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Genetic Testing | 2008

Cancer Genetics Evaluation: Barriers to and Improvements for Referral

Rachael Brandt; Zonera Ali; Allison Sabel; Terri McHugh; Paul Gilman

Despite the availability of cancer susceptibility testing, little information exists regarding physicians selection and referral of eligible patients. This study provides insight into whom, why, and when physicians refer for cancer genetics evaluation, as well as their comfort level within this role. Eighty-two physicians (51 primary care, 15 gynecology, 11 surgery and 5 oncology) completed a survey (response rate: 34%) regarding cancer genetics referral practices. Of these, 59% reported an awareness of the hospitals cancer genetics program. Program awareness was greater among oncologists, surgeons, and gynecologists than among primary care physicians (p < 0.0001). Patients were referred for enhanced risk assessment (88%), improved medical management (85%), and concern for family members (83%). Patient eligibility was based on family cancer history (96%), patient cancer history (83%), and patient request (73%). Patients were not referred mainly due to patient disinterest (54%) or physician concern about either insurance coverage (44%) or insurance discrimination (31%). Primary care physicians were less comfortable with identifying patients for referral (p < 0.001) and with discussing genetics (p < 0.002) than specialists. The largest barriers to referral were lack of program awareness and limited knowledge regarding patient eligibility, improved insurance coverage, and antidiscrimination legislation. Physician-targeted marketing and education may improve the referral process.


Supportive Care in Cancer | 2014

Oral alpha-lipoic acid to prevent chemotherapy-induced peripheral neuropathy: a randomized, double-blind, placebo-controlled trial

Ying Guo; Desiree Jones; J. Lynn Palmer; Arthur D. Forman; Shaker R. Dakhil; Maria R. Velasco; Matthias Weiss; Paul Gilman; Glenn Mills; Stephen J. Noga; Cathy Eng; Michael J. Overman; Michael J. Fisch

ObjectivesChemotherapy-induced peripheral neuropathy is frequently a dose-limiting factor in cancer treatment and may cause pain and irreversible function loss in cancer survivors. We tested whether alpha-lipoic acid (ALA) could decrease the severity of peripheral neuropathy symptoms in patients undergoing platinum-based chemotherapy.MethodsCancer patients 18xa0years or older were randomly selected to receive either 600xa0mg ALA or a placebo three times a day orally for 24xa0weeks while receiving chemotherapy regimens including cisplatin or oxaliplatin. Neuropathy was measured by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) scale and the NCI Common Toxicity Criteria for Adverse Events neurotoxicity grades. Results from timed functional tests and the Brief Pain Inventory (BPI) were secondary endpoints.ResultsSeventy of 243 (29xa0%) patients completed the study (24xa0weeks). Both the ALA and the placebo arms had a comparable drop-out rate. No statistically significant differences were found between the ALA and the placebo groups for FACT/GOG-Ntx scores, BPI scores, and patients functional outcomes.ConclusionThis strategy of oral ALA administration was ineffective at preventing neurotoxicity caused by oxaliplatin or cisplatin. High attrition rates due to poor patient compliance and manner of dosage administration in this trial demonstrated a lack of feasibility for this intervention. Future studies to explore ALA as a neuroprotective agent should take heed of the barriers confronted in this study.


Genetic Testing | 2002

Motivations and concerns of women considering genetic testing for breast cancer: a comparison between affected and at-risk probands.

Rachael Brandt; Ellen Hartmann; Zonera Ali; Rosemarie Tucci; Paul Gilman

Since the discovery of the BRCA1 and BRCA2 genes, there has been an increasing demand for breast cancer risk assessment programs. In an effort to understand and serve the population such programs target better, several studies have identified factors influencing high-risk women to pursue breast cancer risk assessment and genetic testing services; none, however, has focused on how the motivations and concerns of at-risk women may differ from their previously affected counterparts, who are typically the initial members of their families to undergo genetic testing. The majority of both previously affected and unaffected women felt that preventative surgery decisions, surveillance practices, the assessment of childrens risks, and increased breast cancer anxiety were more important or very important issues regarding their thoughts about genetic testing. Significantly more affected women deemed family members opinions more or very important (p < 0.01). Opinions concerning insurance and employment discrimination did not vary significantly between groups; however, a larger percentage of affected women felt this issue was of importance. Although all issues above should be addressed with women seeking cancer risk assessment and genetic testing, this research may help health care providers to gain a greater understanding of how the motivators and concerns of high-risk women can differ with personal cancer status so that referral, counseling, and education can be executed optimally.


