Discovery of ((4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonyl)(propyl)carbamoyloxy)methyl-2-(4-(phosphonooxy)phenyl)acetate (BMS-751324), a Clinical Prodrug of p38α MAP Kinase Inhibitor.

In search for prodrugs to address the issue of pH-dependent solubility and exposure associated with 1 (BMS-582949), a previously disclosed phase II clinical p38α MAP kinase inhibitor, a structurally novel clinical prodrug, 2 (BMS-751324), featuring a carbamoylmethylene linked promoiety containing hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities, was identified. Prodrug 2 was not only stable but also water-soluble under both acidic and neutral conditions. It was effectively bioconverted into parent drug 1 in vivo by alkaline phosphatase and esterase in a stepwise manner, providing higher exposure of 1 compared to its direct administration, especially within higher dose ranges. In a rat LPS-induced TNFα pharmacodynamic model and a rat adjuvant arthritis model, 2 demonstrated similar efficacy to 1. Most importantly, it was shown in clinical studies that prodrug 2 was indeed effective in addressing the pH-dependent absorption issue associated with 1.

Risk of vertebral compression fracture specific to osteolytic renal cell carcinoma spinal metastases after stereotactic body radiotherapy: A multi-institutional study.

PURPOSE: Determine the risk of vertebral compression fracture (VCF) following stereotactic body radiotherapy (SBRT), specific to osteolytic renal cell carcinoma (RCC) spinal metastases, and associated predictive factors. METHODS: 187 RCC osteolytic spinal tumor segments in 116 patients obtained from a multi-institutional pooled database were reviewed. Each segment was evaluated according to the Spinal Instability Neoplastic Score (SINS). RESULTS: The median follow-up was 8.0 months. 34 VCF (34/187, 18%) were observed and median time to VCF was 2.4 months. VCF was observed in 43% (10/23), 24% (4/17) and 14% (20/147) of segments treated with 24Gy/fraction (fx), 20-23Gy/fx and ≤19Gy/fx, respectively. Multivariate analysis identified dose per fx (p=0.005), baseline VCF (p<0.001) and spinal misalignment (p=0.002) as predictors of VCF. Prior conventional radiotherapy (p=0.029) was found to be protective. CONCLUSIONS: 18% of osteolytic RCC spinal metastases fractured post-SBRT. The presence of a baseline fracture, spinal mal-alignment and treatment with ≥20Gy/fx predicted for VCF.

Discovery and preclinical characterization of the cyclopropylindolobenzazepine BMS-791325, a potent allosteric inhibitor of the hepatitis C virus NS5B polymerase.

Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.

Vertebral compression fracture after spine stereotactic body radiotherapy: a multi-institutional analysis with a focus on radiation dose and the spinal instability neoplastic score.

PURPOSE: Vertebral compression fracture (VCF) is increasingly recognized as an adverse event after spine stereotactic body radiotherapy (SBRT). We report a multi-institutional study aimed at clarifying the risk and predictive factors associated with VCF. PATIENTS AND METHODS: A total of 252 patients with 410 spinal segments treated with SBRT were included. The primary outcome was the development of VCF (a new VCF or progression of a baseline VCF). In addition to various patient-, treatment-, and tumor-specific factors, the Spinal Instability Neoplastic Scoring (SINS) system was applied to determine predictive value. RESULTS: The median follow-up was 11.5 months (range, 0.03 to 113 months). The median and mean overall survival rates were 16 and 26 months, respectively. We observed 57 fractures (57 of 410, 14%), with 47% (27 of 57) new fractures and 53% (30 of 57) fracture progression. The median time to VCF was 2.46 months (range, 0.03 to 43.01 months), and 65% occurred within the first 4 months. The 1- and 2-year cumulative incidences of fracture were 12.35% and 13.49%, respectively. Multivariable analysis identified dose per fraction (greatest risk for ≥ 24 Gy v 20 to 23 Gy v ≤ 19 Gy), in addition to three of the six original SINS criteria: baseline VCF, lytic tumor, and spinal deformity, as significant predictors of VCF. CONCLUSION: Caution must be observed when treating with ≥ 20 Gy/fraction, in particular, for patients with lytic tumor, spinal misalignment, and a baseline VCF. Frequent short-term follow-up is required, as nearly two thirds of all VCF occurred within the first 4 months. We also conclude that SINS may have utility in predicting patients at high risk of SBRT-induced VCF.

