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Riedel, Richard Francis

Overview:

Novel therapies for soft tissue and bone sarcomas

Positions:

Associate Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 2000

M.D. — Thomas Jefferson University

News:

Grants:

KCP-330-020

Administered By
Duke Cancer Institute
AwardedBy
Karyopharm Therapeutics
Role
Principal Investigator
Start Date
May 01, 2016
End Date
April 30, 2021

IMDZ-C232

Administered By
Duke Cancer Institute
AwardedBy
Immune Design Corp.
Role
Principal Investigator
Start Date
April 01, 2016
End Date
March 31, 2021

PEComa

Administered By
Duke Cancer Institute
AwardedBy
AADi LLC
Role
Principal Investigator
Start Date
December 01, 2015
End Date
November 30, 2020

Lilly JGDJ

Administered By
Duke Cancer Institute
AwardedBy
Eli Lilly and Company
Role
Principal Investigator
Start Date
December 01, 2015
End Date
November 30, 2020

PLX108-10

Administered By
Duke Cancer Institute
AwardedBy
Daiichi Pharmaceutical Corporation
Role
Principal Investigator
Start Date
August 01, 2015
End Date
July 31, 2020

SARC 028

Administered By
Duke Cancer Institute
AwardedBy
Sarcoma Alliance for Research Through Collaboration
Role
Principal Investigator
Start Date
April 01, 2015
End Date
March 31, 2020

A Phase IB Dose-Escalation Study of TRC105 in combination with Pazopanib in Patients with Advanced Soft Tissue Sarcoma

Administered By
Duke Cancer Institute
AwardedBy
Tracon Pharmaceuticals, Inc.
Role
Principal Investigator
Start Date
November 01, 2013
End Date
October 31, 2018

A blanket protocol to study oral regorafenib in patients with refractory liposarcoma, osteogenic sarcoma, and Ewing/Ewin

Administered By
Duke Cancer Institute
AwardedBy
Sarcoma Alliance for Research Through Collaboration
Role
Principal Investigator
Start Date
February 01, 2014
End Date
December 31, 2017

ARO-012 (CrenoGIST)

Administered By
Duke Cancer Institute
AwardedBy
Arog Pharmaceuticals, Inc.
Role
Principal Investigator
Start Date
January 16, 2017
End Date
August 31, 2017

SARC 024: A blanket protocol to study oral regorafenib in patients with refractory liposarcoma, osteogenic sarcoma, and Ewing/Ewing-like sarcomas

Administered By
Duke Cancer Institute
AwardedBy
Sarcoma Alliance for Research Through Collaboration
Role
Principal Investigator
Start Date
September 01, 2015
End Date
August 31, 2017

Dissecting Mechanisms of Metastasis Through Comparative Systems Genetics

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
September 25, 2008
End Date
July 31, 2013
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Publications:

Phase I study of pazopanib plus TH-302 in advanced solid tumors.

To define the maximum tolerated dose (MTD), recommended phase II dose (RPTD), and assess safety and tolerability for the combination of pazopanib plus TH-302, an investigational hypoxia-activated prodrug (HAP), in adult patients with advanced solid tumors.This was an open-label, non-randomized, single-center, phase I trial consisting 2 stages. Stage 1 was a standard "3 + 3" dose escalation design to determine safety and the RPTD for TH-302 plus pazopanib combination. Stage 2 was an expanded cohort to better describe the tolerability and toxicity profile at the MTD. Pazopanib was orally dosed at 800 mg daily on days 1-28 for all cohorts. TH-302 was administered intravenously on days 1, 8 and 15 of a 28-day cycle at doses of 340 mg/m2 (cohort 1) or 480 mg/m2 (cohort 2). Dose limiting toxicity (DLT) was assessed in the first 28-day cycle. Efficacy was assessed every 2 cycles.Thirty patients were enrolled between December 2011 and September 2013. In the dose escalation stage, 7 patients were enrolled in the 340 mg/m2 TH-302 cohort and 6 patients in the 480 mg/m2 TH-302 cohort. Ten patients were evaluable for DLT. DLTs included grade 2 intolerable esophagitis (n = 1) in the 340 mg/m2 TH-302 cohort, and grade 3 vaginal inflammation (n = 1) and grade 3 neutropenia with grade 3 thrombocytopenia (n = 1, same patient) in the 480 mg/m2 TH-302 cohort. The 340 mg/m2 TH-302 cohort was determined to be MTD and RPTD. The most common treatment-related adverse events were hematologic (anemia, neutropenia, and thrombocytopenia), nausea/vomiting, palmar-plantar erythrodysesthesia syndrome, constipation, fatigue, mucositis, anorexia, pain, and hypertension. Partial response (PR) was observed in 10% (n = 3) of patients, stable disease (SD) in 57% (n = 17), and progressive disease (PD) in 23% (n = 7). Due to toxicity, 3 patients were discontinued from study drug prior to first radiographic assessment but were included in these calculations. Disease control ≥6 months was observed in 37% of patients (n = 11).The RPTD for this novel combination is pazopanib 800 mg daily on days 1-28 plus TH-302 340 mg/m2 on days 1, 8 and 15 of each 28-day cycle. Preliminary activity was seen in treatment-refractory cancers and supports potential value of co-targeting tumor angiogenesis and tumor hypoxia.

Authors
Riedel, RF; Meadows, KL; Lee, PH; Morse, MA; Uronis, HE; Blobe, GC; George, DJ; Crawford, J; Niedzwiecki, D; Rushing, CN; Arrowood, CC; Hurwitz, HI
MLA Citation
Riedel, RF, Meadows, KL, Lee, PH, Morse, MA, Uronis, HE, Blobe, GC, George, DJ, Crawford, J, Niedzwiecki, D, Rushing, CN, Arrowood, CC, and Hurwitz, HI. "Phase I study of pazopanib plus TH-302 in advanced solid tumors." Cancer chemotherapy and pharmacology 79.3 (March 2017): 611-619.
PMID
28238078
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
79
Issue
3
Publish Date
2017
Start Page
611
End Page
619
DOI
10.1007/s00280-017-3256-2

Dose-escalation study of a second-generation non-ansamycin HSP90 inhibitor, onalespib (AT13387), in combination with imatinib in patients with metastatic gastrointestinal stromal tumour.

Gastrointestinal stromal tumours (GIST) treated with the tyrosine kinase inhibitor (TKI) imatinib can become resistant when additional mutations in the receptor tyrosine kinases KIT or PDGFRA block imatinib activity. Mutated KIT requires the molecular chaperone heat-shock protein 90 (HSP90) to maintain stability and activity. Onalespib (AT13387) is a potent non-ansamycin HSP90 inhibitor. We hypothesised that the combination of onalespib and imatinib may be safe and effective in managing TKI-resistant GIST.In this dose-escalation study, we evaluated the safety and efficacy of combination once-weekly intravenous onalespib for 3 weeks and daily oral imatinib in 28-d cycles. Twenty-six patients with TKI-resistant GIST were enrolled into four sequential dose cohorts of onalespib (dose range, 150-220 mg/m(2)) and imatinib 400 mg. The relationship between tumour mutational status (KIT/PDGFRA) and efficacy of treatment was explored.Common onalespib-related adverse events were diarrhoea (58%), nausea (50%), injection site events (46%), vomiting (39%), fatigue (27%), and muscle spasms (23%). Overall, 81% of patients reported more than one onalespib-related gastrointestinal disorder. Nine patients (35%) had a best response of stable disease, including two patients who had KIT mutations known to be associated with resistance to imatinib and sunitinib. Disease control at 4 months was achieved in five patients (19%), and median progression-free survival was 112 d (95% confidence interval 43-165). One patient with PDGFRA-mutant GIST had a partial response for more than 376 d.The combination of onalespib plus imatinib was well tolerated but exhibited limited antitumour activity as dosed in this TKI-resistant GIST patient population. Trial registration ID: clinicaltrials.gov: NCT01294202.

Authors
Wagner, AJ; Agulnik, M; Heinrich, MC; Mahadevan, D; Riedel, RF; von Mehren, M; Trent, J; Demetri, GD; Corless, CL; Yule, M; Lyons, JF; Oganesian, A; Keer, H
MLA Citation
Wagner, AJ, Agulnik, M, Heinrich, MC, Mahadevan, D, Riedel, RF, von Mehren, M, Trent, J, Demetri, GD, Corless, CL, Yule, M, Lyons, JF, Oganesian, A, and Keer, H. "Dose-escalation study of a second-generation non-ansamycin HSP90 inhibitor, onalespib (AT13387), in combination with imatinib in patients with metastatic gastrointestinal stromal tumour." European journal of cancer (Oxford, England : 1990) 61 (July 2016): 94-101.
PMID
27156227
Source
epmc
Published In
European Journal of Cancer
Volume
61
Publish Date
2016
Start Page
94
End Page
101
DOI
10.1016/j.ejca.2016.03.076

Soft Tissue Sarcoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology.

Soft tissue sarcomas (STS) are rare solid tumors of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Guidelines for Soft Tissue Sarcoma (available at NCCN.org) provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as intra-abdominal/retroperitoneal STS, gastrointestinal stromal tumor, desmoid tumors, and rhabdomyosarcoma. This manuscript discusses guiding principles for the diagnosis and staging of STS and evidence for treatment modalities that include surgery, radiation, chemoradiation, chemotherapy, and targeted therapy.

Authors
von Mehren, M; Randall, RL; Benjamin, RS; Boles, S; Bui, MM; Conrad, EU; Ganjoo, KN; George, S; Gonzalez, RJ; Heslin, MJ; Kane, JM; Koon, H; Mayerson, J; McCarter, M; McGarry, SV; Meyer, C; O'Donnell, RJ; Pappo, AS; Paz, IB; Petersen, IA; Pfeifer, JD; Riedel, RF; Schuetze, S; Schupak, KD; Schwartz, HS; Tap, WD; Wayne, JD; Bergman, MA; Scavone, J
MLA Citation
von Mehren, M, Randall, RL, Benjamin, RS, Boles, S, Bui, MM, Conrad, EU, Ganjoo, KN, George, S, Gonzalez, RJ, Heslin, MJ, Kane, JM, Koon, H, Mayerson, J, McCarter, M, McGarry, SV, Meyer, C, O'Donnell, RJ, Pappo, AS, Paz, IB, Petersen, IA, Pfeifer, JD, Riedel, RF, Schuetze, S, Schupak, KD, Schwartz, HS, Tap, WD, Wayne, JD, Bergman, MA, and Scavone, J. "Soft Tissue Sarcoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology." Journal of the National Comprehensive Cancer Network : JNCCN 14.6 (June 2016): 758-786.
PMID
27283169
Source
epmc
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
14
Issue
6
Publish Date
2016
Start Page
758
End Page
786

Effects of enhanced caregiver training program on cancer caregiver's self-efficacy, preparedness, and psychological well-being.

We examined the effects of an enhanced informal caregiver training (Enhanced-CT) protocol in cancer symptom and caregiver stress management to caregivers of hospitalized cancer patients.We recruited adult patients in oncology units and their informal caregivers. We utilized a two-armed, randomized controlled trial design with data collected at baseline, post-training, and at 2 and 4 weeks after hospital discharge. Primary outcomes were self-efficacy for managing patients' cancer symptoms and caregiver stress and preparedness for caregiving. Secondary outcomes were caregiver depression, anxiety, and burden. The education comparison (EDUC) group received information about community resources. We used general linear models to test for differences in the Enhanced-CT relative to the EDUC group.We consented and randomized 138 dyads: Enhanced-CT = 68 and EDUC = 70. The Enhanced-CT group had a greater increase in caregiver self-efficacy for cancer symptom management and stress management and preparation for caregiving at the post-training assessment compared to the EDUC group but not at 2- and 4-week post-discharge assessments. There were no intervention group differences in depression, anxiety, and burden.An Enhanced-CT protocol resulted in short-term improvements in self-efficacy for managing patients' cancer symptoms and caregiver stress and preparedness for caregiving but not in caregivers' psychological well-being. The lack of sustained effects may be related to the single-dose nature of our intervention and the changing needs of informal caregivers after hospital discharge.

Authors
Hendrix, CC; Bailey, DE; Steinhauser, KE; Olsen, MK; Stechuchak, KM; Lowman, SG; Schwartz, AJ; Riedel, RF; Keefe, FJ; Porter, LS; Tulsky, JA
MLA Citation
Hendrix, CC, Bailey, DE, Steinhauser, KE, Olsen, MK, Stechuchak, KM, Lowman, SG, Schwartz, AJ, Riedel, RF, Keefe, FJ, Porter, LS, and Tulsky, JA. "Effects of enhanced caregiver training program on cancer caregiver's self-efficacy, preparedness, and psychological well-being." Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 24.1 (January 2016): 327-336.
PMID
26062925
Source
epmc
Published In
Supportive Care in Cancer
Volume
24
Issue
1
Publish Date
2016
Start Page
327
End Page
336
DOI
10.1007/s00520-015-2797-3

A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer.

Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes.

Authors
Whitley, MJ; Cardona, DM; Lazarides, AL; Spasojevic, I; Ferrer, JM; Cahill, J; Lee, C-L; Snuderl, M; Blazer, DG; Hwang, ES; Greenup, RA; Mosca, PJ; Mito, JK; Cuneo, KC; Larrier, NA; O'Reilly, EK; Riedel, RF; Eward, WC; Strasfeld, DB; Fukumura, D; Jain, RK; Lee, WD; Griffith, LG; Bawendi, MG; Kirsch, DG; Brigman, BE
MLA Citation
Whitley, MJ, Cardona, DM, Lazarides, AL, Spasojevic, I, Ferrer, JM, Cahill, J, Lee, C-L, Snuderl, M, Blazer, DG, Hwang, ES, Greenup, RA, Mosca, PJ, Mito, JK, Cuneo, KC, Larrier, NA, O'Reilly, EK, Riedel, RF, Eward, WC, Strasfeld, DB, Fukumura, D, Jain, RK, Lee, WD, Griffith, LG, Bawendi, MG, Kirsch, DG, and Brigman, BE. "A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer." Science translational medicine 8.320 (January 2016): 320ra4-.
PMID
26738797
Source
epmc
Published In
Science Translational Medicine
Volume
8
Issue
320
Publish Date
2016
Start Page
320ra4
DOI
10.1126/scitranslmed.aad0293

Abstract SY36-03: Intraoperative molecular imaging with protease-activated fluorescent imaging agents

Authors
Whitley, MJ; Cardona, DM; Blazer, DG; Hwang, S; Greenup, RA; Mosca, PJ; Cahill, J; Mito, JK; Cuneo, KC; Larrier, N; O'Reilly, E; Spasojevic, I; Riedel, RF; Eward, WC; Griffith, LG; Bawendi, MG; Ferrer, J; Strasfeld, DB; Lee, WD; Brigman, B; Kirsch, DG
MLA Citation
Whitley, MJ, Cardona, DM, Blazer, DG, Hwang, S, Greenup, RA, Mosca, PJ, Cahill, J, Mito, JK, Cuneo, KC, Larrier, N, O'Reilly, E, Spasojevic, I, Riedel, RF, Eward, WC, Griffith, LG, Bawendi, MG, Ferrer, J, Strasfeld, DB, Lee, WD, Brigman, B, and Kirsch, DG. "Abstract SY36-03: Intraoperative molecular imaging with protease-activated fluorescent imaging agents." August 1, 2015.
Source
crossref
Published In
Cancer Research
Volume
75
Issue
15 Supplement
Publish Date
2015
Start Page
SY36-03
End Page
SY36-03
DOI
10.1158/1538-7445.AM2015-SY36-03

SARC 028: A phase II study of the anti-PD1 antibody pembrolizumab (P) in patients (Pts) with advanced sarcomas.

Authors
Burgess, MA; Crowley, J; Reinke, DK; Riedel, RF; George, S; Movva, S; Van Tine, BA; Davis, LE; Schuetze, S; Hu, J; Attia, S; Priebat, DA; Reed, DR; D'Angelo, SP; Okuno, SH; Maki, RG; Patel, S; Baker, LH; Tawbi, HA-H
MLA Citation
Burgess, MA, Crowley, J, Reinke, DK, Riedel, RF, George, S, Movva, S, Van Tine, BA, Davis, LE, Schuetze, S, Hu, J, Attia, S, Priebat, DA, Reed, DR, D'Angelo, SP, Okuno, SH, Maki, RG, Patel, S, Baker, LH, and Tawbi, HA-H. "SARC 028: A phase II study of the anti-PD1 antibody pembrolizumab (P) in patients (Pts) with advanced sarcomas." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with pazopanib in patients with advanced soft tissue sarcoma (STS)

Authors
Attia, S; Riedel, RF; Robinson, SI; Conry, RM; Sankhala, KK; Seon, BK; Alvarez, D; Adams, BJ; Theuer, CP; Maki, RG
MLA Citation
Attia, S, Riedel, RF, Robinson, SI, Conry, RM, Sankhala, KK, Seon, BK, Alvarez, D, Adams, BJ, Theuer, CP, and Maki, RG. "A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with pazopanib in patients with advanced soft tissue sarcoma (STS)." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

A Phase I Clinical Trial of LUM015: A Protease-activated Fluorescent Imaging Agent to Detect Cancer during Surgery

Authors
Whitley, MJ; Cardona, DM; Blazer, DG; Hwang, E; Greenup, RA; Mosca, PJ; Cahill, J; Mito, JK; Cuneo, KC; Larrier, N; O'Reilly, E; Spasojevic, I; Riedel, RF; Eward, WC; Griffith, LG; Bawendi, MG; Kirsch, DG; Brigman, BE
MLA Citation
Whitley, MJ, Cardona, DM, Blazer, DG, Hwang, E, Greenup, RA, Mosca, PJ, Cahill, J, Mito, JK, Cuneo, KC, Larrier, N, O'Reilly, E, Spasojevic, I, Riedel, RF, Eward, WC, Griffith, LG, Bawendi, MG, Kirsch, DG, and Brigman, BE. "A Phase I Clinical Trial of LUM015: A Protease-activated Fluorescent Imaging Agent to Detect Cancer during Surgery." February 2015.
Source
wos-lite
Published In
Annals of Surgical Oncology
Volume
22
Publish Date
2015
Start Page
S11
End Page
S12

Rhabdomyosarcomatous Transformation of a Gastrointestinal Stromal Tumor following Treatment with Imatinib.

Rhabdomyosarcomatous dedifferentiation of GIST following tyrosine kinase inhibitor (TKI) therapy is rare, with only a handful of cases previously reported in the literature. Herein we present a case of metastatic GIST initially treated with imatinib that developed radiographic evidence of progression after 8 months of standard dose therapy with continued progression despite attempts at using dose-escalated imatinib 400 mg bid. Due to the patient's worsening clinical symptoms and radiographic concerns for colonic thickening, abscess, and extraluminal air, the patient underwent a palliative resection of a large heterogeneous mass arising from the posterior stomach and several metastatic foci. Pathology revealed a dedifferentiated GIST with rhabdomyosarcomatous features. This report will highlight the unique features of this case and review the existing literature.

Authors
Jiang, X; Anderson, HB; Guy, CD; Mosca, PJ; Riedel, RF; Cardona, DM
MLA Citation
Jiang, X, Anderson, HB, Guy, CD, Mosca, PJ, Riedel, RF, and Cardona, DM. "Rhabdomyosarcomatous Transformation of a Gastrointestinal Stromal Tumor following Treatment with Imatinib." Case reports in oncological medicine 2015 (January 28, 2015): 317493-.
PMID
25694839
Source
epmc
Published In
Case Reports in Oncological Medicine
Volume
2015
Publish Date
2015
Start Page
317493
DOI
10.1155/2015/317493

Chemotherapy in soft-tissue sarcoma: where do we go from here?

Authors
Gwin, W; Riedel, RF
MLA Citation
Gwin, W, and Riedel, RF. "Chemotherapy in soft-tissue sarcoma: where do we go from here?." Oncology (Williston Park, N.Y.) 29.1 (January 1, 2015).
Source
scopus
Published In
Oncology
Volume
29
Issue
1
Publish Date
2015

Chemotherapy in soft-tissue sarcoma: where do we go from here?

Authors
Gwin, W; Riedel, RF
MLA Citation
Gwin, W, and Riedel, RF. "Chemotherapy in soft-tissue sarcoma: where do we go from here?." Oncology (Williston Park, N.Y.) 29.1 (January 2015): 50-53.
PMID
25592208
Source
epmc
Published In
Oncology
Volume
29
Issue
1
Publish Date
2015
Start Page
50
End Page
53

Early palliative care on an inpatient oncology unit: Impact of a novel co-rounding partnership on patient and health system outcomes.

3 Background: Early palliative care (PC) improves outcomes for outpatients with advanced cancer, but its impact on an inpatient oncology unit is unknown. We implemented a novel inpatient medical oncology (ONC) and PC co-rounding partnership on September 1, 2011 at Duke University Hospital. Here we report its impact on patient and health system outcomes during its first year of implementation.We extracted patient data including demographics, cancer diagnosis, disease status, length of stay (LOS), ICU transfer rate, discharge disposition, time to ER return, time to readmission, and 7- and 30-day ER return and readmission rates (RR). Pre- and post-intervention cohorts were defined as all patients admitted or transferred to the solid tumor inpatient service from September 1, 2009-June 30, 2010 and September 1, 2011-June 30, 2012, respectively. Nursing and physician surveys assessed satisfaction. We used descriptive statistics, Student's t-test, and Fisher's exact test for analyses.The pre- and post-intervention analysis cohorts included 731 and 783 patients respectively, representing 2,353 encounters. Cohorts were similar in baseline characteristics, including mean age (61 vs. 62; p=0.07), gender (male: 51% vs. 48%; p=0.22), race (white: 68% vs. 71%; p=0.39), insurance coverage (Medicare: 49% vs. 51%; p=0.96), and disease status (recurrent/metastatic: 73% vs. 74%; p=0.6). Post-intervention patients had a statistically significant decrease in mean LOS (p=0.02) from 4.51 days (95% CI 4.3-4.73) to 4.17 days (95% CI 3.97-4.37), and statistically significant improvements in 7- and 30-day readmission rates, representing a 15% (p=0.03) and 23% (p=0.05) improvement, respectively. We observed a trend for increasing hospice referral (p=0.09) and a 15% decrease in ICU transfers. Physicians and nurses universally favored the model.A fully-integrated, inpatient co-rounding partnership between PC and ONC resulted in statistically significant improvements in key health system-related outcomes and indicators of quality cancer care.

Authors
Slusser, K; Power, S; Jones, CA; LeBlanc, TW; Kamal, A; Desai, D; Allen, D; Galanos, AN
MLA Citation
Slusser, K, Power, S, Jones, CA, LeBlanc, TW, Kamal, A, Desai, D, Allen, D, and Galanos, AN. "Early palliative care on an inpatient oncology unit: Impact of a novel co-rounding partnership on patient and health system outcomes." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 32.31_suppl (November 2014): 3-.
PMID
28142849
Source
epmc
Published In
Journal of Clinical Oncology
Volume
32
Issue
31_suppl
Publish Date
2014
Start Page
3

Bone Sarcomas

© 2014 John Wiley and Sons, Inc.This chapter presents a series of case studies with questions related to bone sarcomas. The first case study is about a 17-year-old Caucasian male diagnosed with Ewing sarcoma of the left humerus. Other case studies include a 52-year-old Caucasian male with 1-year history of worsening back pain despite conservative treatment, a 54-year-old Asian male diagnosed with a large chordoma of the sacrum, and a 20-year-old Caucasian male evaluated for unremitting left knee pain. Finally, the chapter discusses the case study of a 58-year-old African-American female with pain in her left leg with weight bearing.

Authors
Larrier, N; Eward, WC; Riedel, RF
MLA Citation
Larrier, N, Eward, WC, and Riedel, RF. "Bone Sarcomas." Cancer Consult: Expertise for Clinical Practice. June 20, 2014. 687-695.
Source
scopus
Publish Date
2014
Start Page
687
End Page
695
DOI
10.1002/9781118589199.ch105

Gastrointestinal stromal tumors, version 2.2014: Featured updates to the NCCN Guidelines

Gastrointestinal stromal tumors (GIST) are the most common soft tissue sarcoma of the gastrointestinal tract, resulting most commonly from KIT or platelet-derived growth factor receptor α (PDGFRα)-activating mutations. These NCCN Guideline Insights high-light the important updates to the NCCN Guidelines for Soft Tissue Sarcoma specific to the management of patients with GIST experiencing disease progression while on imatinib and/or sunitinib. © JNCCN-Journal of the National Comprehensive Cancer Network.

