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Dive into the research topics where Daniel M. Geynisman is active.

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Featured researches published by Daniel M. Geynisman.


Clinical Cancer Research | 2005

Plasmalemmal Vesicle Associated Protein-1 Is a Novel Marker Implicated in Brain Tumor Angiogenesis

Eleanor B. Carson-Walter; Jessica Hampton; Eveline H. Shue; Daniel M. Geynisman; Pramod Kumar Pillai; Ramasri Sathanoori; Stephen L. Madden; Ronald L. Hamilton; Kevin A. Walter

Purpose:Plasmalemmal vesicle associated protein-1 (PV-1) is up-regulated in the endothelium of human glioblastoma. We sought to further characterize the expression pattern of PV-1 in human brain tumors and interrogate its role in brain tumor angiogenesis. Experimental Design: Quantitative reverse transcription-PCR and in situ hybridization were used to measure PV-1 expression in a panel of 46 human brain tumors and related pathologic states. Matrigel tubulogenesis assays and cell migration assays were used to show function of PV-1 in primary human endothelial cells (HMVEC) under gene knockdown conditions. Results:PV-1 is selectively up-regulated in a variety of high-grade human brain tumors, including glioblastoma and metastatic carcinoma, as well as other cerebral disorders associated with blood-brain barrier disruption, such as acute ischemia. Expression levels were reduced in low-grade neoplasia; however, tumors associated with the ependyma and choroid plexus, known sites of PV-1 expression, also exhibited robust expression. Cerebral expression of PV-1 mRNA was confined to endothelial cells in all cases. PV-1 expression was induced in HMVEC cells in vitro by exposure to medium conditioned by U87MG and U251MG human brain tumor cell lines and by medium supplemented with exogenous vascular endothelial growth factor or scatter factor/hepatocyte growth factor. RNA interference–mediated inhibition of PV-1 induction in HMVEC cells blocked Matrigel-induced tubulogenesis and inhibited cell migration induced by conditioned medium or angiogenic growth factors. Conclusions: Our results confirm that PV-1 is preferentially induced in the endothelium of high-grade human brain tumors. Inhibition of PV-1 expression is associated with failure of endothelial differentiation in vitro. PV-1 represents a novel marker of brain tumor angiogenesis and integrity of the blood-brain barrier and is a potential therapeutic target.


Journal of Clinical Oncology | 2015

Trends in the Cost and Use of Targeted Cancer Therapies for the Privately Insured Nonelderly: 2001 to 2011.

Ya Chen Tina Shih; Fabrice Smieliauskas; Daniel M. Geynisman; Ronan J. Kelly; Thomas J. Smith

PURPOSE This study sought to define and identify drivers of trends in cost and use of targeted therapeutics among privately insured nonelderly patients with cancer receiving chemotherapy between 2001 and 2011. METHODS We classified oncology drugs as targeted oral anticancer medications, targeted intravenous anticancer medications, and all others. Using the LifeLink Health Plan Claims Database, we studied and disaggregated trends in use and in insurance and out-of-pocket payments per patient per month and during the first year of chemotherapy. RESULTS We found a large increase in the use of targeted intravenous anticancer medications and a gradual increase in targeted oral anticancer medications; targeted therapies accounted for 63% of all chemotherapy expenditures in 2011. Insurance payments per patient per month and in the first year of chemotherapy for targeted oral anticancer medications more than doubled in 10 years, surpassing payments for targeted intravenous anticancer medications, which remained fairly constant throughout. Substitution toward targeted therapies and growth in drug prices both at launch and postlaunch contributed to payer spending growth. Out-of-pocket spending for targeted oral anticancer medications was ≤ half of the amount for targeted intravenous anticancer medications. CONCLUSION Targeted therapies now dominate anticancer drug spending. More aggressive management of pharmacy benefits for targeted oral anticancer medications and payment reform for injectable drugs hold promise. Restraining the rapid rise in spending will require more than current oral drug parity laws, such as value-based insurance that makes the benefits and costs transparent and involves the patient directly in the choice of treatment.