Frontiers in Oncology | 2018

Indoximod: An Immunometabolic Adjuvant That Empowers T Cell Activity in Cancer

Eric Fox; Thomas Oliver; Melissa Rowe; Sunil Thomas; Yousef Zakharia; Paul Gilman; Alexander J. Muller; George C. Prendergast

Exploding interest in immunometabolism as a source of new cancer therapeutics has been driven in large part by studies of tryptophan catabolism mediated by IDO/TDO enzymes. A chief focus in the field is IDO1, a pro-inflammatory modifier that is widely overexpressed in cancers where it blunts immunosurveillance and enables neovascularization and metastasis. The simple racemic compound 1-methyl-D,L-tryptophan (1MT) is an extensively used probe of IDO/TDO pathways that exerts a variety of complex inhibitory effects. The L isomer of 1MT is a weak substrate for IDO1 and is ascribed the weak inhibitory activity of the racemate on the enzyme. In contrast, the D isomer neither binds nor inhibits the purified IDO1 enzyme. However, clinical development focused on D-1MT (now termed indoximod) due to preclinical cues of its greater anticancer activity and its distinct mechanisms of action. In contrast to direct enzymatic inhibitors of IDO1, indoximod acts downstream of IDO1 to stimulate mTORC1, a convergent effector signaling molecule for all IDO/TDO enzymes, thus possibly lowering risks of drug resistance by IDO1 bypass. In this review, we survey the unique biological and mechanistic features of indoximod as an IDO/TDO pathway inhibitor, including recent clinical findings of its ability to safely enhance various types of cancer therapy, including chemotherapy, chemo-radiotherapy, vaccines, and immune checkpoint therapy. We also review the potential advantages indoximod offers compared to selective IDO1-specific blockade, which preclinical studies and the clinical study ECHO-301 suggest may be bypassed readily by tumors. Indoximod lies at a leading edge of broad-spectrum immunometabolic agents that may act to improve responses to many anticancer modalities, in a manner analogous to vaccine adjuvants that act to boost immunity in settings of infectious disease.


Supportive Care in Cancer | 2017

Preliminary evaluation of a predictive blood assay to identify patients at high risk of chemotherapy-induced nausea

Thomas Kutner; Emily Kunkel; Yue Wang; Kyle George; Erik Zeger; Zonera Ali; George C. Prendergast; Paul Gilman; U. Margaretha Wallon

PurposeThe aim of this study was to test a new blood-based assay for its ability to predict delayed chemotherapy-induced nausea.MethodsBlood drawn from consented patients prior to receiving their first platinum-based therapy was tested for glutathione recycling capacity and normalized to total red cell numbers. This number was used to predict nausea and then compared to patient reported outcomes using the Rotterdam Symptom Check List and medical records.ResultsWe show that the pathways involved in the glutathione recycling are stable for at least 48xa0h and that the test was able to correctly classify the risk of nausea for 89.1xa0% of the patients. The overall incidence of nausea was 21.9xa0% while women had an incidence of 29.6xa0%.ConclusionsThis might be the first objective test to predict delayed nausea for cancer patients receiving highly emetogenic chemotherapy. We believe that this assay could better guide clinicians in their efforts to provide optimal patient-oriented care.


Cancer Research | 2015

Abstract P6-08-54: TIMP-4 is a prognostic and predictive marker in triple-negative breast cancers

U. Margaretha Wallon; Jennifer L Sabol; Vlasta Zemba-Palko; James S DuHadaway; Erica Sutanto-Ward; Zonera Ali; Paul Gilman; Robin M. Ciocca; Ned Z. Carp; George C. Prendergast

