Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors.

Sorafenib is an oral multikinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. It has demonstrated preclinical and clinical activity in several tumor types. Sorafenib 400 mg twice daily (bid) has been approved in several countries worldwide for the treatment of renal cell carcinoma.

CpG island methylation, response to combination chemotherapy, and patient survival in advanced microsatellite stable colorectal carcinoma.

The CpG island methylator phenotype (CIMP) is a distinct epigenetic phenotype in colorectal carcinoma with concordant methylation in multiple promoter CpG islands. The relationship between CpG island methylation and clinical outcomes among colorectal cancer patients treated with chemotherapy has been a controversial subject. Utilizing real-time polymerase chain reaction (PCR; MethyLight technology), we quantified DNA methylation in 13 CpG island loci (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, SOCS1, MINT1, MINT31, IGFBP3, MGMT, and WRN) in 30 metastatic microsatellite stable colorectal carcinomas in phase I/II clinical trials of combination chemotherapy (5-fluorouracil, irinotecan, leucovorin, and gefitinib).

Using a human cardiopulmonary model to study and predict normal and diseased ventricular mechanics, septal interaction, and atrio-ventricular blood flow patterns.

We upgraded our human cardiopulmonary (CP) model with additional data that enables it to more accurately simulate normal physiology. We then tested its ability to explain human disease by changing two parameter values that decrease ventricular compliance, and found that it could predict many of the hemodynamic, gas exchange, and autonomic abnormalities found in patients with left ventricular diastolic dysfunction (LVDD). The newly incorporated information includes high-fidelity pressure tracings simultaneously recorded from the RV and LV of a normal human in a cardiac catheterization laboratory, Doppler echocardiographic inlet flow velocity patterns, measures of right and left ventricular impedance, and atrial volumes.

Ultrasound speckle suppression and edge enhancement using multiscale nonlinear wavelet diffusion.

This paper introduces a novel multiscale nonlinear wavelet diffusion (MNWD) method for ultrasound speckle suppression and edge enhancement. It considers wavelet diffusion as an approximation to nonlinear diffusion within the framework of the dyadic wavelet transform. Consequently, this knowledge is exploited in the design of a speckle suppression filter with an edge enhancement feature.

Ultrasonic speckle suppression using robust nonlinear wavelet diffusion for LV volume quantification.

This work proposes a novel speckle suppression method, called robust nonlinear wavelet diffusion. It shows that the log-transformed speckle can be approximated by Gaussian noise contaminated with long burst outliers. Consequently, we exploit this knowledge to design a speckle suppression filter within the framework of wavelet analysis.

A model of the respiratory central pattern generator.

We have developed a model of the mammalian respiratory central pattern generator (rCPG) to mimic the salient characteristics of its constituent medullary neurons. This model was designed as a network of Hodgkin-Huxley type medullary neurons under the hypothesis that synaptic and network effects predominate over ionic influences in determining the pattern of firing seen in individual neurons. After obtaining satisfactory mimicry of these patterns we validated the model to a different set of data in order to examine its robustness in the face of transient perturbations.

A closed-loop model of the ovine cardiovascular system.

We develop a closed-loop model of the ovine cardiovascular system, with the long term goal of developing a platform for simulating the hemodynamic efficacy of cardiopulmonary assist devices implanted and tested in this animal. The modeling of the systemic circulation is distributed and divided into subsystem circulations. Nonlinear aspects of the systemic venous system are included, such as the pressure-volume relation (PVR) of the systemic veins.

Phase I study of gefitinib, irinotecan, 5-fluorouracil and leucovorin in patients with metastatic colorectal cancer.

Purpose: To determine the maximum tolerated doses (MTD), toxicities, efficacy, and pharmacokinetics (PK) of gefitinib combined with irinotecan, 5-fluorouracil (5-FU) and leucovorin (IFL) in patients with previously untreated advanced colorectal cancer.

Experimental Design: Starting doses were gefitinib 250 mg/day orally without interruption, irinotecan 100 mg/m(2) as a 90 min intravenous (i.v.

Fatal sporotrichosis.