Authors
Von Mehren, M; Randall, RL; Benjamin, RS; Boles, S; Bui, MM; Casper, ES; Conrad, EU; DeLaney, TF; Ganjoo, KN; George, S; Gonzalez, RJ; Heslin, MJ; Kane, JM; Mayerson, J; McGarry, SV; Meyer, C; O'Donnell, RJ; Pappo, AS; Paz, IB; Pfeifer, JD; Riedel, RF; Schuetze, S; Schupak, KD; Schwartz, HS; Van Tine, BA; Wayne, JD; Bergman, MA; Sundar, H
MLA Citation
Von Mehren, M, Randall, RL, Benjamin, RS, Boles, S, Bui, MM, Casper, ES, Conrad, EU, DeLaney, TF, Ganjoo, KN, George, S, Gonzalez, RJ, Heslin, MJ, Kane, JM, Mayerson, J, McGarry, SV, Meyer, C, O'Donnell, RJ, Pappo, AS, Paz, IB, Pfeifer, JD, Riedel, RF, Schuetze, S, Schupak, KD, Schwartz, HS, Van Tine, BA, Wayne, JD, Bergman, MA, and Sundar, H. "Gastrointestinal stromal tumors, version 2.2014: Featured updates to the NCCN Guidelines." JNCCN Journal of the National Comprehensive Cancer Network 12.6 (June 1, 2014): 853-862.
Source
scopus
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
12
Issue
6
Publish Date
2014
Start Page
853
End Page
862

Gastrointestinal stromal tumors, version 2.2014.

Gastrointestinal stromal tumors (GIST) are the most common soft tissue sarcoma of the gastrointestinal tract, resulting most commonly from KIT or platelet-derived growth factor receptor α (PDGFRα)-activating mutations. These NCCN Guideline Insights highlight the important updates to the NCCN Guidelines for Soft Tissue Sarcoma specific to the management of patients with GIST experiencing disease progression while on imatinib and/or sunitinib.

Authors
von Mehren, M; Randall, RL; Benjamin, RS; Boles, S; Bui, MM; Casper, ES; Conrad, EU; DeLaney, TF; Ganjoo, KN; George, S; Gonzalez, RJ; Heslin, MJ; Kane, JM; Mayerson, J; McGarry, SV; Meyer, C; O'Donnell, RJ; Pappo, AS; Paz, IB; Pfeifer, JD; Riedel, RF; Schuetze, S; Schupak, KD; Schwartz, HS; Van Tine, BA; Wayne, JD; Bergman, MA; Sundar, H
MLA Citation
von Mehren, M, Randall, RL, Benjamin, RS, Boles, S, Bui, MM, Casper, ES, Conrad, EU, DeLaney, TF, Ganjoo, KN, George, S, Gonzalez, RJ, Heslin, MJ, Kane, JM, Mayerson, J, McGarry, SV, Meyer, C, O'Donnell, RJ, Pappo, AS, Paz, IB, Pfeifer, JD, Riedel, RF, Schuetze, S, Schupak, KD, Schwartz, HS, Van Tine, BA, Wayne, JD, Bergman, MA, and Sundar, H. "Gastrointestinal stromal tumors, version 2.2014." Journal of the National Comprehensive Cancer Network : JNCCN 12.6 (June 2014): 853-862.
PMID
24925196
Source
epmc
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
12
Issue
6
Publish Date
2014
Start Page
853
End Page
862

A phase I study of the safety and activation of a cathepsin-activalable fluorescent cancer-specific probe LUM015.

Authors
Whitley, MJ; Cardona, DM; Blazer, DG; Hwang, SE; Mosca, PJ; Cahill, J; Ferrer, JM; Strasfeld, DB; Mlto, JK; Cuneo, KC; Lanier, N; Williams, O; Spasojevic, I; Riedel, RF; Eward, W; Lee, WD; Griffith, LG; Bawendi, M; Kirsch, DG; Brigman, BE
MLA Citation
Whitley, MJ, Cardona, DM, Blazer, DG, Hwang, SE, Mosca, PJ, Cahill, J, Ferrer, JM, Strasfeld, DB, Mlto, JK, Cuneo, KC, Lanier, N, Williams, O, Spasojevic, I, Riedel, RF, Eward, W, Lee, WD, Griffith, LG, Bawendi, M, Kirsch, DG, and Brigman, BE. "A phase I study of the safety and activation of a cathepsin-activalable fluorescent cancer-specific probe LUM015." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Soft tissue sarcoma, version 2.2014.

These NCCN Guidelines Insights highlight the important updates to the NCCN Guidelines for Soft Tissue Sarcoma (STS) specific to the role of radiation therapy in the management of patients with retroperitoneal/intra-abdominal STS. The guidelines have also included recommendations for genetic testing and counseling for patients with a clinical and/or family history of genetic cancer syndromes associated with a predisposition for the development of STS.

Authors
von Mehren, M; Randall, RL; Benjamin, RS; Boles, S; Bui, MM; Casper, ES; Conrad, EU; Delaney, TF; Ganjoo, KN; George, S; Gonzalez, RJ; Heslin, MJ; Kane, JM; Mayerson, J; McGarry, SV; Meyer, C; O'Donnell, RJ; Pappo, AS; Paz, IB; Pfeifer, JD; Riedel, RF; Schuetze, S; Schupak, KD; Schwartz, HS; Van Tine, BA; Wayne, JD; Bergman, MA; Sundar, H
MLA Citation
von Mehren, M, Randall, RL, Benjamin, RS, Boles, S, Bui, MM, Casper, ES, Conrad, EU, Delaney, TF, Ganjoo, KN, George, S, Gonzalez, RJ, Heslin, MJ, Kane, JM, Mayerson, J, McGarry, SV, Meyer, C, O'Donnell, RJ, Pappo, AS, Paz, IB, Pfeifer, JD, Riedel, RF, Schuetze, S, Schupak, KD, Schwartz, HS, Van Tine, BA, Wayne, JD, Bergman, MA, and Sundar, H. "Soft tissue sarcoma, version 2.2014." Journal of the National Comprehensive Cancer Network : JNCCN 12.4 (April 2014): 473-483.
PMID
24717567
Source
epmc
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
12
Issue
4
Publish Date
2014
Start Page
473
End Page
483

Abstract C61: Phase I Study of pazopanib in combination with the investigational hypoxia-targeted drug TH-302.

Authors
Meadows, KL; Lee, PH; Riedel, RF; Morse, MA; Uronis, HE; Blobe, GC; George, DJ; Crawford, J; Hurwitz, HI
MLA Citation
Meadows, KL, Lee, PH, Riedel, RF, Morse, MA, Uronis, HE, Blobe, GC, George, DJ, Crawford, J, and Hurwitz, HI. "Abstract C61: Phase I Study of pazopanib in combination with the investigational hypoxia-targeted drug TH-302." Molecular Cancer Therapeutics 12.11_Supplement (November 1, 2013): C61-C61.
Source
crossref
Published In
Molecular cancer therapeutics
Volume
12
Issue
11_Supplement
Publish Date
2013
Start Page
C61
End Page
C61
DOI
10.1158/1535-7163.TARG-13-C61

Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy.

PURPOSE: Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. PATIENTS AND METHODS: Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability. RESULTS: A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P < .001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%). CONCLUSION: Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas.

Authors
Demetri, GD; Chawla, SP; Ray-Coquard, I; Le Cesne, A; Staddon, AP; Milhem, MM; Penel, N; Riedel, RF; Bui-Nguyen, B; Cranmer, LD; Reichardt, P; Bompas, E; Alcindor, T; Rushing, D; Song, Y; Lee, R-M; Ebbinghaus, S; Eid, JE; Loewy, JW; Haluska, FG; Dodion, PF; Blay, J-Y
MLA Citation
Demetri, GD, Chawla, SP, Ray-Coquard, I, Le Cesne, A, Staddon, AP, Milhem, MM, Penel, N, Riedel, RF, Bui-Nguyen, B, Cranmer, LD, Reichardt, P, Bompas, E, Alcindor, T, Rushing, D, Song, Y, Lee, R-M, Ebbinghaus, S, Eid, JE, Loewy, JW, Haluska, FG, Dodion, PF, and Blay, J-Y. "Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy." J Clin Oncol 31.19 (July 1, 2013): 2485-2492.
PMID
23715582
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
31
Issue
19
Publish Date
2013
Start Page
2485
End Page
2492
DOI
10.1200/JCO.2012.45.5766

Practical radiation oncology for extremity sarcomas.

Soft tissue sarcomas are rare cancers. They should be managed by a multidisciplinary team with experience caring for these diverse malignancies. Local control is frequently achieved with a combination of radiation therapy and surgery. This article reviews the data supporting the role of adjuvant radiotherapy in the care of patients with soft tissue sarcoma and describes the side effects of surgery and radiation therapy. Preoperative radiation therapy increases the risk of wound complication from surgery, but has fewer long-term side effects than postoperative radiation therapy. The timing of radiation therapy can be tailored to each patient.

Authors
Larrier, NA; Kirsch, DG; Riedel, RF; Levinson, H; Eward, WC; Brigman, BE
MLA Citation
Larrier, NA, Kirsch, DG, Riedel, RF, Levinson, H, Eward, WC, and Brigman, BE. "Practical radiation oncology for extremity sarcomas." Surg Oncol Clin N Am 22.3 (July 2013): 433-443. (Review)
PMID
23622072
Source
pubmed
Published In
Surgical Oncology Clinics of North America
Volume
22
Issue
3
Publish Date
2013
Start Page
433
End Page
443
DOI
10.1016/j.soc.2013.02.004

Oncologists' perceptions of rounding alongside palliative care physicians: Results of a post-intervention survey study.

Authors
LeBlanc, TW; Tulsky, JA; Abernethy, AP; Jones, CA; Galanos, AN; Riedel, RF
MLA Citation
LeBlanc, TW, Tulsky, JA, Abernethy, AP, Jones, CA, Galanos, AN, and Riedel, RF. "Oncologists' perceptions of rounding alongside palliative care physicians: Results of a post-intervention survey study." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Pathologic complete response of a malignant peripheral nerve sheath tumor in the lung treated with neoadjuvant Ifosfamide and radiation therapy.

Authors
Cuneo, KC; Riedel, RF; Dodd, LG; Harpole, DH; Kirsch, DG
MLA Citation
Cuneo, KC, Riedel, RF, Dodd, LG, Harpole, DH, and Kirsch, DG. "Pathologic complete response of a malignant peripheral nerve sheath tumor in the lung treated with neoadjuvant Ifosfamide and radiation therapy." J Clin Oncol 30.28 (October 1, 2012): e291-e293.
PMID
22869889
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
30
Issue
28
Publish Date
2012
Start Page
e291
End Page
e293
DOI
10.1200/JCO.2012.42.8797

A phase I study of bevacizumab, everolimus and panitumumab in advanced solid tumors.

PURPOSE: Preclinical data suggest concurrent inhibition of VEGF, mTOR and EGFR pathways may augment antitumor and antiangiogenic effects compared to inhibition of each pathway alone. This study evaluated the maximum tolerated dose/recommended phase II dose and safety and tolerability of bevacizumab, everolimus and panitumumab drug combination. METHODS: Subjects with advanced solid tumors received escalating doses of everolimus and flat dosing of panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. RESULTS: Thirty-two subjects were evaluable for toxicity; 31 subjects were evaluable for tumor response. DLTs were observed in cohorts with everolimus at 10 and 5 mg daily and included grade 3 mucositis, skin rash and thrombocytopenia. Therefore, everolimus was dose-reduced to 5 mg three times weekly, which improved the tolerability of the treatment regimen. Common adverse events were skin rash/pruritus (91 %), mucositis/stomatitis (75 %), hypomagnesemia (72 %), hypocalcemia (56 %) and hypokalemia (50 %). There were 3 partial responses; an additional 10 subjects had stable disease ≥6 months. Three subjects with ovarian cancer and one with endometrial cancer achieved prolonged disease control ranging from 11 to >40 months. CONCLUSIONS: The recommended phase II dose is everolimus at 5 mg three times weekly plus panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. This dosing regimen has an acceptable safety and tolerability profile and appears to have moderate the clinical activity in refractory tumors.

Authors
Vlahovic, G; Meadows, KL; Uronis, HE; Morse, MA; Blobe, GC; Riedel, RF; Zafar, SY; Alvarez-Secord, A; Gockerman, J; Starodub, AN; Ready, NE; Anderson, EL; Bendell, JC; Hurwitz, HI
MLA Citation
Vlahovic, G, Meadows, KL, Uronis, HE, Morse, MA, Blobe, GC, Riedel, RF, Zafar, SY, Alvarez-Secord, A, Gockerman, J, Starodub, AN, Ready, NE, Anderson, EL, Bendell, JC, and Hurwitz, HI. "A phase I study of bevacizumab, everolimus and panitumumab in advanced solid tumors." Cancer Chemother Pharmacol 70.1 (July 2012): 95-102.
PMID
22638798
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
70
Issue
1
Publish Date
2012
Start Page
95
End Page
102
DOI
10.1007/s00280-012-1889-8

Phase III, placebo-controlled trial (SUCCEED) evaluating ridaforolimus as maintenance therapy in advanced sarcoma patients following clinical benefit from prior standard cytotoxic chemotherapy: Long-term (>= 24 months) overall survival results.