International Journal of Cancer | 2015

Tumor genome analysis includes germline genome: Are we ready for surprises?

Daniel V.T. Catenacci; Andrea Louise Amico; Sarah M. Nielsen; Daniel M. Geynisman; Brittany Rambo; George B. Carey; Cassandra Gulden; Jim Fackenthal; Robert Marsh; Hedy L. Kindler; Olufunmilayo I. Olopade

We sought to describe the spectrum of potential and confirmed germline genomic events incidentally identified during routine medium‐throughput somatic tumor DNA sequencing, and to provide a framework for pre‐ and post‐test consent and counseling for patients and families. Targeted tumor‐only next‐generation sequencing (NGS) had been used to evaluate for possible druggable genomic events obtained from consecutive new patients with metastatic gastroesophageal, hepatobiliary or colorectal cancer seen at the University of Chicago. A panel of medical oncologists, cancer geneticists and genetic counselors retrospectively grouped these patients (N = 111) based on probability of possessing a potentially inherited mutation in a cancer susceptibility gene, both prior to and after incorporating tumor‐only NGS results. High‐risk patients (determined from NGS results) were contacted and counseled in person by a genetic counselor (N = 21). When possible and indicated, germline genetic testing was offered. Of 8 evaluable high‐risk patients, 7 underwent germline testing. Three (37.5%) had confirmed actionable germline mutations (all in the BRCA2 gene). NGS offers promise, but poses significant challenges for oncologists who are ill prepared to handle incidental findings that have clinical implications for at risk family members. In this relatively small cohort of patients undergoing tumor genomic testing for gastrointestinal malignancies, we incidentally identified 3 BRCA2 mutations carriers. This report underscores the need for oncologists to develop a framework for pre‐ and post‐test communication of risks to patients undergoing routine tumor‐only sequencing.


Nature Reviews Nephrology | 2015

The hallmarks of cancer: relevance to the pathogenesis of polycystic kidney disease

Tamina Seeger-Nukpezah; Daniel M. Geynisman; Anna S. Nikonova; Thomas Benzing; Erica A. Golemis

Autosomal dominant polycystic kidney disease (ADPKD) is a progressive inherited disorder in which renal tissue is gradually replaced with fluid-filled cysts, giving rise to chronic kidney disease (CKD) and progressive loss of renal function. ADPKD is also associated with liver ductal cysts, hypertension, chronic pain and extra-renal problems such as cerebral aneurysms. Intriguingly, improved understanding of the signalling and pathological derangements characteristic of ADPKD has revealed marked similarities to those of solid tumours, even though the gross presentation of tumours and the greater morbidity and mortality associated with tumour invasion and metastasis would initially suggest entirely different disease processes. The commonalities between ADPKD and cancer are provocative, particularly in the context of recent preclinical and clinical studies of ADPKD that have shown promise with drugs that were originally developed for cancer. The potential therapeutic benefit of such repurposing has led us to review in detail the pathological features of ADPKD through the lens of the defined, classic hallmarks of cancer. In addition, we have evaluated features typical of ADPKD, and determined whether evidence supports the presence of such features in cancer cells. This analysis, which places pathological processes in the context of defined signalling pathways and approved signalling inhibitors, highlights potential avenues for further research and therapeutic exploitation in both diseases.


European Urology | 2015

Anti-programmed Cell Death Protein 1 (PD-1) Antibody Nivolumab Leads to a Dramatic and Rapid Response in Papillary Renal Cell Carcinoma with Sarcomatoid and Rhabdoid Features