Disseminated sporotrichosis is a serious fungal infection caused by the soil inhabitant Sporothrix schenckii. It is seen in immunocompromised patients, with a substantial number of recent cases involving patients with acquired immunodeficiency syndrome (AIDS). However, individuals with other conditions that affect the immune system also are at increased risk.

Phase I clinical trial of bortezomib in combination with gemcitabine in patients with advanced solid tumors.

Background: Bortezomib is the first proteasome inhibitor to show preliminary evidence of activity against solid tumors. Findings from preclinical studies prompted a Phase I trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of bortezomib in combination with gemcitabine in patients with recurring/refractory advanced solid tumors. The effect of gemcitabine on proteasome inhibition by bortezomib in whole blood was also investigated.

Phase I study of gefitinib plus FOLFIRI in previously untreated patients with metastatic colorectal cancer.

Background: In this study, the maximum tolerated dose and toxicity profile of FOLFIRI (infusional fluorouracil [5-FU]/leucovorin/irinotecan) plus gefitinib (an oral inhibitor of the epidermal growth factor receptor) were evaluated as first-line therapy in patients with metastatic colorectal cancer.

Patients And Methods: Sixteen patients participated in this study. Oral gefitinib was administered at 250 mg or 500 mg daily in 2 dose-escalation cohorts.

Hemodynamic analysis and design of a paracorporeal artificial lung device.

We have extended our model of the ovine pulmonary circulation to include a model of a paracorporeal artificial lung (AL) and its attachments to the natural pulmonary circulation in two configurations: in series and in parallel. Our model of the natural lung (NL) circulation is first shown to be in agreement with hemodynamic and input impedance data from the open literature. We then study design efficacy of the AL in terms of its housing and attachments.

A phase II trial of irinotecan and cisplatin in patients with metastatic neuroendocrine tumors.

The role of systemic chemotherapy in the treatment of patients with metastatic neuroendocrine tumors is controversial. While combination regimens containing cisplatin and etoposide have activity against more aggressive neuroendocrine tumor variants, such regimens appear to have little efficacy in patients with well-differentiated neuroendocrine tumor subtypes. The combination of irinotecan and cisplatin is active both against small cell lung cancer and in upper gastrointestinal malignancies but has not been prospectively evaluated in patients with metastatic neuroendocrine tumors.

A motion-incorporated reconstruction method for gated PET studies.

Cardiac and respiratory motion artefacts in PET imaging have been traditionally resolved by acquiring the data in gated mode. However, gated PET images are usually characterized by high noise content due to their low photon statistics. In this paper, we present a novel 4D model for the PET imaging system, which can incorporate motion information to generate a motion-free image with all acquired data.

Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas.

Purpose: Specific activating mutations within the epidermal growth factor receptor (EGFR) identify a subset of non-small cell lung cancers with dramatic sensitivity to the specific tyrosine kinase inhibitors (TKI), gefitinib and erlotinib. Despite the abundant expression of EGFR protein in a broad range of epithelial cancers, EGFR mutations have not been reported in a substantial fraction of other cancers. Given recent reports of TKI-responsive cases of esophageal and pancreatic cancer, this study was designed to determine the prevalence of EGFR mutations in these gastrointestinal cancers.

A phase II study of doxorubicin, cisplatin, and 5-fluorouracil in patients with advanced adenocarcinoma of the stomach or esophagus.

Background: The combination of epirubicin, cisplatin, and infusional 5-fluorouracil (ECF) currently represents a standard and effective regimen for the treatment of advanced gastroesophageal cancer. The use of doxorubicin as an alternative to epirubicin in the ECF regimen has not been evaluated.

Methods: Thirty-two patients with metastatic adenocarcinoma of the stomach, gastroesophageal junction, or esophagus were treated with cisplatin 60 mg/m2 and doxorubicin 30 mg/m2 repeated every 21 days, in combination with infusional 5-fluorouracil 200 mg/m2/day (ACF).

Efficacy of cetuximab after treatment with oral epidermal growth factor receptor tyrosine kinase inhibitor-based chemotherapy in metastatic colorectal cancer.

Purpose: We studied the efficacy of cetuximab therapy in patients with metastatic colorectal cancer (mCRC) previously treated with an oral inhibitor of the tyrosine kinase domain of the epidermal growth factor receptor.

