Biomedical subjects

Mark W Kieran

Publications and source records attributed to Mark W Kieran.

At least 19 recordsLinked to original sources

PubMed2006

Identification of fibroblast heterogeneity in the tumor microenvironment.

Tumors are unorganized organs that contain many different cell types. In the recent years, many studies have reported that primary tumors contain fibroblasts/myofibroblasts (carcinoma-associated fibroblasts), mesenchymal cells such as pericytes/mural cells and other vascular smooth muscle cells. Several different markers are used routinely to identify carcinoma-associated fibroblasts (CAFs) such as alpha-smooth muscle actin (alpha-SMA), vimentin, S100A4 protein/fibroblast specific protein-1 (FSP1) and type I collagen. Likewise markers such as platelet derived growth factor receptor-beta (PDGFRbeta) and NG2 chondroitin sulfate proteoglycan (NG2) are used to identify mesenchymal cells such as pericytes and other vasculature associated smooth muscle cells. It is still unknown whether these markers overlap with each other or identify a unique population of cells within the tumor microenvironment. Therefore in the present study we utilized two different mouse models of cancer, the Rip1Tag2 mice that develop progressive pancreatic cancer and an orthotopic 4T1 breast cancer model, to study the overlap between six different mesenchymal markers commonly used in mouse cancer research. Our study demonstrates that among all the markers, S100A4/FSP1 identifies a unique population of fibroblasts with minimal overlap with markers for alphaSMA, PDGFRbeta and NG2. Vimentin and type I collagen are not specific markers for fibroblasts in these tumors. alphaSMA, PDGFRbeta and NG2 significantly overlap with each other in identifying a mixed population of fibroblasts (activated or resting), myofibroblasts, pericytes and vascular smooth muscle cells. Collectively, this study demonstrates that tumor microenvironment associated fibroblasts are a heterogeneous population and thus, the use of alphaSMA or vimentin as the only markers will not identify all the CAFs.

Actins↗

PubMed2006

Phase II study of thalidomide and radiation in children with newly diagnosed brain stem gliomas and glioblastoma multiforme.

A phase II study was conducted to assess the efficacy of administering daily thalidomide concomitantly with radiation and continuing for up to 1 year following radiation in children with brain stem gliomas (BSG) or glioblastoma multiforme (GBM). Secondary objectives were to obtain preliminary evidence of biologic activity of thalidomide and to evaluate toxicities from chronic administration of thalidomide in this population. Thirteen patients (2-14 years old) with newly diagnosed BSG (12 patients) or GBM (one patient) were enrolled between July 1999 and June 2000. All patients received focal radiotherapy to a total dose of 5,580 cGy. Thalidomide was administered once daily beginning on the first day of radiation and continued for 12 months or until the patient came off study. The starting dose was 12 mg/kg (rounded down to the nearest 50 mg) and was increased by 20% weekly, if tolerated, to 24 mg/kg or 1,000 mg (whichever was lower). Advanced imaging techniques and urine and serum analysis for anti-angiogenic markers were performed in some patients in an attempt to correlate changes with clinical effect of therapy. No patients completed the planned 12 months of thalidomide therapy and all have since died of disease progression. The median duration of therapy was 5 months (range 2-11 months). Nine patients came off study for progressive disease (PD), three patients due to toxicity and one patient withdrew consent. Several patients on this study required more extended courses of high dose steroids than would have been otherwise expected for this population due to significant peritumoral edema and necrosis. No consistent pattern emerged from the biologic correlative studies from 11 patients. However, advanced imaging with techniques such as MR spectroscopy, MR perfusion and 18-fluorodeoxyglucose positron emission tomography (FDG-PET) were helpful in distinguishing growing tumor from treatment effect and necrosis in some patients. The median time to progression (TTP) was 5 months (range 2-11 months) and the median time to death (TTD) was 9 months (range 5-17 months). In this small patient sample adding thalidomide to radiation did not improve TTP or TTD from historical controls, however, toxicity appeared to be increased.

Adolescent↗

PubMed2006

AAL881, a novel small molecule inhibitor of RAF and vascular endothelial growth factor receptor activities, blocks the growth of malignant glioma.

