Biomedical subjects

Mark Rosen

Publications and source records attributed to Mark Rosen.

12 recordsLinked to original sources

PubMed2006

Identification and optimization of anthranilic sulfonamides as novel, selective cholecystokinin-2 receptor antagonists.

A high throughput screening approach to the identification of selective cholecystokinin-2 receptor (CCK-2R) ligands resulted in the discovery of a novel series of antagonists, represented by 1-[2-[(2,1,3-benzothiadiazol-4-ylsulfonyl)amino]-5-chlorobenzoyl]-piperidine (1; CCK-2R, pK(I) = 6.4). Preliminary exploration of the structure-activity relationships around the anthranilic ring and the amide and sulfonamide moieties led to a nearly 50-fold improvement of receptor affinity and showed a greater than 1000-fold selectivity over the related cholecystokinin-1 receptor. Pharmacokinetic evaluation led to the identification of 4-[4-iodo-2-[(5-quinoxalinylsulfonyl)amino]benzoyl]-morpholine, 26d, a compound that demonstrates promising pharmacokinetic properties in the rat and dog with respect to plasma clearance and oral bioavailability and is a potent inhibitor in vivo of pentagastrin-stimulated acid secretion in the rat when dosed orally.

Animals↗

PubMed2006

Primer on imaging technologies for cancer.

Medical images represent maps of the spatial distribution of tissue properties. Each modality probes a specific set of tissue properties such as x-ray attenuation for computed tomography, transmission of sound for ultrasound, and the rate of glucose uptake for fluorodeoxyglucose-positron emission tomography. Understanding the basic principal underlying each modality is important for developing approaches to utilize imaging in cancer research and clinical care. In addition, each modality has specific challenges related to reliable quantitation that are important to appreciate.

Fluorodeoxyglucose F18↗

PubMed2006

Lack of benefit of pre-transplant locoregional hepatic therapy for hepatocellular cancer in the current MELD era.

The potential for disease progression in patients awaiting liver transplantation for hepatocellular carcinoma (HCC) has encouraged many centers to employ pre-transplant radiofrequency ablation or chemoembolization in an attempt to control tumor burden while patients are on the wait list. Despite general acceptance by the transplant community, few objective data demonstrate pre-transplant treatment efficacy or improved post-transplant outcomes in HCC patients listed with Model for End-Stage Liver Disease (MELD) exception points. To evaluate the utility of pre-transplant therapy in the current MELD era, we retrospectively compared 31 treated patients (T) with 33 untreated (U) controls. Study endpoints included patient and disease-free survival, tumor recurrence, explant tumor viability, and the ability of MRI to detect viable tumor after therapy. Both cohorts had similar demographic, radiographic, and pathologic characteristics, although untreated patients waited longer for transplantation [119 (U) vs. 54 (T) days after MELD assignment, (P = .05); range: 1 day to 21 months]. Only 20% of treated tumors demonstrated complete ablation (necrosis) as defined by histologic examination of the entire lesion. Only 55% of lesions with histologic viable tumor were detected by MRI after pre-transplant therapy. After 36 months of follow-up, there was no difference between the treated and untreated groups in overall survival (84 vs. 91%), disease free survival (74% vs. 85%), cancer recurrence (23% vs. 12%), or mortality from cancer recurrence (57% vs. 25%) (P > 0.1). In conclusion, viable tumor frequently persists after pre-transplant locoregional therapy, and neoadjuvant treatment does not appear to improve post-transplant outcomes in the current MELD era.

Adult↗

PubMed2006

MR imaging and MR spectroscopy in prostate cancer management.

Currently, endorectal coil MR imaging has the ability to improve accuracy in staging of localized prostate cancer. The addition of MR spectroscopic imaging has further improved the sensitivity of MR imaging for intraprostatic tumor localization. Additional refinements and techniques are expected to further improve the performance of MR imaging for prostate cancer imaging and to aid in patient management. Further studies are required to identify the ideal role for MR imaging in the diagnosis and management of prostate cancer.