Patients And Methods: We reviewed the posttrial records of 73 patients with mCRC who participated in 1 of 3 clinical trials that examined a combination of gefitinib or erlotinib with standard cytotoxic chemotherapy. Medical and pharmacy records were used to identify patients who were subsequently treated with cetuximab-based therapy.

Phase I and pharmacokinetic study of S-1 administered for 14 days in a 21-day cycle in patients with advanced upper gastrointestinal cancer.

Purpose: S-1 is a novel oral fluoropyrimidine that combines tegafur with CDHP and oxonic acid. To decrease the incidence of late onset, severe diarrhea observed in a previous study, a phase I study was conducted to determine the maximum tolerated dose (MTD) of S-1 utilizing a 14-day schedule, repeated every 21 days, in patients with chemotherapy-refractory upper gastrointestinal malignancies.

Methods: S-1 was administered orally, twice-daily, at an initial dose level of 30 mg/m2/dose; doses were escalated by 5 mg/m2 at each level.

Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma.

Purpose: Hepatocellular carcinoma (HCC) is a vascular tumor with poor prognosis. Given the reported activity of gemcitabine and oxaliplatin (GEMOX) in HCC and the potential benefits of targeting the vascular endothelial growth factor pathway with bevacizumab (B), a phase II study of GEMOX-B was undertaken to define efficacy and toxicity profiles in HCC patients.

Patients And Methods: Eligible patients had pathologically proven measurable unresectable or metastatic HCC.

Phase II study of capecitabine, oxaliplatin, and erlotinib in previously treated patients with metastastic colorectal cancer.

Purpose: To investigate the combination of erlotinib, capecitabine, and oxaliplatin in patients who were previously treated for metastatic colorectal cancer.

Patients And Methods: Patients were eligible if they had metastatic colorectal cancer that progressed, were intolerant to first-line chemotherapy, or had disease recurrence within 1 year of adjuvant therapy for early-stage disease. Each 21-day cycle consisted of daily oral erlotinib at 150 mg, oral capecitabine at 1,000 mg/m2 (reduced to 750 mg/m2 after the first 13 patients) twice a day on days 1 to 14, and intravenous oxaliplatin at 130 mg/m2 on day 1.

Nonlinear multiscale wavelet diffusion for speckle suppression and edge enhancement in ultrasound images.

This paper introduces a novel nonlinear multiscale wavelet diffusion method for ultrasound speckle suppression and edge enhancement. This method is designed to utilize the favorable denoising properties of two frequently used techniques: the sparsity and multiresolution properties of the wavelet, and the iterative edge enhancement feature of nonlinear diffusion. With fully exploited knowledge of speckle image models, the edges of images are detected using normalized wavelet modulus.

The combination of capecitabine and thalidomide in previously treated, refractory metastatic colorectal cancer.

Background: With the increasing survival of patients with metastatic colorectal cancer (CRC) there is a growing need for effective second- and third-line agents. We conducted a multicenter, phase II study to examine the combination of capecitabine and thalidomide (Cape/Thal) in patients with refractory metastatic CRC.

Methods: Patients with previously treated stage IV CRC were eligible.

Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: Is rash associated with treatment outcome?

In this analysis of the safety and efficacy of BAY 43-9006 (sorafenib) -- a novel, oral multi-kinase inhibitor with effects on tumour and its vasculature -- pooled data were obtained from four phase I dose-escalation trials. Time to progression (TTP) was compared in patients with/without grade 2 skin toxicity/diarrhoea. Grade 3 hand-foot skin reactions (HFS; 8%) and diarrhoea (6%) were common.

Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors.

Purpose: Standard, intravenous chemotherapy regimens for neuroendocrine tumors have been associated with limited response rates and significant toxicity. We evaluated the efficacy of an oral regimen of temozolomide and thalidomide in patients with metastatic carcinoid, pheochromocytoma, or pancreatic neuroendocrine tumors.

Patients And Methods: Twenty-nine patients were treated with a combination of temozolomide, administered at a dose of 150 mg/m2 for 7 days, every other week, and thalidomide at doses of 50 to 400 mg daily.