BACKGROUND – Tissue inhibitor of metalloproteinase-4 (TIMP-4) is a secreted multi-functional protein associated with poor survival prognosis among early-stage triple-negative breast cancers (TNBC). TNBC represent a highly aggressive form of this disease with an unmet need for effective predictive markers and targeted therapy. Extracellular TIMP-4 binds to the membrane bound tetraspanin CD63 and induces the activation of the tumor promoting PI3K/AKT/mTOR pathway. Here we report that TIMP-4 induced aggressive tumor growth and metastasis can be adverted by directly targeting TIMP-4 using a newly developed monoclonal antibody (mAb) to sequester TIMP-4 and the varied responses to common chemotherapy (CTX) regimen. METHODS – The role of elevated TIMP-4 in TNBC cell behavior was tested in cell culture and animal experiments using the human breast cancer line MDA-MB-468. Cells with or without TIMP-4 added to the medium were used to determine the effects on growth, clonogenic survival and response to chemotherapeutic agents such as adriamycin, Taxol, and the new TIMP-4 mAb. The same cell-line was used to induce tumor growth in nude mice with or without TIMP-4 containing slow-release pellets implanted into the mammary fatpad (mfp). Tumor growth and response to therapy was followed over a six-week period. Lungs, liver, spleen and mfp were collected and analyzed for presence of human cells using a specific anti-human MHC I mAb. Prospectively collected patient samples, in accordance with the IRB approved protocol, were tested for circulating levels of TIMP-4 using a commercially available ELISA assay in samples collected prior to chemotherapy and at each treatment cycle. The medical oncology staff recommended therapy without knowledge of TIMP-4 status. RESULTS – Augmentation of TIMP-4 levels in cell culture medium or the mfp of mice resulted in similar tumor phenotype as in the clinic; fast growing tumors with accelerated disease progression. Elevated TIMP-4 levels in the tumor environment resulted in a 1.5-fold increased growth rate with liver and/or lung metastasis in 25% of animals (N=16). No metastases were found in animals with normal TIMP-4 levels. Treating cell cultures or tumor-bearing mice (i.p. injections) with our TIMP-4 mAb resulted in decelerated growth rate and no detectable metastatic disease in the animals. Results from patient samples demonstrated that circulating TIMP-4 levels in breast cancer patients remain elevated after definitive surgery, indicating that TIMP-4 might continuously stimulate any remaining disseminated tumor cells. Adriamycin containing regiments was the only CTX to suppress the TIMP-4 levels independent of primary tumor size and nodal status. CONCLUSIONS – Based on these clinical and experimental data we suggest that TIMP-4 may represent a prognostic and predictive marker, and a therapeutic target for TNBC patients at highest risk. The presence of TIMP-4 identifies a patient population likely to recur quickly due to continuous activation of the PI3K/AKT/mTOR pathway. Though adriamycin therapy can reduce the TIMP-4 levels, the toxicity of this agent suggests that targeted therapy of the PI3K/AKT pathway and/or a biological therapeutic approach directed against TIMP-4 may be of benefit in this subset of pts and should be further explored. Citation Format: U Margaretha Wallon, Jennifer L Sabol, Vlasta Zemba-Palko, James S DuHadaway, Erica Sutanto-Ward, Zonera A Ali, Paul B Gilman, Robin M Ciocca, Ned Z Carp, George C Prendergast. TIMP-4 is a prognostic and predictive marker in triple-negative breast cancers [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-54.


Molecular Cancer Research | 2013

Abstract B070: TIMP-4 – prognostic marker and treatment target for triple-negative breast cancers

Emily Kunkel; James B. DuHadaway; Erika Sutanto-Ward; Lauren N. Birnhak; Jenny R. Ringqvist; Zonera Ali; Paul Gilman; George C. Prendergast; U. Margaretha Wallon