Contrast Media↗

PubMed2005

MR imaging-guided 9-gauge vacuum-assisted core-needle breast biopsy: initial experience.

PURPOSE: To perform magnetic resonance (MR) imaging-compatible vacuum-assisted 9-gauge core-needle biopsy of suspicious enhancing breast lesions identified at MR imaging. MATERIALS AND METHODS: The institutional review board granted exempt status for this HIPAA-compliant study and waived the requirement for informed consent. The MR imaging-guided 9-gauge vacuum-assisted core-needle biopsy findings of 85 lesions in 75 patients aged 31-89 years were retrospectively reviewed. The biopsies were performed as part of the patients' clinical care with a Food and Drug Administration-approved biopsy system and not within a research protocol. All included patients had received a diagnosis of malignant, benign, or high-risk (for cancer) breast tissue at core-needle biopsy and had undergone subsequent surgery or follow-up imaging. MR imaging-guided biopsy results were compared with final histopathologic or follow-up imaging findings. RESULTS: At MR imaging-guided core-needle biopsy, malignancy was identified in 52 (61%) lesions: 35 invasive cancers and 17 ductal carcinoma in situ (DCIS) lesions. Four (24%) of the 17 DCIS lesions were upgraded to invasive cancer at excisional biopsy or mastectomy. A high-risk lesion (ie, atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, or radial scar) was identified in 18 (21%) cases. Two (25%) of eight atypical ductal hyperplasia lesions were upgraded to DCIS at excision. No malignancy was found in the atypical lobular hyperplasia (n = 2), lobular carcinoma in situ (n = 5), or radial scar (n = 3) lesions. Fifteen (18%) lesions were found to be benign lesions of unknown type at excision or mastectomy. For 13 of these 15 lesions, the benign results were concordant with the imaging findings. Both (two of 86, 2%) discordant cases represented false-negative lesions. The remaining 13 benign lesions were validated at excisional biopsy (n = 9) or follow-up imaging (n = 4). CONCLUSION: Initial experience revealed MR imaging-guided 9-gauge vacuum-assisted core-needle breast biopsy to be a reasonable alternative to MR imaging-guided wire localization of suspicious lesions identified at MR imaging only, on the basis of published information regarding the latter.

Adult↗

PubMed2005

Phase I trial of combretastatin a-4 phosphate with carboplatin.

PURPOSE: Preclinical evidence of synergy led to a phase I trial employing combretastatin A-4 phosphate (CA4P), a novel tubulin-binding antivascular drug, in combination with carboplatin. EXPERIMENTAL DESIGN: Based on preclinical scheduling studies, patients were treated on day 1 of a 21-day cycle. Carboplatin was given as a 30-minute i.v. infusion and CA4P was given 60 minutes later as a 10-minute infusion. RESULTS: Sixteen patients with solid tumors received 40 cycles of therapy at CA4P doses of 27 and 36 mg/m(2) together with carboplatin at area under the concentration-time curve (AUC) values of 4 and 5 mg min/mL. The dose-limiting toxicity of thrombocytopenia halted the dose escalation phase of the study. Four patients were treated at an amended dose level of CA4P of 36 mg/m(2) and carboplatin AUC of 4 mg min/mL although grade 3 neutropenia and thrombocytopenia were still observed. Three lines of evidence are adduced to suggest that a pharmacokinetic interaction between the drugs results in greater thrombocytopenia than anticipated: the carboplatin exposure (as AUC) was greater than predicted; the platelet nadirs were lower than predicted; and the deviation of the carboplatin exposure from predicted was proportional to the AUC of CA4, the active metabolite of CA4P. Patient benefit included six patients with stable disease lasting at least four cycles. CONCLUSION: This study of CA4P and carboplatin given in combination showed dose-limiting thrombocytopenia. Pharmacokinetic/pharmacodynamic modeling permitted the inference that altered carboplatin pharmacokinetics caused the increment in platelet toxicity.

Adult↗

PubMed2005

Graph embedding to improve supervised classification and novel class detection: application to prostate cancer.

