patients with early stage disease is ongoing in the ALTTO (Adjuvant L and/or T Treatment Optimization) study. Endpoint L L + T Hazard/OR 95% CI P value PFS (median, wks) * 8.4 12.0 0.77 0.6, 1.0 0.029 CBR (%) * 13.2 25.2 2.1 1.1, 4.2 0.020 RR (%) * 6.9 10.3 1.5 0.6, 3.9 0.46 OS (median, wks) 39 51.6 0.75 0.5, 1.1 0.106 * Intent to treat. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline Exelixis, GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
Toxic Effects of Steroid Hormones on Organ Cultures of Mouse Mammary Tumors, With a Comment on the Occurrence of Viral Inclusion Bodies&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Evelyn M. Rivera, Joel J. Elias, Howard A. Bern, Nicolay P. Napalkov, Dorothy R. Pitelka
Journal: JNCI Journal of the National Cancer Institute (1963)

Several steroid hormones used in studies of mammary tissue development in organ culture were examined for their effects on spontaneous mammary tumors. Mammary adenocarcinomas from C3H/Crgl mice were cultured for 5 days in medium 199 supplemented with the following steroids in concentrations ranging from 0.02 to 200 μg per ml: estrone, estradiol-17β, progesterone, cortisol, corticosterone, aldosterone, and deoxycorticosterone. All steroids were toxic at the higher dose levels. The responses to the several steroids were compared, and the minimum toxic doses determined. Progesterone was the most toxic of the steroids used, hut its toxicity could be prevented, to some extent, by addition of serum to the medium. The occurrence of cytoplasmic inclusions, representing accumulations of virus-like particles, was also noted as a result of organ culture of these tumors, with and without hormone supplementation of the medium. No consistent effect of the steroids on the occurrence of inclusions, or on the histology of the explanted tumors, was noted.
Two-years biochemical failure-free survival following high intensity focused ultrasound (HIFU) for localized prostate cancer: Prospective single center study of 196 patients
Authors: J. H. Pinthus, F. Farrokhyar, M. M. Hassouna, E. Woods, W. L. Orovan
Journal: Journal of Clinical Oncology (2009)

5117 Background: HIFU is an emerging ablative modality for the treatment of localized prostate cancer with limited reports on oncological outcome. We prospectively analyzed our 2-year results. Methods: 253 consecutive patients (age: 64+8) were treated with a planed single session of HIFU using the Ablatherm integrated imaging model system between January 2006 and June 2008. Patients were followed (median: 12; range 3–24 months) with PSA measurement every 3 months. Patients who received prior radiation or hormonal therapy (n=25) and patient for whom at least 2 consecutive PSA measurements were not available (n = 32) were excluded, leaving a total of 196 patients for analysis. Mean pre-treatment PSA was 6.9+3.3. Biopsy Gleason scores at diagnosis (median 9 cores) were 5, 6, 3+4, 4+3 in 1, 91, 66 and 38 patients, respectively. Biochemical failure (BCF) is reported using the Stephenson (PSA &gt;0.4ng/ml and rising), Horwitz (2 consecutive increases of at least 0.5ng/ml) and Phoenix (nadir+2ng/ml) definitions. Results: 196 patients (age: 64+8) met the inclusion criteria for analysis. 75 had low and 121 had intermediate D'Amico's risk stratification disease. Mean and median absolute PSA nadir levels were 0.28+0.53 and 0.06 ng/ml respectively. It was achieved in median time of 3 months and remained unchanged in 70% of the patients throughout the follow-up. Overall 2 years BCF free rates were 70 % (62–78%), 86 % (81–91%) and 96% (91–99%) according to the Stephenson, Horwitz and Phoenix definitions, respectively; with no significant differences between risk groups. Predictors of BCF were absolute nadir [HR: 3.0 (2.3–3.8)] and pre-treatment PSA [HR: 1.1 (1.0–1.2)]. Conclusions: This is the only study to date that analyzed post HIFU BCF free rates according to post radical prostatectomy definition of BCF. BCF usually occur in the first year and plateau thereafter. Short term results by all BCF definitions are promising with similar results for patients with low and intermediate risk. Pre-HIFU PSA and post-HIFU PSA nadir levels are predictors for BCF. [Table: see text]
Inflammation-Dependent IL18 Signaling Restricts Hepatocellular Carcinoma Growth by Enhancing the Accumulation and Activity of Tumor-Infiltrating Lymphocytes
Authors: Geoffrey J. Markowitz, Pengyuan Yang, Jing Fu, Gregory A. Michelotti, Rui Chen, Jianhua Sui, Bin Yang, Wen-Hao Qin, Zheng Zhang, Fu-Sheng Wang, Anna Mae Diehl, Qi-Jing Li, Hongyang Wang, Xiao-Fan Wang
Journal: Cancer Research (2016)