Authors
Blay, J-Y; Chawla, SP; Ray-Coquard, I; Le Cesne, A; Staddon, AP; Milhem, MM; Penel, N; Riedel, RF; Nguyen, BB; Cranmer, LD; Reichardt, P; Bompas, E; Alcindor, T; Rushing, DA; Song, Y; Ebbinghaus, S; Haluska, FG; Dodion, PF; Demetri, GD
MLA Citation
Blay, J-Y, Chawla, SP, Ray-Coquard, I, Le Cesne, A, Staddon, AP, Milhem, MM, Penel, N, Riedel, RF, Nguyen, BB, Cranmer, LD, Reichardt, P, Bompas, E, Alcindor, T, Rushing, DA, Song, Y, Ebbinghaus, S, Haluska, FG, Dodion, PF, and Demetri, GD. "Phase III, placebo-controlled trial (SUCCEED) evaluating ridaforolimus as maintenance therapy in advanced sarcoma patients following clinical benefit from prior standard cytotoxic chemotherapy: Long-term (>= 24 months) overall survival results." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Retraction in part: A genomic approach to identify molecular pathways associated with chemotherapy resistance.

Authors
Riedel, RF; Porrello, A; Pontzer, E; Chenette, EJ; Hsu, DS; Balakumaran, B; Potti, A; Nevins, J; Febbo, PC
MLA Citation
Riedel, RF, Porrello, A, Pontzer, E, Chenette, EJ, Hsu, DS, Balakumaran, B, Potti, A, Nevins, J, and Febbo, PC. "Retraction in part: A genomic approach to identify molecular pathways associated with chemotherapy resistance." Mol Cancer Ther 11.5 (May 2012): 1214-1215.
PMID
22461660
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
11
Issue
5
Publish Date
2012
Start Page
1214
End Page
1215
DOI
10.1158/1535-7163.MCT-12-0210

Systemic therapy for advanced soft tissue sarcomas: highlighting novel therapies and treatment approaches.

Soft tissue sarcomas (STS) are a rare, heterogeneous group of solid tumors in need of improved therapeutic options. First-line chemotherapy is considered the current standard of care for patients with advanced, symptomatic STS, but the median survival is only 8 to 12 months. Efforts to increase response rates by using combination or dose-dense regimens have largely failed to improve patient outcomes. However, increasing evidence supports the use of specific treatments for certain histological subtypes of STS, and novel therapies, including tyrosine kinase and mammalian target of rapamycin inhibitors, are currently under active investigation. In addition, novel treatment approaches (such as maintenance therapy) designed to prolong the duration of response to chemotherapy and delay disease progression are being explored. This article provides an overview of current systemic therapies for patients with advanced STS and discusses ongoing efforts designed to improve patient outcomes through the use of novel therapeutic agents and treatment strategies.

Authors
Riedel, RF
MLA Citation
Riedel, RF. "Systemic therapy for advanced soft tissue sarcomas: highlighting novel therapies and treatment approaches." Cancer 118.6 (March 15, 2012): 1474-1485. (Review)
PMID
21837668
Source
pubmed
Published In
Cancer
Volume
118
Issue
6
Publish Date
2012
Start Page
1474
End Page
1485
DOI
10.1002/cncr.26415

Targeted therapy in sarcoma: should we be lumpers or splitters?

The identification of KIT as a critical driver in the pathogenesis of GI stromal tumor (GIST), and its subsequent inhibition with imatinib, have resulted in tremendous efforts to identify other potential therapeutic targets for the heterogeneous group of diseases known as sarcomas. Because of the rarity of sarcoma and the often limited number of patients per individual sarcoma subtype, clinical trials to date have often utilized unselected patient populations including multiple subtypes. Although this strategy increases the ease with which a particular trial may accrue patients, statistically significant therapeutic responses across an unselected patient population are often limited. Furthermore, in the absence of biologic correlatives, the identification of significant activity and subsequent interpretation of clinical trial results utilizing targeted therapies for this patient population have been challenging. However, hints have emerged, on the basis of preclinical and clinical observations, to suggest that certain targeted therapeutic approaches are appropriate in select histologic subtypes. This brief review will highlight data supporting the use of targeted therapy in both unselected and selected sarcoma patient populations.

Authors
Riedel, RF; Maki, RG; Wagner, AJ
MLA Citation
Riedel, RF, Maki, RG, and Wagner, AJ. "Targeted therapy in sarcoma: should we be lumpers or splitters?." American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Meeting (January 2012): 652-657.
PMID
24451813
Source
epmc
Published In
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting
Publish Date
2012
Start Page
652
End Page
657
DOI
10.14694/edbook_am.2012.32.652

Efficacy of phosphatidylinositol-3 kinase inhibitors in a primary mouse model of undifferentiated pleomorphic sarcoma.

Recent advances in sarcoma genomics have identified novel mutations in the PI3K pathway in human sarcomas. Here, we use a mouse model of primary soft-tissue sarcoma for preclinical testing of doxorubicin and inhibitors of the PI3K pathway: BKM120 (PI3K inhibitor) and BEZ235 (a dual PI3K/mTOR inhibitor). Doxorubicin-treated tumors (n = 15) showed a partial response rate of 6.6%, just as the majority of human sarcomas do not respond to doxorubicin. Treatment with BKM120 elicited a partial response in 50% of tumors (n = 10), which was also seen in combination with doxorubicin (n = 10). Additionally, BKM120 treatment produced a robust delay in tumor growth kinetics. BEZ235-treated tumors (n = 9) showed a complete response rate of 11.1%. Combining BEZ235 with doxorubicin (n = 10) increased the complete response rate to 50% (P = 0.035). These studies demonstrate that PI3K pathway inhibition is a viable and attractive target for soft-tissue sarcomas.

Authors
Kim, S; Dodd, RD; Mito, JK; Ma, Y; Kim, Y; Riedel, RF; Kirsch, DG
MLA Citation
Kim, S, Dodd, RD, Mito, JK, Ma, Y, Kim, Y, Riedel, RF, and Kirsch, DG. "Efficacy of phosphatidylinositol-3 kinase inhibitors in a primary mouse model of undifferentiated pleomorphic sarcoma." Sarcoma 2012 (2012): 680708-.
PMID
22619567
Source
pubmed
Published In
Sarcoma
Volume
2012
Publish Date
2012
Start Page
680708
DOI
10.1155/2012/680708

Soft tissue sarcoma, version 2.2012 featured updates to the NCCN guidelines

The major changes to the 2012 and 2011 NCCN Guidelines for Soft Tissue Sarcoma pertain to the management of patients with gastrointestinal stromal tumors (GISTs) and desmoid tumors (aggressive fibromatosis). Postoperative imatinib following complete resection for primary GIST with no preoperative imatinib is now included as a category 1 recommendation for patients with intermediate or high risk of recurrence. The panel also reaffirmed the recommendation for preoperative use of imatinib in patients with GISTs that are resectable with negative margins but associated with significant surgical morbidity. Observation was included as an option for patients with resectable desmoid tumors that are small and asymptomatic, not causing morbidity, pain, or functional limitation. Sorafenib is included as an option for systemic therapy for patients with desmoid tumors. © JNCCN - Journal of the National Comprehensive Cancer Network.

Authors
Mehren, MV; Benjamin, RS; Bui, MM; Casper, ES; III, EUC; DeLaney, TF; Ganjoo, KN; George, S; Gonzalez, R; Heslin, MJ; III, JMK; Mayerson, J; McGarry, SV; Meyer, C; O'Donnell, RJ; Paz, IB; Pfeifer, JD; Pollock, RE; Randall, RL; Riedel, RF; Schuetze, S; Schupak, KD; Schwartz, HS; Shankar, S; Tine, BAV; Wayne, J; Sundar, H; McMillian, NR
MLA Citation
Mehren, MV, Benjamin, RS, Bui, MM, Casper, ES, III, EUC, DeLaney, TF, Ganjoo, KN, George, S, Gonzalez, R, Heslin, MJ, III, JMK, Mayerson, J, McGarry, SV, Meyer, C, O'Donnell, RJ, Paz, IB, Pfeifer, JD, Pollock, RE, Randall, RL, Riedel, RF, Schuetze, S, Schupak, KD, Schwartz, HS, Shankar, S, Tine, BAV, Wayne, J, Sundar, H, and McMillian, NR. "Soft tissue sarcoma, version 2.2012 featured updates to the NCCN guidelines." JNCCN Journal of the National Comprehensive Cancer Network 10.8 (2012): 951-960.
PMID
22878820
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
10
Issue
8
Publish Date
2012
Start Page
951
End Page
960

Targeted agents for sarcoma: is individualized therapy possible in such a diverse tumor type?

A wide variety of cytogenetic abnormalities and molecular pathways have been implicated in the pathogenesis of sarcoma, and significant progress has been made in the past decade toward identifying potential therapeutic targets. However, apart from gastrointestinal stromal tumors (GISTs) and dermatofibrosarcoma protuberans (DFSP), little progress has been made toward translating that knowledge into effective therapeutic strategies. The identification of activating KIT mutations in the majority of GISTs was a defining moment that led to the first effective targeted therapy for sarcoma, and the subsequent use of imatinib mesylate has revolutionized the treatment of GISTs. Beyond imatinib, the most promising agents to date--and the agents most extensively studied--are the multitargeted tyrosine kinase inhibitors. Several other classes of agents have also shown some activity in soft tissue sarcomas, including mammalian target of rapamycin inhibitors, inhibitors of growth factor receptors, histone deacetylase inhibitors, agents that modulate the p53 pathway, inhibitors of molecular chaperone proteins (eg, heat shock protein 90 [Hsp90]), and other signal transduction inhibitors. Despite a large number of completed and ongoing phase II studies, few agents have moved to phase III testing, and much work remains to be done to fully validate the identified targets and determine the optimal treatment strategy. Ongoing studies are exploring a wide range of combination strategies. This review will highlight some of the emerging targeted therapies that appear to hold promise and may eventually contribute to improved systemic therapy for sarcoma.

Authors
Riedel, RF
MLA Citation
Riedel, RF. "Targeted agents for sarcoma: is individualized therapy possible in such a diverse tumor type?." Semin Oncol 38 Suppl 3 (October 2011): S30-S42. (Review)
PMID
22055970
Source
pubmed
Published In
Seminars in Oncology
Volume
38 Suppl 3
Publish Date
2011
Start Page
S30
End Page
S42
DOI
10.1053/j.seminoncol.2011.09.003

Emerging therapeutic targets for soft tissue sarcoma.

Soft tissue sarcomas (STS) are malignancies of mesenchymal origin that represent approximately 1% of cancers in adults. Systematic research into the treatment of STS is challenging given its rarity and disease heterogeneity. Despite the ability to histologically subtype STS, only recently has our approach to therapy begun to differentiate along these lines. The purpose of this review is to highlight emerging therapeutic targets and therapies that hold the potential to add to the current state of systemic treatment for STS.

Authors
Smith, JL; Riedel, RF
MLA Citation
Smith, JL, and Riedel, RF. "Emerging therapeutic targets for soft tissue sarcoma." Curr Oncol Rep 13.4 (August 2011): 350-358. (Review)
PMID
21523334
Source
pubmed
Published In
Current Oncology Reports
Volume
13
Issue
4
Publish Date
2011
Start Page
350
End Page
358
DOI
10.1007/s11912-011-0175-y

Results of the phase III, placebo-controlled trial (SUCCEED) evaluating the mTOR inhibitor ridaforolimus (R) as maintenance therapy in advanced sarcoma patients (pts) following clinical benefit from prior standard cytotoxic chemotherapy (CT).

Authors
Chawla, SP; Blay, J; Ray-Coquard, IL; Le Cesne, A; Staddon, AP; Milhem, MM; Penel, N; Riedel, RF; Nguyen, BB; Cranmer, LD; Reichardt, P; Bompas, E; Song, Y; Lee, R; Eid, JE; Loewy, J; Haluska, FG; Dodion, PF; Demetri, GD
MLA Citation
Chawla, SP, Blay, J, Ray-Coquard, IL, Le Cesne, A, Staddon, AP, Milhem, MM, Penel, N, Riedel, RF, Nguyen, BB, Cranmer, LD, Reichardt, P, Bompas, E, Song, Y, Lee, R, Eid, JE, Loewy, J, Haluska, FG, Dodion, PF, and Demetri, GD. "Results of the phase III, placebo-controlled trial (SUCCEED) evaluating the mTOR inhibitor ridaforolimus (R) as maintenance therapy in advanced sarcoma patients (pts) following clinical benefit from prior standard cytotoxic chemotherapy (CT)." JOURNAL OF CLINICAL ONCOLOGY 29.15 (May 20, 2011).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
29
Issue
15
Publish Date
2011

Results of the phase III, placebo-controlled trial (SUCCEED) evaluating the mTOR inhibitor ridaforolimus (R) as maintenance therapy in advanced sarcoma patients (pts) following clinical benefit from prior standard cytotoxic chemotherapy (CT).