Recently there has been a great deal of interest in algorithms for constructing low-dimensional feature-space embeddings of high dimensional data sets in order to visualize inter- and intra-class relationships. In this paper we present a novel application of graph embedding in improving the accuracy of supervised classification schemes, especially in cases where object class labels cannot be reliably ascertained. By refining the initial training set of class labels we seek to improve the prior class distributions and thus classification accuracy. We also present a novel way of visualizing the class embeddings which makes it easy to appreciate inter-class relationships and to infer the presence of new classes which were not part of the original classification. We demonstrate the utility of the method in detecting prostatic adenocarcinoma from high-resolution MRI.

Adenocarcinoma↗

PubMed2004

Liver transplantation for hepatocellular carcinoma validation of present selection criteria in predicting outcome.

Appropriate patient selection is crucial in ensuring acceptable outcomes from orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). The United Network for Organ Sharing (UNOS) has elected to prioritize HCC patients for OLT based on criteria of tumor burden. However, it is unclear whether these criteria correlate with outcome, or with the pathobiological features associated with tumor recurrence. Therefore, we analyzed 109 consecutive patients undergoing OLT for HCC at our center, to determine the utility of present selection criteria in predicting outcome. Pathologic tumor staging of the explanted liver was based on the American Tumor Study Group modified tumor node metastases (pTNM) classification system. Multifocality was defined as >4 tumor nodules on explant. Survival analysis was performed using Kaplan-Meier and Cox proportional hazards regression methods. At a median follow-up of 18.9 months, the overall mortality was 19% with 15 patients (14%) dying of recurrent HCC. Kaplan-Meier 1, 3 and 5-year survival rates were 89.5%, 68%, and 65%, respectively. Recurrence-free rates of 1, 3, and 5 years were 89%, 75%, and 65%, respectively. On univariate analysis, the factors found to be significantly associated with recurrence of HCC were explant features of macrovascular invasion, tumor size (per centimeter increase), pTNM stage (per 1-stage increase), and pre-transplant serum alphafetoprotein (AFP) >300 ng/mL. In defining a threshold level, we found that explant tumor diameter > or =3 cm, and those tumors classified as at least pT3 on pathological examination, were significantly associated with recurrence (P =.01 and.03, respectively). Tumor size on explant was found to be strongly correlated with multifocality (P =.017) and vascular invasion (P =.02). Patients exceeding pathological UNOS criteria were 3.1 times more likely to have recurrence of HCC (P =.03). In conclusion, we found that tumor size appears to be a surrogate marker for negative pathobiological predictors of outcome, i.e., vascular invasion and multifocality. Present UNOS selection criteria for HCC based on tumor burden appear to provide adequate discriminatory power in predicting outcome of OLT.

Adult↗

PubMed2003

Phase I trial of the antivascular agent combretastatin A4 phosphate on a 5-day schedule to patients with cancer: magnetic resonance imaging evidence for altered tumor blood flow.

PURPOSE: Combretastatin A4 (CA4) phosphate (CA4P) inhibits microtubule polymerization and is toxic to proliferating endothelial cells in vitro. It causes reversible vascular shutdown in established tumors in vivo, consistent with an antivascular mechanism of action. The present study investigated escalating doses of CA4P administered intravenously to patients with advanced cancer. PATIENTS AND METHODS: Patients with solid malignancies and good performance status received CA4P as a 10-minute infusion daily for 5 days repeated every 3 weeks. Pharmacokinetic sampling was performed during cycle 1. Patients receiving >/= 52 mg/m2/d had serial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies to measure changes in tumor perfusion with CA4P treatment. RESULTS: Thirty-seven patients received 133 treatment cycles. CA4P dose levels ranged from 6 mg/m2 to 75 mg/m2 daily. Severe pain at sites of known tumor was dose limiting at 75 mg/m2. Dose-limiting cardiopulmonary toxicity (syncope and dyspnea or hypoxia) was noted as well in two patients treated at 75 mg/m2. Other toxicities included hypotension, ataxia, dyspnea, nausea or vomiting, headache, and transient sensory neuropathy. Plasma CA4P and CA4 area under the concentration-time curve and maximal concentration values increased linearly with dose. Tumor perfusion, as measured by the first-order rate constant of gadolinium plasma to tissue transfer during DCE-MRI studies, was found to decrease in eight of 10 patients. Relationships were also demonstrated between perfusion changes and pharmacokinetic indices. A partial response was observed in a patient with metastatic soft tissue sarcoma, and 14 patients exhibited disease stability for a minimum of two cycles. CONCLUSION: Doses of CA4P on a daily times five schedule of 52 to 65 mg/m2 were reasonably well-tolerated. The 52 mg/m2 dose is recommended for further study based on cumulative phase I experience with CA4P. Antitumor efficacy was observed, and the use of DCE-MRI provided a valuable noninvasive measure of the vascular effects of CA4P treatment.