Malignant gliomas are highly proliferative and angiogenic cancers resistant to conventional therapies. Although RAS and RAF mutations are uncommon in gliomas, RAS activity is increased in gliomas. Additionally, vascular endothelial growth factor and its cognate receptors are highly expressed in gliomas. We now report that AAL881, a novel low-molecular weight inhibitor of the kinase activities associated with B-RAF, C-RAF (RAF-1), and VEGF receptor-2 (VEGFR2), showed activity against glioma cell lines and xenografts. In culture, AAL881 inhibited the downstream effectors of RAF in a concentration-dependent manner, with inhibition of proliferation associated with a G(1) cell cycle arrest, induction of apoptosis, and decreased colony formation. AAL881 decreased the proliferation of bovine aortic endothelial cells as well as the tumor cell secretion of vascular endothelial growth factor and inhibited the invasion of glioma cells through an artificial extracellular matrix. Orally administered AAL881 was well tolerated with minimal weight loss in non-tumor-bearing mice. Established s.c. human malignant glioma xenografts grown in immunocompromised mice treated with a 10-day course of oral AAL881 exhibited growth delays relative to control tumors, frequently resulting in long-term complete regressions. AAL881 treatment extended the survival of immunocompromised mice bearing orthotopic glioma xenografts compared with placebo controls. The intraparenchymal portions of orthotopic AAL881-treated tumors underwent widespread necrosis consistent with vascular disruption compared with the subarachnoid elements. These effects are distinct from our prior experience with VEGFR2 inhibitors, suggesting that targeting RAF itself or in combination with VEGFR2 induces profound tumor responses in gliomas and may serve as a novel therapeutic approach in patients with malignant gliomas.

Animals↗

PubMed2006

Everyday cognitive function after craniopharyngioma in childhood.

Despite clinical impressions that cognitive complaints are prominent in patients with a history of craniopharyngioma, formal neuropsychologic documentation is inconsistent. This study assessed everyday cognitive complaints and neuropsychologic test performance to evaluate the prevalence of problems and the relationship of these domains to one another in patients treated for craniopharyngioma in childhood or adolescence. Ten patients treated for craniopharyngioma completed measures of everyday cognitive function (Cognitive Failures Questionnaire, Rivermead Behavioural Memory Test) and a battery of standard neuropsychologic tests. The prevalence of problems was ascertained for each measure. Most patients demonstrated significant deficits in everyday memory (Cognitive Failures Questionnaire, 9/10 patients; Rivermead Behavioural Memory Test, 7/10 patients). Scores were within normal limits, however, for intelligence quotient, achievement, attention, verbal memory, and spatial working memory. Processing speed was slow (5/10 patients). Spatial working memory predicted Cognitive Failures Questionnaire (P < 0.07), as did somatic symptoms from the Beck Depression Inventory (P < 0.01), but these associations appeared independent. Adolescents and young adults with treated craniopharyngioma experience deficits in everyday cognitive functions, many involving memory, that are not easily detected by standard neuropsychologic testing. The extent of self-rated cognitive problems is related to spatial working memory and somatic concerns.

Activities of Daily Living↗

PubMed2006

Transverse myelitis after therapy for primitive neuroectodermal tumors.

Traditional therapy for malignant primitive neuroectodermal tumors in children includes surgery, multi-agent chemotherapy, and radiation. Given the poor prognosis with conventional therapy alone, newer treatment approaches have incorporated high-dose chemotherapy followed by autologous stem cell rescue. Treatment with chemotherapy and radiation is not without unanticipated and unwanted side effects. Specifically, radiation-induced damage to the central nervous system can occur, though the frequency is thought to be acceptably low. This report describes two cases of treatment-related transverse myelitis in patients who received induction chemotherapy and craniospinal irradiation followed by high-dose chemotherapy with autologous stem cell rescue. Other patients treated with a similar strategy but different sequence and timing of treatment did not experience symptoms of myelitis, suggesting that the specific timing of radiation in relationship to the chemotherapy may be of critical importance.

Adolescent↗

PubMed2005

ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors.