10005 Background: The mTOR signaling pathway is activated in most sarcomas. R, an oral mTOR inhibitor, demonstrated activity in phase I-II trials in advanced sarcomas following failure of prior CT.This trial is an international, double-blind study randomized 1:1 between R (40 mg orally for 5 days/week) vs. placebo (P) as maintenance therapy in pts with metastatic sarcoma (stratified soft-tissue vs bone; 1st vs, 2nd/3rd line prior CT) following stable disease or better response to prior CT. Primary endpoint is progression-free survival (PFS) based on independent radiological review (IRR). Secondary endpoints include overall survival (OS), best target lesion response, cancer-related symptoms, and safety and tolerability.711 pts were randomized from Jun '07 to Jan '10 and analyzed for efficacy. At data cut-off, 53 pts remained on blinded drug. Baseline characteristics were well balanced between the study arms. Analysis of 552 PFS events per IRR showed that R met the prespecified study endpoint with a statistically significant improvement in PFS compared to P (Hazard Ratio HR=0.72, P=0.0001, stratified log-rank). Median PFS improved by 21% (17.7 wks R vs. 14.6 wks P). Based on local site assessment of PFS, R demonstrated an improvement with HR=0.69 (P<0.0001) and a 52% gain in median (22.4 wks R vs. 14.7 wks P). PFS benefit was noted across all prespecified strata. Follow-up for OS is ongoing; results at data cut-off (313 OS events) indicate a trend favoring R (median OS: 88.0 wks R vs. 78.7 wks P; HR=0.92, 95% CI (0.74, 1.15)). While incidence of stomatitis (52%) and other adverse events was higher in pts receiving R, the overall safety profile was consistent with other mTOR inhibitors.This randomized trial of ridaforolimus met the primary endpoint of improved PFS in pts with metastatic soft-tissue or bone sarcomas to maintain benefit from prior standard CT. The rapid progression of metastatic sarcomas demonstrates the aggressive nature of these malignancies, and maintenance therapy with R will provide a new option for pts with this life-threatening disease.

Authors
Chawla, SP; Blay, J; Ray-Coquard, IL; Le Cesne, A; Staddon, AP; Milhem, MM; Penel, N; Riedel, RF; Bui Nguyen, B; Cranmer, LD; Reichardt, P; Bompas, E; Song, Y; Lee, R; Eid, JE; Loewy, J; Haluska, FG; Dodion, PF; Demetri, GD
MLA Citation
Chawla, SP, Blay, J, Ray-Coquard, IL, Le Cesne, A, Staddon, AP, Milhem, MM, Penel, N, Riedel, RF, Bui Nguyen, B, Cranmer, LD, Reichardt, P, Bompas, E, Song, Y, Lee, R, Eid, JE, Loewy, J, Haluska, FG, Dodion, PF, and Demetri, GD. "Results of the phase III, placebo-controlled trial (SUCCEED) evaluating the mTOR inhibitor ridaforolimus (R) as maintenance therapy in advanced sarcoma patients (pts) following clinical benefit from prior standard cytotoxic chemotherapy (CT)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): 10005-.
PMID
28021073
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
10005

Retraction: Genomic signatures to guide the use of chemotherapeutics.

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Retraction: Genomic signatures to guide the use of chemotherapeutics." Nat Med 17.1 (January 2011): 135-.
PMID
21217686
Source
pubmed
Published In
Nature Medicine
Volume
17
Issue
1
Publish Date
2011
Start Page
135
DOI
10.1038/nm0111-135

Primary meningeal rhabdomyosarcoma.

Primary meningeal rhabdomyosarcoma is a rare primary brain malignancy, with scant case reports. While most reports of primary intracranial rhabdomyosarcoma occur in pediatric patients, a handful of cases in adult patients have been reported in the medical literature. We report the case of a 44-year-old male who developed primary meningeal rhabdomyosarcoma. After developing episodes of right lower extremity weakness, word finding difficulty, and headaches, a brain magnetic resonance imaging (MRI) demonstrated a vertex lesion with radiographic appearance of a meningeal-derived tumor. Subtotal surgical resection was performed due to sagittal sinus invasion and initial pathology was interpreted as an anaplastic meningioma. Re-review of pathology demonstrated rhabdomyosarcoma negative for alveolar translocation t(2;13). Staging studies revealed no evidence of disseminated disease. He was treated with stereotactic radiotherapy with concurrent temozolamide to be followed by vincristine, actinomycin-D, and cyclophosphamide (VAC) systemic therapy.

Authors
Palta, M; Riedel, RF; Vredenburgh, JJ; Cummings, TJ; Green, S; Chang, Z; Kirkpatrick, JP
MLA Citation
Palta, M, Riedel, RF, Vredenburgh, JJ, Cummings, TJ, Green, S, Chang, Z, and Kirkpatrick, JP. "Primary meningeal rhabdomyosarcoma." Sarcoma 2011 (2011): 312802-.
PMID
21772793
Source
pubmed
Published In
Sarcoma
Volume
2011
Publish Date
2011
Start Page
312802
DOI
10.1155/2011/312802

Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12 (1294-1300))

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12 (1294-1300))." Nature Medicine 17.1 (2011): 135--.
Source
scival
Published In
Nature Medicine
Volume
17
Issue
1
Publish Date
2011
Start Page
135-
DOI
10.1038/nm0111-135

Characterizing the developmental pathways TTF-1, NKX2-8, and PAX9 in lung cancer (Proceedings of the National Academy of Sciences of the United States of America (2009) 106, 13 (5312-5317) DOI: 10.1073/pnas.0900827106)

Authors
Hsu, DS; Acharya, CR; Balakumaran, BS; Riedel, RF; Kim, MK; Stevenson, M; Tuchman, S; Mukherjee, S; Barry, W; Dressman, HK; al, E
MLA Citation
Hsu, DS, Acharya, CR, Balakumaran, BS, Riedel, RF, Kim, MK, Stevenson, M, Tuchman, S, Mukherjee, S, Barry, W, Dressman, HK, and al, E. "Characterizing the developmental pathways TTF-1, NKX2-8, and PAX9 in lung cancer (Proceedings of the National Academy of Sciences of the United States of America (2009) 106, 13 (5312-5317) DOI: 10.1073/pnas.0900827106)." Proceedings of the National Academy of Sciences of the United States of America 108.35 (2011): 14705--.
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
108
Issue
35
Publish Date
2011
Start Page
14705-
DOI
10.1073/pnas.1111196108

Soft tissue sarcoma.

Authors
Demetri, GD; Antonia, S; Benjamin, RS; Bui, MM; Casper, ES; Conrad, EU; DeLaney, TF; Ganjoo, KN; Heslin, MJ; Hutchinson, RJ; Kane, JM; Letson, GD; McGarry, SV; O'Donnell, RJ; Paz, IB; Pfeifer, JD; Pollock, RE; Randall, RL; Riedel, RF; Schupak, KD; Schwartz, HS; Thornton, K; von Mehren, M; Wayne, J; National Comprehensive Cancer Network Soft Tissue Sarcoma Panel,
MLA Citation
Demetri, GD, Antonia, S, Benjamin, RS, Bui, MM, Casper, ES, Conrad, EU, DeLaney, TF, Ganjoo, KN, Heslin, MJ, Hutchinson, RJ, Kane, JM, Letson, GD, McGarry, SV, O'Donnell, RJ, Paz, IB, Pfeifer, JD, Pollock, RE, Randall, RL, Riedel, RF, Schupak, KD, Schwartz, HS, Thornton, K, von Mehren, M, Wayne, J, and National Comprehensive Cancer Network Soft Tissue Sarcoma Panel, . "Soft tissue sarcoma." J Natl Compr Canc Netw 8.6 (June 2010): 630-674.
PMID
20581298
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
8
Issue
6
Publish Date
2010
Start Page
630
End Page
674

NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors.

The standard of care for managing patients with gastrointestinal stromal tumors (GISTs) rapidly changed after the introduction of effective molecularly targeted therapies involving tyrosine kinase inhibitors (TKIs), such as imatinib mesylate and sunitinib malate. A better understanding of the molecular characteristics of GISTs have improved the diagnostic accuracy and led to the discovery of novel immunomarkers and new mechanisms of resistance to TKI therapy, which in turn have resulted in the development of novel treatment strategies. To address these issues, the NCCN organized a task force consisting of a multidisciplinary panel of experts in the fields of medical oncology, surgical oncology, molecular diagnostics, and pathology to discuss the recent advances, identify areas of future research, and recommend an optimal approach to care for patients with GIST at all stages of disease. The task force met for the first time in October 2003 and again in December 2006 and October 2009. This supplement describes the recent developments in the field of GIST as discussed at the October 2009 meeting.

Authors
Demetri, GD; von Mehren, M; Antonescu, CR; DeMatteo, RP; Ganjoo, KN; Maki, RG; Pisters, PWT; Raut, CP; Riedel, RF; Schuetze, S; Sundar, HM; Trent, JC; Wayne, JD
MLA Citation
Demetri, GD, von Mehren, M, Antonescu, CR, DeMatteo, RP, Ganjoo, KN, Maki, RG, Pisters, PWT, Raut, CP, Riedel, RF, Schuetze, S, Sundar, HM, Trent, JC, and Wayne, JD. "NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors." J Natl Compr Canc Netw 8 Suppl 2 (April 2010): S1-41.
PMID
20457867
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
8 Suppl 2
Publish Date
2010
Start Page
S1
End Page
41

Pharmacogenomic strategies provide a rational approach to the treatment of cisplatin-resistant patients with advanced cancer (Journal of Clinical Oncology (2007) 25, (4350-4357))

Authors
Hsu, DS; Balakumaran, BS; Acharya, CR; Vlahovic, V; Walters, KS; Garman, K; Anders, C; Riedel, RF; Lancaster, J; Harpole, D; al, E
MLA Citation
Hsu, DS, Balakumaran, BS, Acharya, CR, Vlahovic, V, Walters, KS, Garman, K, Anders, C, Riedel, RF, Lancaster, J, Harpole, D, and al, E. "Pharmacogenomic strategies provide a rational approach to the treatment of cisplatin-resistant patients with advanced cancer (Journal of Clinical Oncology (2007) 25, (4350-4357))." Journal of Clinical Oncology 28.35 (2010): 5229--.
Source
scival
Published In
Journal of Clinical Oncology
Volume
28
Issue
35
Publish Date
2010
Start Page
5229-
DOI
10.1200/JCO.2010.33.7311

Cross species genomic analysis identifies a mouse model as undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma.

Undifferentiated pleomorphic sarcoma/Malignant Fibrous Histiocytoma (MFH) is one of the most common subtypes of human soft tissue sarcoma. Using cross species genomic analysis, we define a geneset from the LSL-Kras(G12D); Trp53(Flox/Flox) mouse model of soft tissue sarcoma that is highly enriched in human MFH. With this mouse geneset as a filter, we identify expression of the RAS target FOXM1 in human MFH. Expression of Foxm1 is elevated in mouse sarcomas that metastasize to the lung and tissue microarray analysis of human MFH correlates overexpression of FOXM1 with metastasis. These results suggest that genomic alterations present in human MFH are conserved in the LSL-Kras(G12D); p53(Flox/Flox) mouse model of soft tissue sarcoma and demonstrate the utility of this pre-clinical model.

Authors
Mito, JK; Riedel, RF; Dodd, L; Lahat, G; Lazar, AJ; Dodd, RD; Stangenberg, L; Eward, WC; Hornicek, FJ; Yoon, SS; Brigman, BE; Jacks, T; Lev, D; Mukherjee, S; Kirsch, DG
MLA Citation
Mito, JK, Riedel, RF, Dodd, L, Lahat, G, Lazar, AJ, Dodd, RD, Stangenberg, L, Eward, WC, Hornicek, FJ, Yoon, SS, Brigman, BE, Jacks, T, Lev, D, Mukherjee, S, and Kirsch, DG. "Cross species genomic analysis identifies a mouse model as undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma. (Published online)" PLoS One 4.11 (November 30, 2009): e8075-.
PMID
19956606
Source
pubmed
Published In
PloS one
Volume
4
Issue
11
Publish Date
2009
Start Page
e8075
DOI
10.1371/journal.pone.0008075

Bevacizumab (B) plus everolimus (E) and panitumumab (P) in refractory advanced solid tumors

Authors
Howard, LA; Bullock, KE; Bendell, JC; Uronis, HE; Vlahovic, G; Blobe, GC; Riedel, RF; Nixon, AB; Gockerman, JP; Hurwitz, HI
MLA Citation
Howard, LA, Bullock, KE, Bendell, JC, Uronis, HE, Vlahovic, G, Blobe, GC, Riedel, RF, Nixon, AB, Gockerman, JP, and Hurwitz, HI. "Bevacizumab (B) plus everolimus (E) and panitumumab (P) in refractory advanced solid tumors." May 20, 2009.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Bevacizumab (B) plus everolimus (E) and panitumumab (P) in refractory advanced solid tumors.