Adult↗

PubMed2003

CEP-701 and CEP-751 inhibit constitutively activated RET tyrosine kinase activity and block medullary thyroid carcinoma cell growth.

All of the cases of medullary thyroid carcinoma (MTC) express the RET receptor tyrosine kinase. In essentially all of the hereditary cases and approximately 40% of the sporadic cases of MTC, the RET kinase is constitutively activated by mutation. This suggests that RET may be an effective therapeutic target for treatment of MTC. We show that the indolocarbazole derivatives, CEP-701 and CEP-751, inhibit RET in MTC cells. These compounds effectively inhibit RET phosphorylation in a dose-dependent manner at concentrations <100 nM in 0.5% serum and at somewhat higher concentrations in the presence of 16% serum. They also blocked the growth of these MTC cells in culture. CEP-751 and its prodrug, CEP-2563, also inhibited tumor growth in MTC cell xenografts. These results show that inhibiting RET can block the growth of MTC cells and may have a therapeutic benefit in MTC.

Animals↗

PubMed2003

Magnetic resonance-defined periportal steatosis following intraportal islet transplantation: a functional footprint of islet graft survival?

There is growing interest in more widespread application of isolated islet transplantation for the treatment of type 1 diabetes; however, the sequelae of long-term islet residence within the liver are unknown. We report herein a consequence of intraportal islet transplantation, specifically the development of periportal hepatic steatosis apparently induced by the local secretion of insulin within the liver.

Follow-Up Studies↗

PubMedDate not supplied

Electrotherapy promotes healing and microcirculation of infrapopliteal ischemic wounds: a prospective pilot study.

OBJECTIVE: To determine if high-voltage pulsed current (HVPC) electrotherapy augments ischemic wound healing and increases periwound microcirculation. DESIGN: A prospective, randomized, single-blinded, sham-controlled clinical trial was conducted on a homogenous subset of quasi-stable ischemic wounds. INTERVENTION: Active HVPC or sham HVPC was applied to wounds for a 14-week period. MAIN OUTCOME MEASURE: Wounds were monitored every 4 weeks, except 2 weeks between weeks 12 and 14, for wound area, wound appearance, and microcirculation, which was measured by transcutaneous oxygen (TcPO2) levels and laser Doppler flow. RESULTS: Ischemic wounds treated with active HVPC decreased in size, contrary to the expected increase in ischemic wound size that was observed in wounds in the control group (P <.05, Student t test; week 4). A trend toward smaller wound area occurred in wounds in the HVPC group compared with wounds in the control group (week 14). Among the HVPC group, an improvement in periwound microcirculation occurred at weeks 8 (P <.05, TcPO2; P <.01, laser Doppler) and 12 (P <.05, laser Doppler). These increases suggest that HVPC promotes arteriolar vasodilation and dermal capillary formation. HVPC was well tolerated. CONCLUSION: The results of this study demonstrate that HVPC decreased the area of ischemic wounds, reversing the expected increase in wound size, and improved microcirculation. The promising results of this pilot study require a larger Phase II study to confirm and generalize these findings. CLINICAL RELEVANCE: Electrotherapy may prove to be a relatively safe and effective complement to surgical revascularization to improve the odds of healing ischemic wounds and promoting limb salvage.

Adult↗