Daniel M. Geynisman

We report on a 34-yr-old man with no medical history who presented in September 2014 with night sweats, fevers, bilateral pulmonary masses, extensive bony disease, and a left renal mass of 4.3 cm 4.1 cm. A lung biopsy showed poorly differentiated carcinoma with rhabdoid features consistent with high-grade renal cell carcinoma (RCC). Therapy with carboplatin and gemcitabine was initiated for palliative reasons, but a subsequent biopsy of the renal mass revealed papillary RCC with sarcomatoid and rhabdoid features. Genomic profiling revealed alterations in FAT1, as well as a number of variants of unknown significance (VUS) including DICER1, FANCL, SPTA1 and WISP3; most interestingly, a PBRM1 VUS was noted. After a brief clinical improvement on cytotoxic chemotherapy, the patient’s disease progressed and sunitinib was initiated at first alone and then with gemcitabine. Unfortunately, rapid progression once again occurred. ByMarch 2015 the patient was on 30 mg of long-acting morphine twice daily, as well as a short-acting narcotic for breakthrough pain. His performance statuswas rapidly declining and subcutaneous lesions were appearing. At that point we decided to treat the patient with the anti-programmed cell death protein 1 (PD-1) antibody nivolumab, as it was felt that no other standard therapy targeting vascular endothelial growth factor (VEGF) or mammalian target of rapamycin would be helpful given the rapidly progressive nature of his disease. At 3 wk after a single dose of nivolumab at 0.3 mg/kg, the patient felt dramatically better, with dissipation of all pain and discontinuation of all narcotics, improvement in laboratory values and energy, and disappearance of all subcutaneous lesions. After three doses of nivolumab, the patient’s hemoglobin increased from 10.5 to 14.3 g/dl, thrombocytosis resolved from 489 to 190 k/ml, and C-reactive protein decreased from 67.8 mg/dl in October 2014 to 0.7 mg/dl. Radiographic studies with magnetic resonance imaging and computed tomography before and after nivolumab demonstrated significant improvement in pulmonary, subcutaneous, and bony lesions (Fig. 1). No adverse reactions to nivolumab have occurred so far and the patient is working full time. Immunotherapy is rapidly being integrated into oncology practice and is poised to alter the therapeutic landscape for a variety of malignancies [1]. In RCC, single-agent and combination checkpoint inhibitor trials are either completed or under way, with promising results already published or presented [2]. Importantly, thus far all checkpoint inhibitor trials in RCC have required at least some clear cell component for enrollment [3], and patients with pure non–clear cell (NCC) histology have been excluded. In the patient described here, a PBRM1 variantwas noted. PBRM1 is a tumor suppressor gene that is mutated in approximately 40–50% of clear cell RCCs [4], but was only noted in 3% of papillary RCC patients in one analysis [5]. Thus, although no VHL alteration was reported and no response to a VEGF inhibitor was observed, it is possible that the patient has an aggressive form of clear cell RCC and not papillary RCC as histologically determined. Nevertheless, he would not have been eligible for any current clinical trial and the papillary histology was confirmed by two separate institutions. Previous analysis of tumor samples from 50 patients with papillary RCC demonstrated PD-1 ligand (PD-L1) positivity ranging from 10% to 60% depending on whether tumor cells or immune infiltrating cells were evaluated [6]. Other NCC subtypes such as chromophobe and translocation Xp11.2 type also express PD-L1. In clear cell RCC and other tumor types, although PD-L1 positivity is not required for a response, it appears to lead to a higher likelihood of benefit from anti-PD-1 therapy. Given the PDL1 expression in NCC RCC and clinical observations such as EU RO P E AN URO L OG Y 6 8 ( 2 0 1 5 ) 9 1 2 – 9 1 5


Journal for ImmunoTherapy of Cancer | 2013

A randomized pilot phase I study of modified carcinoembryonic antigen (CEA) peptide (CAP1-6D)/montanide/GM-CSF-vaccine in patients with pancreatic adenocarcinoma

Daniel M. Geynisman; Yuanyuan Zha; Rangesh Kunnavakkam; Mebea Aklilu; Daniel V.T. Catenacci; Blase N. Polite; Cara A. Rosenbaum; Azadeh Namakydoust; Theodore Karrison; Thomas F. Gajewski; Hedy L. Kindler