Probabilities of radiation myelopathy specific to stereotactic body radiation therapy to guide safe practice.

PURPOSE: Dose-volume histogram (DVH) results for 9 cases of post spine stereotactic body radiation therapy (SBRT) radiation myelopathy (RM) are reported and compared with a cohort of 66 spine SBRT patients without RM. METHODS AND MATERIALS: DVH data were centrally analyzed according to the thecal sac point maximum (Pmax) volume, 0.1- to 1-cc volumes in increments of 0.1 cc, and to the 2 cc volume. 2-Gy biologically equivalent doses (nBED) were calculated using an α/ß = 2 Gy (units = Gy(2/2)). For the 2 cohorts, the nBED means and distributions were compared using the t test and Mann-Whitney test, respectively. Significance (P<.05) was defined as concordance of both tests at each specified volume. A logistic regression model was developed to estimate the probability of RM using the dose distribution for a given volume. RESULTS: Significant differences in both the means and distributions at the Pmax and up to the 0.8-cc volume were observed. Concordant significance was greatest for the Pmax volume. At the Pmax volume the fit of the logistic regression model, summarized by the area under the curve, was 0.87. A risk of RM of 5% or less was observed when limiting the thecal sac Pmax volume doses to 12.4 Gy in a single fraction, 17.0 Gy in 2 fractions, 20.3 Gy in 3 fractions, 23.0 Gy in 4 fractions, and 25.3 Gy in 5 fractions. CONCLUSION: We report the first logistic regression model yielding estimates for the probability of human RM specific to SBRT.

Laser interstitial thermal therapy for focal cerebral radiation necrosis: a case report and literature review.

Whole-brain radiotherapy and stereotactic radiosurgery (SRS) play a central role in the treatment of metastatic brain tumors. Radiation necrosis occurs in 5% of patients and can be very difficult to treat. The available treatment options for radiation necrosis include prolonged high-dose corticosteroids, hyperbaric oxygen, anticoagulation, bevacizumab, and surgical resection. We present the first report and results using laser-interstitial thermal therapy (LITT) for medically refractory radionecrosis. A 74-year-old diabetic patient who had a history of non-small cell lung cancer with brain metastases and subsequent treatment with SRS, presented with a focal lesion in the left centrum semiovale with progressively worsening edema. Image findings were consistent with radiation necrosis that was refractory despite prolonged, high-dose steroid therapy. His associated comorbidities obviated alternative interventions and the lesion was not in a location amenable to surgical resection. We used laser thermal ablation to treat the biopsy-proven radionecrosis. The procedure was tolerated well and the patient was discharged 48 hours postoperatively. Imaging at 7-week follow-up showed near complete resolution of the edema and associated mass effect. Additionally, the patient was completely weaned off steroids. To our knowledge this is the first report using LITT for the treatment of focal radiation necrosis. LITT may be an effective treatment modality for patients with medically refractory radiation necrosis with lesions not amenable to surgical decompression.

Reirradiation human spinal cord tolerance for stereotactic body radiotherapy.

PURPOSE: We reviewed the treatment for patients with spine metastases who initially received conventional external beam radiation (EBRT) and were reirradiated with 1-5 fractions of stereotactic body radiotherapy (SBRT) who did or did not subsequently develop radiation myelopathy (RM). METHODS AND MATERIALS: Spinal cord dose-volume histograms (DVHs) for 5 RM patients (5 spinal segments) and 14 no-RM patients (16 spine segments) were based on thecal sac contours at retreatment. Dose to a point within the thecal sac that receives the maximum dose (P(max)), and doses to 0.1-, 1.0-, and 2.0-cc volumes within the thecal sac were reviewed. The biologically effective doses (BED) using α/ß = 2 Gy for late spinal cord toxicity were calculated and normalized to a 2-Gy equivalent dose (nBED = Gy(2/2)). RESULTS: The initial conventional radiotherapy nBED ranged from ~30 to 50 Gy(2/2) (median ~40 Gy(2/2)). The SBRT reirradiation thecal sac mean P(max) nBED in the no-RM group was 20.0 Gy(2/2) (95% confidence interval [CI], 10.8-29.2), which was significantly lower than the corresponding 67.4 Gy(2/2) (95% CI, 51.0-83.9) in the RM group. The mean total P(max) nBED in the no-RM group was 62.3 Gy(2/2) (95% CI, 50.3-74.3), which was significantly lower than the corresponding 105.8 Gy(2/2) (95% CI, 84.3-127.4) in the RM group. The fraction of the total P(max) nBED accounted for by the SBRT P(max) nBED for the RM patients ranged from 0.54 to 0.78 and that for the no-RM patients ranged from 0.04 to 0.53. CONCLUSIONS: SBRT given at least 5 months after conventional palliative radiotherapy with a reirradiation thecal sac P(max) nBED of 20-25 Gy(2/2) appears to be safe provided the total P(max) nBED does not exceed approximately 70 Gy(2/2), and the SBRT thecal sac P(max) nBED comprises no more than approximately 50% of the total nBED.