PURPOSE: Primary central nervous system (CNS) tumors represent a diverse group of tumor types with heterogeneous molecular mechanisms that underlie their formation and maintenance. CNS tumors depend on angiogenesis and often display increased activity of ErbB-associated pathways. Current nonspecific therapies frequently have poor efficacy in many of these tumor types, so there is a pressing need for the development of novel targeted therapies. EXPERIMENTAL DESIGN: ZD6474 is a novel, orally available low molecular weight inhibitor of the kinase activities associated with vascular endothelial growth factor receptor-2 and epidermal growth factor receptor. We hypothesized that ZD6474 may provide benefit in the treatment of several CNS tumor types. RESULTS: In mice bearing established s.c. tumor xenografts of CNS tumors (malignant glioma and ependymoma) or rhabdomyosarcoma, a limited course of ZD6474 treatment produced significant tumor growth delays and a high rate of partial tumor regression in most models examined. Mice with i.c. malignant glioma xenografts treated with ZD6474 experienced a significant prolongation of survival. Tumors from mice treated with ZD6474 displayed a lower proliferative index and disrupted tumor vascularity. Notably, some of these models are insensitive to low molecular weight kinase inhibitors targeting only vascular endothelial growth factor receptor-2 or epidermal growth factor receptor functions, suggesting that the combined disruption of both epidermal growth factor receptor and vascular endothelial growth factor receptor-2 activities may significantly increase tumor control. CONCLUSIONS: In conclusion, ZD6474 shows significant activity against xenograft models of several primary human CNS tumor types. Consideration for clinical development in this disease setting seems warranted.

Animals↗

PubMed2005

Cutaneovisceral angiomatosis with thrombocytopenia.

We describe 10 children with multiple vascular lesions of the skin and gastrointestinal tract associated with sustained, minor thrombocytopenia. In some children, there was involvement of the lung (n = 5), bone (n = 2), liver (n = 1), spleen (n = 1), and muscle (n = 1). The cutaneous lesions were congenital, multifocal, discrete, red-brown and variably blue macules and papules; in 3 children, a large dominant plaque was also present. All children developed hematemesis and/or melena and endoscopic evaluation revealed several to numerous small mucosal lesions that involved all levels of the gastrointestinal tract. Three of 5 children with pulmonary nodules had cough and 1 also had hemoptysis. Biopsies of cutaneous, gastrointestinal, and pulmonary lesions showed thin-walled, blood-filled vascular channels and variable endothelial hyperplasia. The endothelial nuclei were elongated, round, crescentic, or hobnailed. Cytoplasmic and extracellular periodic acid-Schiff positive deposits were often present in the zones of endothelial hyperplasia. The platelets were small in some children, suggesting a primary defect, possibly accounting for the thrombocytopenia. Gastrointestinal hemorrhage and hemoptysis required antiangiogenic therapy. The constellation of findings defines a congenital proliferative disorder of blood vessels with a distinctive microscopic appearance. We have termed this relatively indolent or slowly progressive disorder cutaneovisceral angiomatosis with thrombocytopenia because this designation incorporates its major clinical and histopathologic features.

Angiogenesis Inhibitors↗

PubMed2005

PPARgamma as a therapeutic target for tumor angiogenesis and metastasis.

Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors with pleiotropic effects on cell fate and metabolism. Because of its anti-proliferative, pro-apoptotic and differentiation promoting activities, PPARgamma has been intensively evaluated as a target for anti-cancer therapy in preclinical models. However, PPARgamma has been reported to act both as a promoter and suppressor of neoplasia, and the role of PPARgamma activating ligands as well as antagonists in therapy remains controversial. In the past decade a new picture of tumors as a disease that involves changes in the non-cancerous tumor bed, including angiogenesis, inflammation and other stromal changes has emerged. PPARgamma has strong anti-inflammatory and anti-angiogenic effects, extending the repertoire of potential targets of PPARgamma ligands beyond cell autonomous mechanisms of cancer. The heterogeneous cellular targets and the biphasic effects of PPARgamma on various pro and anti-tumor processes may account for the apparent paradoxical effects of PPARgamma agonists. Here we review the action of PPARgamma agonists on angiogenesis and inflammation in the context of tumorigenesis as an integrated tissue process and discuss potential explanations for the conflicting effects of PPARgamma agonists on tumor progression and metastasis. Sorting out the various modes of action and defining their relative contribution in the context of tumor and host tissue as a heterogeneous target will therefore be crucial to understand the multi facetted effects of PPARgamma. This will be paramount if the potent biological activity of PPARgamma agonists are to be harnessed for cancer therapy.