Background: Tissue inhibitor of metalloproteinase-4 (TIMP-4) is a secreted multi-functional protein associated with poor survival prognosis among early-stage triple-negative breast cancers (TNBC) a . Triple-negative breast cancers (TNBC) represent a highly aggressive form of this disease with few treatment options available. Current standard chemotherapy (CTX) includes taxane or adriamycin based regiments. Extracellular TIMP-4 binds to the membrane bound tetraspanin CD63 and induces the activation of PI3K/AKT/mTOR survival pathway. Here we report that TIMP-4 induced aggressive tumor growth and metastasis can be adverted by targeting TIMP-4 either directly by sequestering extracellular pools of TIMP-4 or indirectly by blocking the activation of downstream survival pathways. Methods: Prospectively collected patient samples, in accordance with the IRB approved protocol, were tested for circulating levels of TIMP-4 using a commercially available ELISA assay in samples from time of surgery and at each treatment cycle. The medical oncology staff recommended therapy without knowledge of TIMP-4 status. The role of elevated TIMP-4 in TNBC cell behavior was tested in cell culture and animal experiments using the human breast cancer line MDA-MB-468. Cells with or without TIMP-4 added to the medium were used to determine the effects on growth, clonogenic survival and response to chemotherapeutic agents such as adriamycin, Taxol, the new anti-TIMP-4 antibody b and the PI3K/AKT/mTOR inhibitor GDC-0941. The same cell-line was used to induce tumor growth in nude mice with or without TIMP-4 containing slow-release pellets implanted into the mammary fatpad (mfp). Tumor growth and response to therapy was followed over a six-week period. Results: Results from patient samples demonstrated that circulating TIMP-4 levels in breast cancer patients remain unaffected after surgical removal of the primary tumor. Adriamycin containing regiments was the only CTX to suppress the TIMP-4 levels independent of primary tumor size and nodal status. Adding TIMP-4 to cell culture medium or the mfp of mice resulted in an 1.5-fold increased tumor growth rate. Elevated TIMP-4 in mice also resulted in liver metastasis in 25% of animals (N=8). In cell cultures, the TIMP-4 induced effects were completely adverted by addition of GDC-0941. Adding the TIMP-4 antibody, to cell culture medium or i.p. injections to mice, resulted in a decelerated growth rate and no metastasis. Conclusions: On the basis of these clinical and experimental data we suggest that TIMP-4 may represent a simple prognostic and predictive marker for TNBC patients at highest risk. The presence of TIMP-4 identifies a patient population likely to recur quickly based on the continuous activation of the PI3K/AKT/mTOR pathway. Though adriamycin therapy can reduce the TIMP-4 levels, the toxicity of this agent suggests that targeted therapy of the PI3K/AKT pathway and/or a biological therapeutic approach directed against TIMP-4 may be of benefit in this subset of pts and should be further explored. a Liss, M et.al. Am. J. Pathol. 2009 b Donover, P et.al. J. Cell. Biochem. 2010 Citation Format: Emily K. Kunkel, James DuHadaway, Erika Sutanto-Ward, Lauren N. Birnhak, Jenny R. Ringqvist, Zonera A. Ali, Paul B. Gilman, George C. Prendergast, U. Margaretha Wallon. TIMP-4 – prognostic marker and treatment target for triple-negative breast cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B070.


Cancer Immunotherapy (Second Edition)#R##N#Immune Suppression and Tumor Growth | 2013

Chapter 12 – Principles of Cytotoxic Chemotherapy

Bradley W. Lash; Paul Gilman

While the use of targeted therapies such as monoclonal antibodies, tyrosine kinase inhibitors and immunotherapies is increasing in medical oncology, the cornerstone of therapy in both the curative and palliative settings remains cytotoxic chemotherapy. This chapter will review the core principles of combination chemotherapy including scheduling, dosing and clinical uses. In addition, a brief overview of resistance to therapy and a general overview of commonly used medications is provided.


Journal of Clinical Oncology | 2005

Cancer genetics evaluation: Barriers to and improvements for referral

Rachael Brandt; Z. Ali; A. Sabel-Soteres; Paul Gilman

6109 Background: Cancer susceptibility testing is now an integral part of cancer risk management. Little information exists regarding physicians’ selection and referral of eligible patients. This study’s purpose was to understand who, why and when physicians refer and to assess comfort with this role. Methods: A survey was sent to 243 physicians identified by specialty as potential referrers to a local cancer genetics program to assess prior awareness of and referral to the program, factors used to determine eligibility, and comfort level identifying suitable patients and discussing genetics. Data analysis was performed using chi-square and independent samples t-tests. Results: The survey was completed by 82 physicians (34%). Only 59% reported program awareness and of these, 80% had previously referred (p<0.0001). Awareness was greater among oncologists, surgeons and gynecologists than primary care physicians (PCP) (p<0.0001). Patients were referred for enhanced risk assessment (88%), improved medical man...


Journal of Clinical Oncology | 2011

A randomized, double-blinded, placebo-controlled trial of oral alpha lipoic acid to prevent platinum-induced polyneuropathy.

Ying Guo; J. L. Palmer; A. Forman; Shaker R. Dakhil; M. R. Velasco; Matthias Weiss; Paul Gilman; Glenn Mills; S. J. Noga; Cathy Eng; Michael J. Overman; Michael J. Fisch

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Zonera Ali

Lankenau Medical Center

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George C. Prendergast

Lankenau Institute for Medical Research

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U. Margaretha Wallon

Lankenau Institute for Medical Research

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Cathy Eng

University of Texas MD Anderson Cancer Center

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Emily Kunkel

Lankenau Medical Center

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Erik Zeger

Lankenau Medical Center

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Margaretha Wallon

Lankenau Institute for Medical Research

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Michael J. Fisch

University of Texas MD Anderson Cancer Center

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