Relationship between HER2 status and prognosis in women with brain metastases from breast cancer.

PURPOSE: To analyze factors affecting outcomes in breast cancer patients with brain metastases (BM) and characterize the role of HER2 status. METHODS AND MATERIALS: We identified 264 breast cancer patients treated between 1999 and 2008 for BM. HER2 status was known definitively for 172 patients and was used to define cohorts in which survival and risk factors were analyzed. RESULTS: Kaplan-Meier survival analysis demonstrated improved mean overall survival (105.7 vs. 74.3 months, p < 0.02), survival after diagnosis of BM (neurologic survival, NS) (32.2 vs. 18.9 months, p < 0.01), and survival after treatment with stereotactic radiosurgery (RS) (31.3 vs. 14.1, p < 0.01) in HER2+ patients relative to those with HER2- breast cancer. HER2+ status was an independent, positive prognostic factor for survival on univariate and multivariate hazard analysis (hazard ratio: overall survival = 0.66, 0.18; NS = 0.50, 0.34). Additionally, subgroup analysis suggests that stereotactic radiosurgery may be of particular benefit in patients with HER2+ tumors. CONCLUSIONS: Overall survival, NS, and RS are improved in patients with HER2+ tumors, relative to those with HER2- lesions, and HER2 amplification is independently associated with increased survival in patients with BM from breast cancer. Our findings suggest that the prognosis of HER2+ patients may be better than that of otherwise similar patients who are HER2- and that stereotactic radiosurgery may be beneficial for some patients with HER2+ lesions.

Stereotactic body radiotherapy is an effective treatment in reirradiating spinal metastases: current status and practical considerations for safe practice.

Spinal metastases are a relatively common manifestation in advanced cancer patients. Low-dose conventional radiotherapy has long been the mainstay of treatment under the assumption that patients have a limited life expectancy in the order of 3-6 months. However, with new developments in systemic therapies, patients are surviving longer than expected. As the spinal retreatment rates, secondary to conventional radiation, can approach 20-50%, retreatments are likely to be more frequent. Rather than a second course of even lower-dose conventional radiation, spine stereotactic body radiotherapy (SBRT) has been developed predominantly to overcome the limitations of conventional reirradiation. Spine SBRT permits a second course of high-dose radiation aimed at local tumor control while sparing the spinal cord, and other surrounding normal tissues, of a toxic dose. The focus of this review is to provide an overview of reirradiation spine SBRT, and address key issues surrounding safe and effective practice.

Gamma knife stereotactic radiosurgery for the management of incidentally-identified brain metastasis from non-small cell lung cancer.

Initial staging workup of non-small cell lung cancer (NSCLC) patients has led to increased identification of incidental brain metastases in patients who otherwise have minimal or no neurologic symptoms. We present our experience treating these metastases with stereotactic radiosurgery (SRS) alone and compare outcomes to those of patients with brain metastases treated with other strategies. We queried our neuro-oncology and radiation oncology databases for patients with incidentally-identified NSCLC brain metastases treated with upfront SRS alone between 1997 and 2006. We performed a retrospective analysis to evaluate outcomes in these patients. We found 26 patients with incidentally-identified NSCLC brain metastases (KPS 90-100) treated with SRS alone within 60 days of diagnosis of the metastases. These patients underwent SRS at a median 15 days from diagnosis to an average of 1.6 lesions (range: 1-7), with a mean lesion volume of 1.86 cm(3). The median prescription was 24 Gy delivered to the median 53% isodose line. The median survival for these patients was 8.2 months (mean 12.3 months) from diagnosis of brain metastases. Local CNS progression occurred in 2 patients (7.7%, mean 229.7 days). Survival was not statistically different from similar patients treated with whole brain radiotherapy (WBRT) (P = 0.98), WBRT + Surgery (P = 0.07) or WBRT + SRS (P = 0.62). Patients with incidentally-identified NSCLC brain metastases treated with SRS alone may achieve a survival rate comparable to patients managed with other standard therapeutic modalities. Our findings suggest that SRS alone may be a viable therapeutic option for patients with incidentally-discovered NSCLC brain metastases.