3551 Background: In preclinical models, VEGF, mTOR, and EGFR inhibitors have anti-tumor and anti-angiogenesis effects as monotherapies and in combination. B inhibits VEGF; E inhibits mTOR; P inhibits EGFR. There is also potential for interaction between the pathways. Previously BE and BE + erlotinib were evaluated and showed signs of clinical activity.Patients (pts) with refractory advanced solid tumors were accrued in a phase I dose escalation of B + E + P on a 28d cycle. Dose levels are shown in the table below. DLT was defined as any treatment-related grade 4 heme, grade 3/4 non-heme adverse event (AE), or receiving <85% any study drug in Cycle 1. Blood, skin, and tumor biopsies pre- and on-treatment were collected for correlative biomarkers of angiogenesis.At this time, 12 pts (3M: 9F) are evaluable for toxicity; 9 for efficacy. Median age: 54 years (range 23-72). 9 of 12 pts had prior B exposure. Dose level 1 was expanded due to 1/3 DLT, with total of 3/6 DLT (Grade (Gr) 3 mucositis (n=2), Gr3 hypokalemia (n=1)). Dose level -1 had 3/3 DLT (Gr3, Gr4 mucositis (n=2), Gr3 non-acneform rash (n=1)). Dose level -2 had 0/3 pts DLT. Gr 3-4 related toxicities in cycle 2+: hypokalemia (n=4); hypophosphatemia (n = 1); hypomagnesemia (n = 1); diarrhea (n=1); hoarseness (n=1). Other events of interest were: Gr1-2 mucositis (n=7); Gr1 hyperlipidemia (n=5); Gr1-2 hyperglycemia (n=4); Gr2 hypertension (n=2); Gr1-2 neutropenia (n=5); Gr1-2 thrombocytopenia (n=5). 8/9 evaluable pts had SD as best response (median 26 wks, range 8+ to 32+ wks): 1 pt with pancreatic cancer and progression on 2 prior EGFR inhibitors had prolonged 32+ wk SD. There was 1 minor response (23.3%) in a pt with bevacizumab-refractory ovarian cancer (32+ wks). No CR or PR were seen.B + E + P at full doses has dose limiting toxicities of rash and mucositis. B 10 mg/kg q2wks + E 5 mg q48h + P 4.8 mg/kg q2wks is the maximum tolerated dose. This dose is currently being expanded in 20 patients with extensive pre- and on-treatment biomarker analyses. Updated clinical and biomarker data will be presented. [Table: see text] [Table: see text].

Authors
Howard, LA; Bullock, KE; Bendell, JC; Uronis, HE; Vlahovic, G; Blobe, GC; Riedel, RF; Nixon, AB; Gockerman, JP; Hurwitz, HI
MLA Citation
Howard, LA, Bullock, KE, Bendell, JC, Uronis, HE, Vlahovic, G, Blobe, GC, Riedel, RF, Nixon, AB, Gockerman, JP, and Hurwitz, HI. "Bevacizumab (B) plus everolimus (E) and panitumumab (P) in refractory advanced solid tumors." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.15_suppl (May 2009): 3551-.
PMID
27961368
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
3551

The clinical management of chondrosarcoma.

OPINION STATEMENT: Chondrosarcomas (CHS) represent a heterogeneous group of disorders ranging from indolent, low-grade tumors to aggressive, high-grade forms. Surgical resection represents the primary and preferred treatment modality for individuals with localized disease. Radiation therapy is appropriate for the treatment of positive surgical margins or palliation of disease-related symptoms. The treatment of advanced, metastatic disease is particularly challenging given the recognition that conventional chemotherapy has proven to be largely ineffective. Systemic chemotherapy may be considered in variant forms such as mesenchymal or dedifferentiated chondrosarcomas but high-quality data supporting its use is limited. There is universal agreement, however, that novel treatment strategies are desperately needed. This review will highlight the need for a coordinated multidisciplinary approach to optimize the management and care of patients.

Authors
Riedel, RF; Larrier, N; Dodd, L; Kirsch, D; Martinez, S; Brigman, BE
MLA Citation
Riedel, RF, Larrier, N, Dodd, L, Kirsch, D, Martinez, S, and Brigman, BE. "The clinical management of chondrosarcoma." Curr Treat Options Oncol 10.1-2 (April 2009): 94-106. (Review)
PMID
19238552
Source
pubmed
Published In
Current Treatment Options in Oncology
Volume
10
Issue
1-2
Publish Date
2009
Start Page
94
End Page
106
DOI
10.1007/s11864-009-0088-2

Characterizing the developmental pathways TTF-1, NKX2-8, and PAX9 in lung cancer.

We investigated the clinical implications of lung developmental transcription factors (TTF-1, NKX2-8, and PAX9) that we recently discovered as cooperating oncogenes activated by way of gene amplification at chromosome 14q13 in lung cancer. Using stable transfectants of human bronchial epithelial cells, RNA expression profiles (signatures) representing activation of the biological pathways defined by each of the 3 genes were determined and used to risk stratify a non-small-cell lung cancer (NSCLC) clinical data set consisting of 91 early stage tumors. Coactivation of the TTF-1 and NKX2-8 pathways identified a cluster of patients with poor survival, representing approximately 20% of patients with early stage NSCLC, whereas activation of individual pathways did not reveal significant prognostic power. Importantly, the poor prognosis associated with coactivation of TTF-1 and NKX2-8 was validated in 2 other independent clinical data sets. Furthermore, lung cancer cell lines showing coactivation of the TTF-1 and NKX2-8 pathways were shown to exhibit resistance to cisplatin, the standard of care for the treatment of NSCLC. This suggests that the cohort of patients with coactivation of TTF-1 and NKX2-8 pathways appears to be resistant to standard cisplatin therapy, suggesting the need for alternative therapies in this cohort of high-risk patients.

Authors
Hsu, DS; Acharya, CR; Balakumaran, BS; Riedel, RF; Kim, MK; Stevenson, M; Tuchman, S; Mukherjee, S; Barry, W; Dressman, HK; Nevins, JR; Powers, S; Mu, D; Potti, A
MLA Citation
Hsu, DS, Acharya, CR, Balakumaran, BS, Riedel, RF, Kim, MK, Stevenson, M, Tuchman, S, Mukherjee, S, Barry, W, Dressman, HK, Nevins, JR, Powers, S, Mu, D, and Potti, A. "Characterizing the developmental pathways TTF-1, NKX2-8, and PAX9 in lung cancer." Proc Natl Acad Sci U S A 106.13 (March 31, 2009): 5312-5317.
PMID
19279207
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
106
Issue
13
Publish Date
2009
Start Page
5312
End Page
5317
DOI
10.1073/pnas.0900827106

Inhalation with Tobramycin® to improve healing of tracheobronchial reconstruction

Objective: Sleeve resections were introduced to preserve lung function in patients with limited pulmonary reserve. Ischaemia and infection of the distal part of the anastomosis is the leading cause of bronchial anastomotic leakage. We have learned from our experience in lung transplantation that inhalation with Tobramycin® helps prevent anastomotic insufficiency. We would like to present our experience in patients with tracheobronchial sleeve and prophylactic Tobramycin® inhalation. Patients and methods: Retrospective analysis of 114 patient records, between 01.01.2005 and 31.12.2006, where a bronchial anastomosis (patients with tracheal resection were excluded) was performed. All patients received Tobramycin® inhalation (2 × 80 mg) for 7 days. Data analysed were; length of chest tube drainage in days, complications, morbidity and hospital mortality. Results: In 694 patients, an anatomic resection was performed. Of these, 114 (16%) were sleeve resections and 63 (9%) pneumonectomies. In 21 women and 93 men, between 25 and 84 years old, sleeve lobectomy was performed 104 times and carinal resection 10 times. A preoperative neoadjuvant therapy had been given in 26%. Radical (R0) resection was possible in 94%. The duration of the operation was between 83 and 225 min (median: 127 min). Chest tubes were removed on average after 6 days. Patients were discharged after 11 days. The rate of bronchial anastomotic leakage was 4.4%. There were two patients with postoperative respiratory insufficiency and mechanical ventilation, two patients with technical failure required early correction of the suture and one patient with a necrosis of the anastomosis. Thirty-day hospital mortality was 2.6% (3/114). Conclusions: Increasing experience with sleeve resection has reduced the rate of pneumonectomy below 10%, although a number of the patients had received neoadjuvant therapy and the carinal resection rate of necrosis and infection of the anastomosis was low. We therefore recommend use of local antibiotic inhalation after sleeve resection. © 2009 European Association for Cardio-Thoracic Surgery.

Authors
Ludwig, C; Riedel, R; Schnell, J; Stoelben, E
MLA Citation
Ludwig, C, Riedel, R, Schnell, J, and Stoelben, E. "Inhalation with Tobramycin® to improve healing of tracheobronchial reconstruction." European Journal of Cardio-thoracic Surgery 35.5 (2009): 797-800.
PMID
19269844
Source
scival
Published In
European Journal of Cardio-Thoracic Surgery
Volume
35
Issue
5
Publish Date
2009
Start Page
797
End Page
800
DOI
10.1016/j.ejcts.2008.12.048

A genomic approach to identify molecular pathways associated with chemotherapy resistance.

Resistance to chemotherapy in cancer is common. As gene expression profiling has been shown to anticipate chemotherapeutic resistance, we sought to identify cellular pathways associated with resistance to facilitate effective combination therapy. Gene set enrichment analysis was used to associate pathways with resistance in two data sets: the NCI-60 cancer cell lines deemed sensitive and resistant to specific chemotherapeutic agents (Adriamycin, cyclophosphamide, docetaxel, etoposide, 5-fluorouracil, paclitaxel, and topotecan) and a series of 40 lung cancer cell lines for which sensitivity to cisplatin and docetaxel was determined. Candidate pathways were further screened in silico using the Connectivity Map. The lead candidate pathway was functionally validated in vitro. Gene set enrichment analysis associated the matrix metalloproteinase, p53, methionine metabolism, and free pathways with cytotoxic resistance in the NCI-60 cell lines across multiple agents, but no gene set was common to all drugs. Analysis of the lung cancer cell lines identified the bcl-2 pathway to be associated with cisplatin resistance and the AKT pathway enriched in cisplatin- and docetaxel-resistant cell lines. Results from Connectivity Map supported an association between phosphatidylinositol 3-kinase/AKT and docetaxel resistance but did not support the association with cisplatin. Targeted inhibition of the phosphatidylinositol 3-kinase/AKT pathway with LY294002, in combination with docetaxel, resulted in a synergistic effect in previously docetaxel-resistant cell lines but not with cisplatin. These results support the use of a genomic approach to identify drug-specific targets associated with the development of chemotherapy resistance and underscore the importance of disease context in identifying these pathways.

Authors
Riedel, RF; Porrello, A; Pontzer, E; Chenette, EJ; Hsu, DS; Balakumaran, B; Potti, A; Nevins, J; Febbo, PG
MLA Citation
Riedel, RF, Porrello, A, Pontzer, E, Chenette, EJ, Hsu, DS, Balakumaran, B, Potti, A, Nevins, J, and Febbo, PG. "A genomic approach to identify molecular pathways associated with chemotherapy resistance." Mol Cancer Ther 7.10 (October 2008): 3141-3149.
PMID
18852117
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
7
Issue
10
Publish Date
2008
Start Page
3141
End Page
3149
DOI
10.1158/1535-7163.MCT-08-0642

Use of co-activation of lung cancer specific developmental pathway genes, TTF-1, NKX2-8, and PAX9, to predict prognosis and guide therapeutic strategies

Authors
Hsu, SD; Acharya, CR; Riedel, RF; Redman, RC; Garman, KS; Dressman, HK; Ginsburg, G; Powers, S; Mu, D; Potti, A
MLA Citation
Hsu, SD, Acharya, CR, Riedel, RF, Redman, RC, Garman, KS, Dressman, HK, Ginsburg, G, Powers, S, Mu, D, and Potti, A. "Use of co-activation of lung cancer specific developmental pathway genes, TTF-1, NKX2-8, and PAX9, to predict prognosis and guide therapeutic strategies." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

A genomic approach to identify therapeutic targets in histologic subtypes of soft tissue sarcoma

Authors
Riedel, RF; Friedman, D; Febbo, PG
MLA Citation
Riedel, RF, Friedman, D, and Febbo, PG. "A genomic approach to identify therapeutic targets in histologic subtypes of soft tissue sarcoma." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Use of co-activation of lung cancer specific developmental pathway genes, TTF-1, NKX2-8, and PAX9, to predict prognosis and guide therapeutic strategies.