BackgroundCEA is expressed in >90% of pancreatic cancers (PC) and may be an appropriate immunotherapy target. CEA is poorly immunogenic due to immune tolerance; CAP1-6D, an altered peptide ligand can help bypass tolerance. We conducted a pilot randomized phase I trial in PC patients to determine the peptide dose required to induce an optimal CD8+ T cell response.MethodsPatients with a PS 0-1, HLA-A2+ and CEA-expressing, previously-treated PC were randomized to receive 10 μg (arm A), 100 μg (arm B) or 1000 μg (arm C) of CEA peptide emulsified in Montanide and GM-CSF, given every 2 weeks until disease progression.ResultsSixty-six patients were screened and 19 enrolled of whom 14 received at least 3 doses of the vaccine and thus evaluated for the primary immunologic endpoint. A median of 4 cycles (range 1-81) was delivered. Median and mean peak IFN-γ T cell response by ELISPOT (spots per 104 CD8+ cells, Arm A/B/C) was 11/52/271 (A vs. C, p = 0.028) for medians and 37/148/248 (A vs. C, p = 0.032) for means. T cell responses developed or increased in 20%/60%/100% of pts in Arms A/B/C. Seven of the 19 patients remain alive at a minimum 32 months from trial initiation, including three with unresectable disease.ConclusionsThe T cell response in this randomized phase I trial was dose-dependent with the 1 mg CEA peptide dose eliciting the most robust T cell responses. A signal of clinical benefit was observed and no significant toxicity was noted. Further evaluation of 1 mg CEA peptide with stronger adjuvants, and/or combined with agents to overcome immune inhibitory pathways, may be warranted in PC pts.Trial registrationClinicalTrials.gov NCT00203892


Clinical Genitourinary Cancer | 2015

Treatment Patterns and Costs for Metastatic Renal Cell Carcinoma Patients With Private Insurance in the United States

Daniel M. Geynisman; Jim C. Hu; Lei Liu; Ya Chen Tina Shih

BACKGROUND To evaluate the evolution of treatment patterns and associated costs for metastatic renal cell carcinoma (mRCC) in the United States. MATERIALS AND METHODS The LifeLink Health Plan Claims Database was used to create a cohort of mRCC patients with at least 12 months of continuous enrollment from 2004 to 2011. We summarized treatment patterns over time; we used a nonparametric bootstrapping method to compare costs and logistic regression to examine the association between the likelihood of advancing to third-line therapy and beyond and the number of targeted therapy agents available. RESULTS A total of 1527 mRCC patients were analyzed. In 2010, nine unique treatment regimens were used for first-line treatment, 8 for second-line treatment, and 8 for third-line treatment. A significant association (odds ratio 1.26; P = .001) between the odds of advancing to third-line therapy or beyond and the number of targeted agents available was noted. For 767 patients receiving modern therapy who were < 65 years old, and stratifying by whether the first-line treatment was oral or intravenous, drug cost per patient with ancillary services was


Therapeutic Advances in Urology | 2015

Muscle-invasive urothelial bladder cancer: an update on systemic therapy

Hayley Knollman; J. Luke Godwin; Rishi Jain; Yu-Ning Wong; Elizabeth R. Plimack; Daniel M. Geynisman

59,664 versus


Human Vaccines & Immunotherapeutics | 2014

Economic evaluation of therapeutic cancer vaccines and immunotherapy: A systematic review

Daniel M. Geynisman; Chun Ru Chien; Fabrice Smieliauskas; Chan Shen; Ya Chen Tina Shih

86,518, respectively (P = .001). Total costs and drug out-of-pocket costs per patient during the first year increased by the number of switches:


Current Treatment Options in Oncology | 2017

Checkpoint Inhibitors for the Treatment of Renal Cell Carcinoma

Pooja Ghatalia; Matthew Zibelman; Daniel M. Geynisman; Elizabeth R. Plimack

111,680 to

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Yu-Ning Wong

Fox Chase Cancer Center

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