Role of stereotactic radiosurgery for multiple (>4) brain metastases.

Stereotactic radiosurgery (SRS) is a very important treatment option for patients with brain metastases. Prospective data supports the use of SRS for patients with 1-4 brain metastases. Although whole brain radiation therapy (WBRT) has been an effective adjunct to SRS and surgery and has also provided effective palliation for many patients with brain metastases, the potential side effects especially neurocognitive function decline has increased the use of SRS alone even for patients with multiple (>4) brain metastases despite data that suggests that tumor progression is worse than the potential neurocognitive effects of WBRT. In addition, current stereotactic radiosurgery machines and techniques allow the delivery of SRS to multiple lesions in an efficient manner. As a result, the optimal management of multiple brain metastases (>4) is becoming more contentious given the lack of prospective data. Until further data is available, a multidisciplinary team of neurosurgeons, radiation oncologists, medical oncologists and medical physicists should work closely together to implement individualized treatment for patients with multiple brain metastases. This paper will review some of the institutional, multi-institutional and randomized trials of SRS for patients with brain metastases, and review the outcomes for patients with multiple (>4) brain metastases treated by SRS and the associated costs.

Phase II trial of ritonavir/lopinavir in patients with progressive or recurrent high-grade gliomas.

Current therapies for recurrent or progressive high-grade gliomas (HGG, WHO grade 3-4) produce a 6-month progression-free survival of only 10-25%. Migration and invasion by HGG is mediated in part by matrix metalloproteases (MMPs) which promote remodeling of the extracellular matrix. Several HIV protease inhibitors (HIVPI) decrease the expression of MMPs in astrocytes and microglia. Given these mechanisms of antitumor activity of HIVPI, we evaluated the efficacy of ritonavir/lopinavir, a combination HIVPI, in patients with progressive or recurrent HGG in an open label phase II trial. Nineteen patients were treated in this study. Patients received ritonavir/lopinavir (400 mg/100 mg) orally twice daily. All patients were treated until progression of disease or unacceptable toxicity. A complete response was seen in one patient (5%). Three patients (16%) had stable disease as the best response. Fifteen patients (79%) had progressive disease. The 6-month progression free survival (PFS(6)) was 11% (2 of 19 patients). Ritonavir/lopinavir was well tolerated in patients with heavily pretreated refractory HGG, and no grade 3 or 4 toxicity was seen. The activity at the dose and schedule used in this study, however, was modest and the study did not meet its efficacy endpoint.

Stereotactic radiosurgery as single-modality treatment of incidentally identified renal cell carcinoma brain metastases.

BACKGROUND: Initial staging evaluation of patients with renal cell carcinoma (RCC) has led increasingly to the diagnosis of brain metastases in patients who are otherwise neurologically asymptomatic. We present our experience treating patients with incidentally identified brain metastases with initial stereotactic radiosurgery (SRS) monotherapy and compare outcomes with those of patients treated at our institution with other strategies and with those reported in the literature. METHODS: We conducted a retrospective outcomes analysis in patients with incidentally identified RCC brain metastasis treated with initial SRS monotherapy. Our radiation oncology and tumor databases were reviewed, identifying 80 patients treated between 1990 and 2006. RESULTS: We found 19 patients with asymptomatic, incidentally identified brain metastasis (KPS, 90-100) treated with SRS monotherapy within 60 days of diagnosis. Stereotactic radiosurgery was performed at a mean of 17.8 days from diagnosis to an average of 3.1 lesions (range, 3-11; mean lesion volume, 1.72 cm(3); mean total volume, 4.53 cm(3)). The mean prescription was 21.3 Gy delivered to the mean 59.97% isodose line. The mean survival for these patients was 21.5 months (median, 12.6 months) and was not statistically different from survival in similar patients treated with other therapeutic modalities. Local control was achieved in 95% of patients; distant central nervous system progression occurred in 79% of patients at a mean of 450 days. CONCLUSIONS: We demonstrate that patients with incidentally identified RCC brain metastases treated with initial SRS monotherapy achieved a survival rate comparable with that of patients managed with standard therapeutic modalities. Our findings suggest that SRS alone is an attractive therapeutic option for patients with incidentally identified brain metastases from RCC.