Angiogenesis Inhibitors↗

PubMed2005

Continuous remission of newly diagnosed and relapsed central nervous system atypical teratoid/rhabdoid tumor.

Atypical teratoid/rhabdoid tumors (AT/RT) are highly malignant lesions of childhood that carry a very poor prognosis. AT/RT can occur in the central nervous system (CNS AT/RT) and disease in this location carries an even worse prognosis with a median survival of 7 months. In spite of multiple treatment regimens consisting of maximal surgical resection (including second look surgery), radiation therapy (focal and craniospinal), and multi-agent intravenous, oral and intrathecal chemotherapy, with or without high-dose therapy and stem cell rescue, only seven long-term survivors of CNS AT/RT have been reported, all in patients with newly diagnosed disease. For this reason, many centers now direct such patients, particularly those under 5 years of age, or those with recurrent disease, towards comfort care rather than attempt curative therapy. We now report on four children, two with newly diagnosed CNS AT/RT and two with progressive disease after multi-agent chemotherapy who are long term survivors (median follow-up of 37 months) using a combination of surgery, radiation therapy, and intensive chemotherapy. The chemotherapy component was modified from the Intergroup Rhabdomyosarcoma Study Group (IRS III) parameningeal protocol as three of the seven reported survivors in the literature were treated using this type of therapy. Our four patients, when added to the three reported survivors in the literature using this approach, suggest that patients provided this aggressive therapy can significantly alter the course of their disease. More importantly, we report on the first two survivors after relapse with multi-agent intravenous and intrathecal chemotherapy treated with this modified regimen.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Anti-angiogenic therapy in pediatric neuro-oncology.

In order to grow, tissues require additional nutrients and oxygen as well as removal of waste products. Tumors achieve this by up-regulating angiogenic cytokines and/or down-regulating natural inhibitory proteins that allow neovascularization to proceed. Brain tumors continue to account for significant morbidity and mortality, in spite of significant advances in neurosurgical and radiation techniques and new chemotherapy combinations. As such, there is a real and immediate need for novel biologic therapies that can target these tumors. A number of new drugs that target different aspects of the angiogenic cascade have been identified and are now in clinical trials in children with primary brain tumors. In many of these pre-clinical and clinical studies, anti-angiogenic therapy has been well tolerated, has lacked many of the traditional toxicities of radiation and chemotherapy, does not require blood-brain barrier penetration, and targets a critical pathway in central nervous system tumor development. This review will discuss what angiogenesis is, how pediatric brain tumors regulate angiogenesis to obtain a vascular supply, what types of inhibitors are available, how different classes of inhibitors work, the types of resistance possible, how rapidly these inhibitors may work, and what surrogate markers of activity are available to follow response.

Angiogenesis Inhibitors↗

PubMed2005

The rationale for nonsteroidal anti-inflammatory drug therapy for inflammatory myofibroblastic tumors: a Children's Oncology Group study.

BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are neoplasms that are highly vascularized, have an intermediate prognosis, and are associated with infiltration, obstruction, local recurrence, and rare metastasis. Resection of large IMTs can lead to substantial morbidity and even mortality. Anecdotal experience suggests that nonsteroidal anti-inflammatory drugs may eradicate large IMTs or shrink them to a more readily resectable size and configuration. To support the hypothesis that nonsteroidal anti-inflammatory drugs are antiangiogenic for IMTs by interfering with vascular endothelial growth factor (VEGF) signaling via cyclooxygenase 2 (COX-2) inhibition, IMT specimens were immunohistochemically examined for expression of COX-2 enzyme and VEGF. METHODS: The diagnosis of IMT was confirmed in all 18 cases comprising the study. Intensity of COX-2 and VEGF staining was graded, and staining uniformity was examined. ALK-1 protein expression, found in up to two thirds of IMTs, was also determined. RESULTS: COX-2 and VEGF expression were identified in all tissue examined, with staining intensity varying independently. ALK-1 protein expression was identified in 33% of specimens. Its presence was not related to the intensity of COX-2 or VEGF staining. CONCLUSIONS: Our data suggest that the mediators of angiogenesis, VEGF and COX-2, are present and may play an important role in the growth of IMTs.