7511 Background: We recently described a novel, recurring amplicon (14q13.3) specific to NSCLC that harbors three genes, TTF- 1, NKX2-8, and PAX9, important in lung development (Kendall et al. PNAS 2007).Using stable transfectants of human bronchial epithelial cells, gene expression profiles representing activation of the biological pathways defined by TTF-1, NKX2-8, and PAX9 were created. Using samples from patients with early stage NSCLC (n=306) and advanced stage (n=41), the clinical relevance of these developmental genes in NSCLC initiation, progression and response to therapy was evaluated.In an initial discovery dataset of patients with early stage NSCLC (n=91), we observed that individual activation of TTF-1, NKX2-8 and PAX9 was not prognostic; however, co- activation of TTF-1 and NKX2-8 pathways identified a cluster of patients representing approximately 20% of patients with poor survival (p=0.01). Using an independent validation set (n=215, 133 squamous and 84 adenocarcinomas), the prognostic validity of TTF-1/NKX2-8 co-activation was further confirmed. Additionally, the independent (of age, gender, pathologic stage, tumor size, and histology) prognostic value of TTF- 1/NKX2-8 co-activation was verified in multivariate analyses (p=0.03). Using in vitro studies involving more than 40 lung cancer cell lines, we demonstrate that TTF-1/NKX2-8 co-activation also predicts resistance to cisplatin, the standard of care for patients with NSCLC. Further in vitro experiments demonstrated the ability of a RAS pathway specific therapy (farnesyl thiosalicyclic acid) to inhibit tumor cell growth in TTF-1/NKX-2 activated cells (p=0.01), suggesting that modulation of the RAS pathway is a rational therapeutic strategy in high risk NSCLC patients with co- activation of specific lung developmental pathways.Genes critical to lung development, TTF-1, NKX2-8, and PAX9, play a key role in the pathogenesis of NSCLC. Furthermore, knowledge of the activation status of developmental genes specific to lung cancer identifies patients with poor prognosis and provides a novel approach to targeted therapeutics in the adjuvant setting by guiding the appropriate use of RAS pathway specific inhibitors. No significant financial relationships to disclose.

Authors
Hsu, SD; Acharya, CR; Riedel, RF; Redman, RC; Garman, KS; Dressman, HK; Ginsburg, G; Powers, S; Mu, D; Potti, A
MLA Citation
Hsu, SD, Acharya, CR, Riedel, RF, Redman, RC, Garman, KS, Dressman, HK, Ginsburg, G, Powers, S, Mu, D, and Potti, A. "Use of co-activation of lung cancer specific developmental pathway genes, TTF-1, NKX2-8, and PAX9, to predict prognosis and guide therapeutic strategies." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26.15_suppl (May 2008): 7511-.
PMID
27947211
Source
epmc
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
7511

A genomic approach to identify therapeutic targets in histologic subtypes of soft tissue sarcoma.

10577 Background: Sarcomas are a rare, heterogeneous group of tumors with varying degrees of aggressiveness and responsiveness to therapy. In the advanced setting, chemotherapy results in unsatisfactory long-term outcomes. Novel therapeutic strategies that rationally target specific sarcoma subtypes are desired to improve outcomes and limit chemotherapy resistance. Our research uses a genomic approach to identify unique biological mechanisms and signaling pathways associated with specific sarcoma subtypes so as to guide future rational combinations of standard cytotoxic agents with novel "targeted" therapies.Publicly-available gene expression datasets ( GSE6481 , GSE2719 ) were obtained from Gene Expression Omnibus (GEO) representing 141 human sarcoma samples across 12 histologic subtypes. Datasets were combined, adjusted and standardized using ComBat to limit batch effect and assessed using hierarchical clustering (Gene Pattern) with filtering. Gene set enrichment analysis (GSEA) was performed using a two-class discriminator (i.e., synovial sarcoma vs. other sarcomas) to identify biologic pathways unique to specific histologic subtypes. Gene sets with a false discovery rate (FDR) <0.25 were deemed statistically significant as originally described.Hierarchical clustering identified well-defined clusters for synovial sarcoma, GIST, and myxoid/round cell liposarcoma with less organized clustering for the remaining subtypes. GSEA identified 11 enriched gene sets, representing biological pathways of activity, at FDR <0.25 for synovial sarcoma with 3 of 11 gene sets related to Wnt signaling (WNTPATHWAY, PITX2PATHWAY, PS1PATHWAY). Twenty-nine gene sets were significant at FDR <0.25 for myxoid/round cell liposarcoma with 2 gene sets related to mTOR signaling (MTORPATHWAY, IGF1MTORPATHWAY). Additional pathways and subtypes are being analyzed and will be reported.These preliminary data support the use of a genomic approach to identify pathways associated with specific histologic sarcoma subtypes. This strategy may be used to identify novel agents that can be used alone or in combination with conventional cytotoxic chemotherapy. No significant financial relationships to disclose.

Authors
Riedel, RF; Friedman, D; Febbo, PG
MLA Citation
Riedel, RF, Friedman, D, and Febbo, PG. "A genomic approach to identify therapeutic targets in histologic subtypes of soft tissue sarcoma." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26.15_suppl (May 2008): 10577-.
PMID
27948301
Source
epmc
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
10577

Corrigendum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12, (1294-1300))

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Corrigendum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12, (1294-1300))." Nature Medicine 14.8 (2008): 889--.
Source
scival
Published In
Nature Medicine
Volume
14
Issue
8
Publish Date
2008
Start Page
889-
DOI
10.1038/nm0808-889

Pharmacogenomic strategies provide a rational approach to the treatment of cisplatin-resistant patients with advanced cancer.

PURPOSE: Standard treatment for advanced non-small-cell lung cancer (NSCLC) includes the use of a platinum-based chemotherapy regimen. However, response rates are highly variable. Newer agents, such as pemetrexed, have shown significant activity as second-line therapy and are currently being evaluated in the front-line setting. We utilized a genomic strategy to develop signatures predictive of chemotherapeutic response to both cisplatin and pemetrexed to provide a rational approach to effective individualized medicine. METHODS: Using in vitro drug sensitivity data, coupled with microarray data, we developed gene expression signatures predicting sensitivity to cisplatin and pemetrexed. Signatures were validated with response data from 32 independent ovarian and lung cancer cell lines as well as 59 samples from patients previously treated with cisplatin. RESULTS: Genomic-derived signatures of cisplatin and pemetrexed sensitivity were shown to accurately predict sensitivity in vitro and, in the case of cisplatin, to predict treatment response in patients treated with cisplatin. The accuracy of the cisplatin predictor, based on available clinical data, was 83.1% (sensitivity, 100%; specificity 57%; positive predictive value, 78%; negative predictive value, 100%). Interestingly, an inverse correlation was seen between in vitro cisplatin and pemetrexed sensitivity, and importantly, between the likelihood of cisplatin and pemetrexed response in patients. CONCLUSION: The use of genomic predictors of response to cisplatin and pemetrexed can be incorporated into strategies to optimize therapy for advanced solid tumors.

Authors
Hsu, DS; Balakumaran, BS; Acharya, CR; Vlahovic, V; Walters, KS; Garman, K; Anders, C; Riedel, RF; Lancaster, J; Harpole, D; Dressman, HK; Nevins, JR; Febbo, PG; Potti, A
MLA Citation
Hsu, DS, Balakumaran, BS, Acharya, CR, Vlahovic, V, Walters, KS, Garman, K, Anders, C, Riedel, RF, Lancaster, J, Harpole, D, Dressman, HK, Nevins, JR, Febbo, PG, and Potti, A. "Pharmacogenomic strategies provide a rational approach to the treatment of cisplatin-resistant patients with advanced cancer." J Clin Oncol 25.28 (October 1, 2007): 4350-4357.
PMID
17906199
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
28
Publish Date
2007
Start Page
4350
End Page
4357
DOI
10.1200/JCO.2007.11.0593

A phase II trial of carboplatin/vinorelbine with pegfilgrastim support for the treatment of patients with advanced non-small cell lung cancer.

INTRODUCTION: The impact of chemotherapy dose delivery has not been well studied in patients with non-small cell lung cancer (NSCLC). Overlapping hematologic toxicities commonly limit planned dose intensity of combination chemotherapy regimens. A phase II study investigating carboplatin and vinorelbine, supported by pegfilgrastim, in the treatment of patients with advanced NSCLC was performed. METHODS: Chemotherapy-naïve patients with locally advanced or metastatic NSCLC were treated with carboplatin area under the curve (AUC) 6 mg/ml per minute intravenously on day 1 and vinorelbine 30 mg/m2 intravenously on days 1 and 8 every 3 weeks for four planned cycles. Pegfilgrastim was administered on day 9 of each cycle as a 6-mg subcutaneous injection. The primary endpoint was incidence of cycle 1 febrile neutropenia. Secondary endpoints included incidence of grade 3/4 hematologic and nonhematologic toxicities, delivered dose intensity, and overall survival. RESULTS: Thirty patients (21 men, 9 women) with a median age of 61 years (range, 43-79) were enrolled. Of 120 planned patient cycles, 101 (84%) were completed. There was one episode of cycle 1 febrile neutropenia. Overall response rate was 27%. Median dose delivered for vinorelbine was 17.2 mg/m2 per week, representing a delivered dose intensity of 86%. Median survival was 9.4 months (95% confidence interval: 6.1-18.0) with a 3-year survival rate of 20%. CONCLUSIONS: This regimen of carboplatin and vinorelbine with pegfilgrastim support was associated with a low rate of febrile neutropenia and good maintenance of planned dose intensity. Although response and survival are similar to other chemotherapy regimens in advanced NSCLC, studies optimizing chemotherapy delivery in this setting may help inform treatment approaches in patients with earlier stage disease.

Authors
Riedel, RF; Andrews, C; Garst, J; Dunphy, F; Herndon, JE; Blackwell, S; Barbour, S; Crawford, J
MLA Citation
Riedel, RF, Andrews, C, Garst, J, Dunphy, F, Herndon, JE, Blackwell, S, Barbour, S, and Crawford, J. "A phase II trial of carboplatin/vinorelbine with pegfilgrastim support for the treatment of patients with advanced non-small cell lung cancer." Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2.6 (June 2007): 520-525. (Academic Article)
PMID
17545847
Source
manual
Published In
Journal of Thoracic Oncology
Volume
2
Issue
6
Publish Date
2007
Start Page
520
End Page
525

Identifying mechanisms of resistance in patients with locally advanced non-small cell lung cancer receiving dose-dense neoadjuvant/induction chemotherapy.

Authors
Riedel, RF; Febbo, PG; Crawford, L
MLA Citation
Riedel, RF, Febbo, PG, and Crawford, L. "Identifying mechanisms of resistance in patients with locally advanced non-small cell lung cancer receiving dose-dense neoadjuvant/induction chemotherapy." January 2007.
Source
wos-lite
Published In
Journal of Investigative Medicine
Volume
55
Issue
1
Publish Date
2007
Start Page
S282
End Page
S282

Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature (2006) 12, (1294-1300))

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature (2006) 12, (1294-1300))." Nature Medicine 13.11 (2007): 1388--.
Source
scival
Published In
Nature Medicine
Volume
13
Issue
11
Publish Date
2007
Start Page
1388-
DOI
10.1038/nm1107-1388

Phase II study of carboplatin, irinotecan, and thalidomide combination in patients with extensive stage small-cell lung cancer.

Authors
Riedel, RF; Crawford, J; Dunphy, F; Herndon, JE; Garst, J; Kelley, MJ
MLA Citation
Riedel, RF, Crawford, J, Dunphy, F, Herndon, JE, Garst, J, and Kelley, MJ. "Phase II study of carboplatin, irinotecan, and thalidomide combination in patients with extensive stage small-cell lung cancer." Lung cancer (Amsterdam, Netherlands) 54.3 (December 2006): 431-432. (Academic Article)
PMID
17005294
Source
manual
Published In
Lung Cancer
Volume
54
Issue
3
Publish Date
2006
Start Page
431
End Page
432

Genomic signatures to guide the use of chemotherapeutics.

Using in vitro drug sensitivity data coupled with Affymetrix microarray data, we developed gene expression signatures that predict sensitivity to individual chemotherapeutic drugs. Each signature was validated with response data from an independent set of cell line studies. We further show that many of these signatures can accurately predict clinical response in individuals treated with these drugs. Notably, signatures developed to predict response to individual agents, when combined, could also predict response to multidrug regimens. Finally, we integrated the chemotherapy response signatures with signatures of oncogenic pathway deregulation to identify new therapeutic strategies that make use of all available drugs. The development of gene expression profiles that can predict response to commonly used cytotoxic agents provides opportunities to better use these drugs, including using them in combination with existing targeted therapies.