Covered stents for late postoperative arterial hemorrhage after pancreaticoduodenectomy.

The use of covered stents in treating delayed postoperative hepatic artery hemorrhage after pancreaticoduodenectomy may preserve hepatic arterial flow. The authors report two cases of massive hemorrhage after pancreaticoduodenectomy that were successfully treated with covered stents. Computed tomographic angiography demonstrated postprocedure patency of the hepatic arteries at 13 and 15 months, respectively. When technically feasible, percutaneous placement of stent-grafts may be used as a first-line intervention in delayed hemorrhage after pancreaticoduodenectomy.

Design and synthesis of a G-protein-coupled receptor antagonist library of aryloxyalkanolamines using a polymer-supported acyclic acetal linker.

A G-Protein-coupled receptor-targeted library of aryloxypropanolamines and aryloxybutanolamines was efficiently executed using a novel, polymer-supported acyclic acetal linker, producing compounds in good yields and purities.

Discovery of a tetrazole-based growth hormone secretagogue: 4-(hydroxybutyl)carbamic acid 2-{5-[1-(2-amino-2-methylpropionylamino)-2- benzyloxyethyl]tetrazol-1-yl}ethyl ester (BMS-317180).

A tetrazole-based peptidomimetic 2 (BMS-317180) was discovered as a human growth hormone secretagogue (GHS). Compound 2 is a potent, novel, orally effective GHS that shows an excellent safety profile in preclinical studies. The compound was advanced into clinical development.

Acridone-based inhibitors of inosine 5'-monophosphate dehydrogenase: discovery and SAR leading to the identification of N-(2-(6-(4-ethylpiperazin-1-yl)pyridin-3-yl)propan-2-yl)-2- fluoro-9-oxo-9,10-dihydroacridine-3-carboxamide (BMS-566419).

Inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo synthesis of guanosine nucleotides, catalyzes the irreversible nicotinamide-adenine dinucleotide dependent oxidation of inosine-5'-monophosphate to xanthosine-5'-monophosphate. Mycophenolate Mofetil (MMF), a prodrug of mycophenolic acid, has clinical utility for the treatment of transplant rejection based on its inhibition of IMPDH. The overall clinical benefit of MMF is limited by what is generally believed to be compound-based, dose-limiting gastrointestinal (GI) toxicity that is related to its specific pharmacokinetic characteristics. Thus, development of an IMPDH inhibitor with a novel structure and a different pharmacokinetic profile may reduce the likelihood of GI toxicity and allow for increased efficacy. This article will detail the discovery and SAR leading to a novel and potent acridone-based IMPDH inhibitor 4m and its efficacy and GI tolerability when administered orally in a rat adjuvant arthritis model.

SIBAS: a blood bank information system and its 5-year implementation at Macau.

Automation systems and information technology can greatly help medical facilities to improve their working efficiency and optimize the whole workflow. This article surveys electronic information management in blood donation and transfusion service, and explores the rationale and archetype of blood bank information systems, then exemplifies a successful in-running system-Sistema Integrado de Bancos de Sangue (SIBAS), which is developed by the Institute of Systems and Computer Engineering of Macau (INESC-Macau) in cooperation with the Macau Blood Transfusion Center (CTS-Macau). Its implementation and the related lessons are briefly introduced too. In essence, this article is oriented to serve as a reference of contemporary blood bank information systems.

Discovery and development of 5-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl-methyl]-3-thiophenecarboxylic acid (BMS-587101)--a small molecule antagonist of leukocyte function associated antigen-1.

LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.

Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan- 2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor.

A series of substituted 4-(4-fluoro-1H-indol-5-yloxy)pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of vascular endothelial growth factor receptor-2 kinase is reported. Structure-activity relationship studies revealed that a methyl group at the 5-position and a substituted alkoxy group at the 6-position of the pyrrolo[2,1-f][1,2,4]triazine core gave potent compounds. Biochemical potency, kinase selectivity, and pharmacokinetics of the series were optimized and in vitro safety liabilities were minimized to afford BMS-540215 (12), which demonstrated robust preclinical in vivo activity in human tumor xenograft models. The l-alanine prodrug of 12, BMS-582664 (21), is currently under evaluation in clinical trials for the treatment of solid tumors.