Activin Receptors, Type II↗

PubMed2005

A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer.

Standard chemotherapeutic drugs, when modified by the frequency and dose of administration, can target angiogenesis. This approach is referred to as antiangiogenic chemotherapy, low-dose chemotherapy, or metronomic chemotherapy. This study evaluated the feasibility of 6 months of metronomic chemotherapy, its toxicity and tolerability, surrogate markers of activity, and preliminary evidence of activity in children with recurrent or progressive cancer. Twenty consecutive children were enrolled and received continuous oral thalidomide and celecoxib with alternating oral etoposide and cyclophosphamide every 21 days for a planned duration of 6 months using antiangiogenic doses of all four drugs. Surrogate markers including bFGF, VEGF, endostatin, and thrombospondin were also evaluated. Therapy was well tolerated in this heavily pretreated population. Toxicities (predominantly reversible bone marrow suppression) responded to dose modifications. Sixty percent of the patients received less than the prescribed 6 months of therapy due to toxicity (one case of deep vein thrombosis), personal choice (1 patient), or disease progression (10 patients). Forty percent of the patients completed the 6 months of therapy, resulting in prolonged or persistent disease-free status. One quarter of all patients continue to be progression free more than 123 weeks from starting therapy. Sixteen percent of patients showed a radiographic partial response. Only elevated thrombospondin-1 levels appeared to correlate with prolonged response. This oral antiangiogenic chemotherapy regimen was well tolerated in this heavily pretreated pediatric population, which showed prolonged or persistent disease-free status, supporting the continued study of antiangiogenic/metronomic chemotherapy in human clinical trials.

Administration, Oral↗

PubMed2004

Perfusion MRI of U87 brain tumors in a mouse model.

Continuous arterial spin labeling (CASL) was used to obtain an index of cerebral blood flow (ICBF) in the normal mouse brain and in an orthotopic mouse model of human U87 high-grade glioma at 8.5 T. Under the assumption of a constant tissue:blood partition coefficient for water in different tissues, the mean ICBF (n = 14) was found to be 50 +/- 9 mL/100g/min for tumor core and 209 +/- 11 mL/100g/min for normal tissue. The apparent T(1) (T(1app)) was 2.01 +/- 0.06 sec for tumor core and 1.66 +/- 0.03 sec for normal tissue. The ICBF and the T(1app) values were significantly different (P < 0.001) between these two regions. The detailed changes of ICBF and T(1app) in the transition from the tumor core through the tumor periphery to surrounding tissue were studied. Immunohistochemistry indicated that tumor vascularity was not uniform, with microvessel density highest in normal brain and the tissue surrounding the tumor and lowest in the tumor core. The large difference in ICBF between the tumor core and normal tissue suggests that this index might be useful for the assessment of the efficacy of antiangiogenic therapy.

Animals↗

PubMed2004

Quantification of water diffusion and relaxation times of human U87 tumors in a mouse model.

Assessing the potential of anti-cancer agents can be greatly facilitated by applying MRI methods to investigations with animal models. Quantitative diffusion imaging, T1, and T2 measurements may offer valuable information for understanding properties of the tumor and for evaluating new therapeutic approaches. The human U87 high-grade glial tumor is widely used for cancer investigations in orthotopic murine models. The physiological features of this model at the cellular and sub-cellular level have not, however, been well characterized by MRI. In this study, we measured the diffusion, T1 and T2 characteristics of water in the human U87 tumor at 8.5 T in an orthotopic murine model in vivo and analyzed their detailed changes in the transition from the tumor core through the tumor periphery, and out to surrounding tissue using custom developed radial profile analysis software. For the tumor bearing mice (n = 10), the mean average apparent diffusion coefficient (ADC) of the tumor core was 1.03 +/- 0.02 ( x 10(-3) mm2/s), while in the contralateral normal brain it was 0.73 +/- 0.03 ( x 10(-3) mm2/s). The mean T1 in tumor was 2.03 +/- 0.08 s and in normal brain tissue was 1.64 +/- 0.06 s. The mean T(2) in tumor was 0.062 +/- 0.002 s and in normal brain tissue was 0.048 +/- 0.001 s. The mean ADC, T1 and T2 of the tumor compared to normal tissue were significantly different (p < 0.005).