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Genomic signatures to guide the use of chemotherapeutics." Nat Med 12.11 (November 2006): 1294-1300.
PMID
17057710
Source
pubmed
Published In
Nature Medicine
Volume
12
Issue
11
Publish Date
2006
Start Page
1294
End Page
1300
DOI
10.1038/nm1491

Impact of a multidisciplinary thoracic oncology clinic on the timeliness of care.

BACKGROUND: Multidisciplinary clinics have been recommended for the evaluation of patients with lung cancer. Evidence to support this recommendation, however, is limited. A single-center, retrospective review of lung cancer patients at a Veterans Affairs hospital was performed comparing timeliness of diagnostic and treatment decisions during the operation of a multidisciplinary thoracic oncology clinic (MTOC) with a period after it closed (non-MTOC), during which only a weekly multidisciplinary conference was held. METHODS: Patients were identified from a tumor registry. Manual chart reviews were performed on all patients. Outcome measures included time from initial presentation to diagnosis (TTD) and time from diagnosis to treatment initiation (TTT). RESULTS: Three hundred forty-five patients (244 in MTOC, 101 in non-MTOC) diagnosed with lung cancer between 1999 and 2003 were included in the study. Baseline characteristics were similar between the two groups. Median TTD was 48 days (95% confidence interval [CI]: 37-61) and 47 days (95% CI: 39-55) in the MTOC (n = 164) and non-MTOC cohorts (n = 89), respectively (p = 0.09). Median TTT was 22 days (95% CI: 20-27) and 23 days (95% CI: 20-34) in the MTOC (n = 165) and non-MTOC cohorts (n = 89), respectively (p = 0.71). There was no difference in overall survival. CONCLUSION: Retrospective comparison of sequential cohorts failed to reveal benefit in the timeliness of care measures during the time period of MTOC operation. Potential confounders include the absence of a surgeon in the MTOC setting, an ongoing weekly multidisciplinary conference in the non-MTOC cohort, and existing infrastructures based on previous MTOC experiences and past provider experience. Confirmation of these findings in other health care settings is warranted, preferably in a prospective fashion.

Authors
Riedel, RF; Wang, X; McCormack, M; Toloza, E; Montana, GS; Schreiber, G; Kelley, MJ
MLA Citation
Riedel, RF, Wang, X, McCormack, M, Toloza, E, Montana, GS, Schreiber, G, and Kelley, MJ. "Impact of a multidisciplinary thoracic oncology clinic on the timeliness of care." J Thorac Oncol 1.7 (September 2006): 692-696.
PMID
17409938
Source
pubmed
Published In
Journal of Thoracic Oncology
Volume
1
Issue
7
Publish Date
2006
Start Page
692
End Page
696

Thymoma: benign appearance, malignant potential.

Thymoma is a rare tumor with a largely indolent growth pattern. It does, however, have malignant potential as a result of its ability to invade locally and metastasize regionally. Often associated with a number of immune- and nonimmune-mediated paraneoplastic syndromes, patient outcomes are directly related to stage of disease and the ability to achieve a complete surgical resection. Surgery is the mainstay of treatment, with adjuvant radiation recommended for invasive thymoma. Sensitive to both chemotherapy and radiation, durable responses are achievable in incompletely resected and inoperable patients. We present two cases of thymoma followed by a general discussion with an emphasis on treatment for both early and advanced-stage disease.

Authors
Riedel, RF; Burfeind, WR
MLA Citation
Riedel, RF, and Burfeind, WR. "Thymoma: benign appearance, malignant potential." Oncologist 11.8 (September 2006): 887-894.
PMID
16951392
Source
pubmed
Published In
The oncologist
Volume
11
Issue
8
Publish Date
2006
Start Page
887
End Page
894
DOI
10.1634/theoncologist.11-8-887

Epidermal growth factor receptor mutations predict sensitivity to gefitinib in patients with non-small-cell lung cancer.

Despite advances in chemotherapeutics, overall survival for advanced lung cancer patients remains poor. Consequently, efforts have focused on the use of targeted therapies to improve response rates and survival. The epidermal growth factor receptor (EGFR) is overexpressed in a variety of cancers, including lung, and may play a critical role in the pathogenesis of disease. Small molecule tyrosine kinase inhibitors, such as gefitinib (Iressa(R)), have response rates of between 10 and 27% in Phase II trials, and anecdotal reports of dramatic and sustained responses. Two recent studies published simultaneously, identified mutations in the ATP-binding cleft of the EGFR that are associated with clinical response to gefitinib. This finding has extraordinary implications and serves as a critical step toward individualized, patient-specific treatment plans based on the molecular constitution of the tumor of each individual.

Authors
Riedel, RF; Febbo, PG
MLA Citation
Riedel, RF, and Febbo, PG. "Epidermal growth factor receptor mutations predict sensitivity to gefitinib in patients with non-small-cell lung cancer." Future Oncol 1.4 (August 2005): 461-466. (Review)
PMID
16556022
Source
pubmed
Published In
Future oncology (London, England)
Volume
1
Issue
4
Publish Date
2005
Start Page
461
End Page
466
DOI
10.2217/14796694.1.4.461

Small-cell lung cancer: a review of clinical trials.

Small-cell lung cancer (SCLC) is expected to account for 25% of the approximate 170,000 cases of lung cancer diagnosed in the United States in 2002. Although sensitive and responsive to chemotherapy, SCLC has an increased propensity for early metastases, with relapses being common and long-term survival rates being poor. Clinical trials have played a vital role in expanding our knowledge base for this disease and have resulted in newer modalities, including chemotherapeutic agents, prophylactic cranial irradiation, and thoracic radiotherapy designed to improve overall outcomes. Clinical trials have also served to clarify the role of surgery in a disease that traditionally has been thought to be nonoperable. This review will focus on the results of clinical trials that have had an effect on the treatments of patients with limited and extensive-stage SCLC, with recommendations from the National Comprehensive Cancer Network being emphasized.

Authors
Riedel, RF; Crawford, J
MLA Citation
Riedel, RF, and Crawford, J. "Small-cell lung cancer: a review of clinical trials." Semin Thorac Cardiovasc Surg 15.4 (October 2003): 448-456. (Review)
PMID
14710387
Source
pubmed
Published In
Seminars in Thoracic and Cardiovascular Surgery
Volume
15
Issue
4
Publish Date
2003
Start Page
448
End Page
456

Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development.

Targeted mice lacking functional EGF or amphiregulin (AR) were derived and bred to the TGFalpha-knockout to generate mice lacking various combinations of the three ligands. In contrast to EGF receptor (EGFR) knockout mice, triple null mice lacking half of the EGFR ligand family were healthy and fertile, indicative of overlapping or compensatory functions among EGF family members. Nevertheless, pups born to triple null dams frequently died or were runted, suggesting a mammary gland defect. Comparison of individual and combinatorial knockouts established that specific loss of AR severely stunted ductal outgrowth during puberty, consistent with dramatic expression of AR transcripts in normal developing ducts. Surprisingly, loss of all three ligands did not significantly affect cellular proliferation, apoptosis, or ERK activation within terminal end buds. Following pregnancy, most AR single null females, but few triple null females could nurse their young, revealing collaborative roles for EGF and TGFalpha in mammopoiesis and lactogenesis. In triple null glands, alveoli were poorly organized and differentiated, and milk protein gene expression was decreased. Additionally, Stat5a activation was frequently reduced in AR single and combinatorial nulls in association with impaired lactation. Collectively, our results provide genetic confirmation of a requirement for EGFR signaling throughout the development of the mouse mammary gland, and reveal stage-dependent activities for different EGFR ligands. Finally, the additional loss of growth factors from pups nursed by triple null dams further worsened their survival and growth, establishing functions for both maternal- and neonatal-derived growth factors.

Authors
Luetteke, NC; Qiu, TH; Fenton, SE; Troyer, KL; Riedel, RF; Chang, A; Lee, DC
MLA Citation
Luetteke, NC, Qiu, TH, Fenton, SE, Troyer, KL, Riedel, RF, Chang, A, and Lee, DC. "Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development." Development 126.12 (June 1999): 2739-2750.
PMID
10331984
Source
pubmed
Published In
Development (Cambridge)
Volume
126
Issue
12
Publish Date
1999
Start Page
2739
End Page
2750

Expression of constitutively active Raf-1 in the mitochondria restores antiapoptotic and leukemogenic potential of a transformation-deficient BCR/ABL mutant.

The oncogenic BCR/ABL protein protects hematopoietic cells from apoptosis induced by growth factor deprivation, but the mechanisms are only partially understood. A BCR/ABL mutant lacking amino acids 176-426 in the BCR domain (p185DeltaBCR) failed to protect interleukin 3-deprived 32Dcl3 myeloid precursor cells from apoptosis, although it possessed tyrosine kinase activity and was capable of activating the Ras-Raf-MAP kinase pathway. Compared to p185 wild-type transfectants, p185DeltaBCR-transfected cells showed markedly reduced levels of Bcl-2 and expressed the hypophosphorylated, proapoptotic form of BAD. Bcl-2 expression in the mitochondrial fraction of p185DeltaBCR cells was also markedly diminished and mitochondrial RAF was undetectable. In p185DeltaBCR cells transfected with a mitochondria-targeted, constitutively active RAF (M-Raf) BAD was expressed in the hyperphosphorylated form and released from the mitochondria into the cytosol. p185DeltaBCR/M-Raf-transfected cells were completely resistant to apoptosis induced by growth factor deprivation in vitro. Moreover, constitutive expression of dominant-negative M-Raf (K375W) enhanced the susceptibility of 32Dcl3 cells expressing wild-type BCR/ABL to apoptosis. In severe combined immunodeficiency (SCID) mice, p185DeltaBCR/M-Raf double transfectants were leukemogenic, whereas cells expressing only p185DeltaBCR showed no leukemogenic potential. Together, these data support the existence of a BCR/ABL-dependent pathway that leads to expression of an active RAF in the mitochondria and promotes antiapoptotic and leukemia-inducing effects of BCR/ABL.

Authors
Salomoni, P; Wasik, MA; Riedel, RF; Reiss, K; Choi, JK; Skorski, T; Calabretta, B
MLA Citation
Salomoni, P, Wasik, MA, Riedel, RF, Reiss, K, Choi, JK, Skorski, T, and Calabretta, B. "Expression of constitutively active Raf-1 in the mitochondria restores antiapoptotic and leukemogenic potential of a transformation-deficient BCR/ABL mutant." J Exp Med 187.12 (June 15, 1998): 1995-2007.
PMID
9625759
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
187
Issue
12
Publish Date
1998
Start Page
1995
End Page
2007

Characterization of the mouse transforming growth factor alpha gene: its expression during eyelid development and in waved 1 tissues.

The spontaneous mouse waved 1 (wa1) mutation is allelic with the transforming growth factor alpha (TGF-alpha) gene and produces phenotypes similar to those of TGF-alpha knockout mice. Here, we show that TGF-alpha mRNA and protein levels are measurable in wa1 tissues but reduced 5- to 30-fold relative to wild type. Because the wa1-coding sequence is identical to that of the normal mRNA, wa1 is not a null mutation. Nuclear run-on analyses revealed decreased transcription of the TGF-alpha gene in wa1 tissues, but the sequence of a 3.2-kb 5' flanking fragment containing the promoter was unaltered. Moreover, pulsed field gel electrophoresis analysis did not reveal alterations within 750 kb upstream or 350 kb downstream of the gene, and chromosome 6 was karyotypically normal. Hence, we speculate that the wa1 mutation may be subtle and/or reside at a greater distance from the TGF-alpha gene. TGF-alpha deficiency elicits a spectrum of variably penetrant eye anomalies in wa1 and knockout mice that are associated with open eyes at birth. We found that late-gestation wa1 and TGF-alpha-null embryos display a significant delay in eyelid closure, although the eyes of most embryos fuse prior to birth. In situ hybridization localized TGF-alpha expression to the advancing margins of the eyelid epithelium and epidermal growth factor receptor expression throughout the eyelid and corneal epithelia. These results suggest that eye problems observed in TGF-alpha-deficient adult mice arise from premature exposure and trauma to open eyes during or following parturition.

Authors
Berkowitz, EA; Seroogy, KB; Schroeder, JA; Russell, WE; Evans, EP; Riedel, RF; Phillips, HK; Harrison, CA; Lee, DC; Luetteke, NC
MLA Citation
Berkowitz, EA, Seroogy, KB, Schroeder, JA, Russell, WE, Evans, EP, Riedel, RF, Phillips, HK, Harrison, CA, Lee, DC, and Luetteke, NC. "Characterization of the mouse transforming growth factor alpha gene: its expression during eyelid development and in waved 1 tissues." Cell Growth Differ 7.9 (September 1996): 1271-1282.
PMID
8877107
Source
pubmed
Published In
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research
Volume
7
Issue
9
Publish Date
1996
Start Page
1271
End Page
1282
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