Abstract Chronic inflammation in liver tissue is an underlying cause of hepatocellular carcinoma. High levels of inflammatory cytokine IL18 in the circulation of patients with hepatocellular carcinoma correlates with poor prognosis. However, conflicting results have been reported for IL18 in hepatocellular carcinoma development and progression. In this study, we used tissue specimens from hepatocellular carcinoma patients and clinically relevant mouse models of hepatocellular carcinoma to evaluate IL18 expression and function. In a mouse model of liver fibrosis that recapitulates a tumor-promoting microenvironment, global deletion of the IL18 receptor IL18R1 enhanced tumor growth and burden. Similarly, in a carcinogen-induced model of liver tumorigenesis, IL18R1 deletion increased tumor burden. Mechanistically, we found that IL18 exerted inflammation-dependent tumor-suppressive effects largely by promoting the differentiation, activity, and survival of tumor-infiltrating T cells. Finally, differences in the expression of IL18 in tumor tissue versus nontumor tissue were more predictive of patient outcome than overall tissue expression. Taken together, our findings resolve a long-standing contradiction regarding a tumor-suppressive role for IL18 in established hepatocellular carcinoma and provide a mechanistic explanation for the complex relationship between its expression pattern and hepatocellular carcinoma prognosis. Cancer Res; 76(8); 2394–405. ©2016 AACR.
Safety of Same-Day Discharge After Percutaneous Coronary Intervention
Authors: Olivier F. Bertrand, Eltigani Abdelaal, Sunil V. Rao, Ian C. Gilchrist, Ivo Bernat, Adhir R. Shroff, Ronald P. Caputo, Olivier Costerousse, Samir B. Pancholy
Journal: Journal of the American College of Cardiology (2014)
Reduction in chemotherapy administered at the end of life (CAEOL) through quality improvement processes in a large community oncology clinic: The West Clinic experience.
Authors: Lee Steven Schwartzberg, Yonatan Freiden, Aaron Thul, Arthur C. Houts
Journal: Journal of Clinical Oncology (2013)

159 Background: Giving chemotherapy (CTX) near the end of life is futile and costly in human and financial terms. We analyzed patterns of chemotherapy administered at the end of life (CAEOL) by disease, provider, and line of therapy as part of a broad quality initiative. We hypothesized that measuring CAEOL in our practice could identify modifiable practice patterns. Methods: All patients (pts) with an ICD-9 diagnosis of cancer who died between 1/09 and 6/10 were identified by EMR or by searching SSDI records. We focused on the cohort receiving CTX within 14 or 28 days (d) of death, stratified by tumor type, provider and line of therapy by electronic chart review. Initial results were distributed to practice physicians for review and discussion with a clinic-wide goal to be below 5% and 10% at 14 and 28d, respectively. Subsequent cohorts were then evaluated periodically with results disseminated. Results: There was a 14.5% reduction in CAEOL within 14d and a 25% reduction within 28d over time (Table), meeting the clinic-wide standard. In the 2009-2010 cohort there was a difference in 1st line pts receiving CTX within 28 d for NSCLC (24/56 pts, 42.9%) or pancreas cancer (13/19, 68.4%) and the next 4 most common diagnoses: breast, colorectal, small cell lung, and head and neck cancer (15/84, 17.9%), p= .0024. CAEOL beyond 3rd line in non-breast, or &gt;5th line in breast cancer was uncommon. In the 2013 cohort, 1st line accounted for 28/51 pts (54.9%) receiving CTX within 28 d with NSCLC (8/15), pancreas (3/3) and lymphoma (4/4) the most prevalent diagnoses. Conclusions: CAEOL is a relatively rare event in our practice, now meeting practice standards after measurement and delving into root causes. A certain irreducible number of pts will be treated at the end-of-life, including those with potentially life-prolonging intent. First line therapy represents the majority, so identifying inappropriate candidates at diagnosis remains a quality improvement opportunity. [Table: see text]