Animals↗

PubMed2004

Anti-angiogenic chemotherapy in central nervous system tumors.

Primary central nervous system tumors are infrequent lesions observed in both pediatric and adult patients that account for a disproportionate amount of cancer related morbidity and mortality. A significant number of advances in neurosurgical and radiation therapy techniques have occurred over the last few decades and yet only small improvements in long-term outcome have resulted. The major reason for this is the ability of these advances to minimize surgical or radiation morbidity on surrounding normal tissue rather than eradicating the microscopic infiltrating disease that remains after up-front standard therapy. As such, a great deal of effort has gone into adjuvant chemotherapy that might complement the standard surgical and radiation approaches. This paper will review the literature on anti-angiogenic therapies in central nervous system (CNS) tumor models and clinical disease, with a focus on anti-angiogenic chemotherapy (also referred to as metronomic or low-dose chemotherapy) and the utilization of this approach in conjunction with standard radiation and surgery. A number of excellent reviews covering related aspects of this topic are also available (1-13).

Angiogenesis Inhibitors↗

PubMed2004

Treatment of low-grade gliomas in children: an update.

Pediatric low-grade gliomas are a heterogeneous group of tumors that require integration of the pathology and radiographic appearance with the biologic heterogeneity associated with these tumors. Balancing surgery, radiation and chemotherapy to optimize disease control while limiting treatment-related morbidity is of critical importance in this susceptible population and is the focus of this review.

Brain Neoplasms↗

PubMed2003

A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors.

The vast majority of brain tumors in adults exhibit glial characteristics. Brain tumors in children are diverse: Many have neuronal characteristics, whereas others have glial features. Here we show that activation of the Gi protein-coupled receptor CXCR4 is critical for the growth of both malignant neuronal and glial tumors. Systemic administration of CXCR4 antagonist AMD 3100 inhibits growth of intracranial glioblastoma and medulloblastoma xenografts by increasing apoptosis and decreasing the proliferation of tumor cells. This reflects the ability of AMD 3100 to reduce the activation of extracellular signal-regulated kinases 1 and 2 and Akt, all of which are pathways downstream of CXCR4 that promote survival, proliferation, and migration. These studies (i) demonstrate that CXCR4 is critical to the progression of diverse brain malignances and (ii) provide a scientific rationale for clinical evaluation of AMD 3100 in treating both adults and children with malignant brain tumors.

Animals↗

PubMed2003

Psychosocial and behavioral functioning among pediatric brain tumor survivors.

OBJECTIVE: To describe the psychosocial and behavioral functioning, as described by patient, parent and teacher, of a cohort of adolescents who have been previously treated for a brain tumor. METHODS: A cohort of 32 patients, 12-18 years old, were evaluated between 1 and 5 years post-treatment for brain tumor during the patient's regularly scheduled follow-up clinic appointment at the Dana-Farber Cancer Institute. The Self-Report questionnaire and the Parent-Report of the Behavioral Assessment System for Children (BASC) were administered to the patient and to one of the patient's parents, respectively. In addition, the BASC Teacher-Report was completed by the patient's teacher. Descriptive statistics were generated; binomial distribution analyses were carried out to assess whether the proportion of individuals with impaired performance on each measure exceeded normative expectations. RESULTS: Comparison of the proportion of patients with elevated scores to normative expectations indicated no excess of elevated scores on any of the BASC scales of the Self-Report. However, parents endorsed items in the areas of attention problems and leadership; teachers endorsed items concerning learning problems; and both parents and teachers endorsed items indicative of somatization behaviors. CONCLUSIONS: Parent and teacher feedback indicate some level of psychosocial and behavioral morbidity for adolescents treated for a brain tumor; this finding contrasts with adolescent Self-Report indicating no difficulties in behavioral and psychosocial functioning. The extent to which these vulnerabilities impact quality of life and the discrepancy between reporters should be assessed in follow-up studies with a larger cohort of patients.

Adaptation, Psychological↗