Diagnostic implications of neuroimaging in epilepsy and other seizure disorders.

Epilepsy is the most common neurological disorder that affects ~1-2% of the global population, leading to presentation in the emergency room. The neuroimaging modalities have an important application in diagnosing new onset unprovoked seizures and epilepsy. This article discusses the various neuroimaging modalities for diagnosing seizures and epilepsy and addresses that the MRI is the investigation of choice, and urgent imaging is more commonly done by computed tomography in patients with new-onset seizures. The goal of the article was to diagnose seizures and epilepsy for early intervention to prevent complications or damage to the brain. MRI detects even small cortical epileptogenic lesions, whereas computed tomography is used in screening, diagnosis, evaluation, and monitoring of the prognosis of seizures in children. Magnetic resonance spectroscopy provides biochemical measurements of reduced N-acetyl aspartate and increased creatinine and choline in dysfunctioning epileptic zones. Volumetric MRI is very sensitive and specific in determining seizures originating in extratemporal and extrahippocampal sites. Even though diffusion tensor magnetic resonance imaging has a limited role, it is used in specific pediatric patient groups with temporal lobe epilepsy. Functional radionuclide imaging modalities (positron emission tomography and single-photon emission computerized tomography) are increasingly significant for the identification of the epileptic region. Furthermore, the authors recommend the use of artificial intelligence and further research on imaging modalities for early diagnosis of seizures and epilepsy.

Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors represent the standard of care in patients with EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). The availability of several EGFR tyrosine kinase inhibitors approved for use in the first-line or later settings in NSCLC warrants an in-depth understanding of the pharmacological properties of, and clinical data supporting, these agents. The second-generation, irreversible ErbB-family blocker, afatinib, has been extensively studied in the context of EGFRm+ NSCLC. Results from the LUX-Lung 3 and 6 studies showed that afatinib was more active and better tolerated than chemotherapy in patients with tumors harboring EGFR mutations. Subanalysis of these trials, along with real-world data, indicates that afatinib is active in patients with certain uncommon EGFR mutations (S768I/G719X/L861Q) as well as common mutations (Del19/L858R), and in patients with active brain metastases. In LUX-Lung 7, a head-to-head phase IIb trial, afatinib improved progression-free survival and time-to-treatment failure versus the first-generation reversible EGFR tyrosine kinase inhibitor, gefitinib, albeit with a higher incidence of serious treatment-related adverse events. Nevertheless, afatinib is generally well tolerated, and adverse events are manageable through supportive care and a well-defined tolerability-guided dose adjustment scheme. In this review, we provide a detailed overview of the pharmacology, efficacy, and safety of afatinib, discuss treatment sequencing strategies following emergence of different resistance mechanisms, and shed light on the economic impact of afatinib. We also provide a comparison of afatinib with the available EGFR tyrosine kinase inhibitors and discuss its position within treatment strategies for patients with EGFRm+ NSCLC.

The Role of Pharmacists in Managing Adverse Events Related to Immune Checkpoint Inhibitor Therapy.

OBJECTIVE: To provide an overview of immune checkpoint inhibitor (ICI) therapy-associated immune-related adverse events (irAEs) and their management, focusing on the key responsibilities for pharmacists in recognizing, distinguishing, and treating irAEs and in educating patients about irAEs and their management. DATA SOURCES: Literature published from January 2000 to March 2018 available from online sources. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language studies, guidelines, and articles. DATA SYNTHESIS: ICI therapies have been approved for the treatment of several cancers as single-agent therapies, combined ICI therapies, or in combination with other agents. ICI therapies increase the activity of the immune system and consequently can have autoimmune-like adverse effects that are often termed irAEs. irAE management can be challenging as irAEs can vary in their frequency and severity among patients, according to the specific agent, and can occur at any time during treatment or after therapy discontinuation. Additionally, for patients treated with ICI therapies in combination with other therapies, ICI-associated irAEs must be distinguished from adverse events associated with chemotherapy or targeted therapies, which often require different management. Pharmacists can provide essential support to diagnose and manage irAEs. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Early and accurate diagnosis and prompt management of irAEs by pharmacists are critical to reduce the risk of severe or life-threatening complications and prevent premature ICI discontinuation. CONCLUSIONS: Pharmacists have a key role in the recognition, monitoring, and management of irAEs and in educating patients about irAEs associated with ICI therapies and the agents used to manage them.

Pharmacist perspectives and considerations for implementation of therapeutic oncology biosimilars in practice.

PURPOSE: An overview of therapeutic oncology biosimilars, the U.S. biosimilars regulatory pathway, and the clinical development of selected biosimilar products is provided, including discussion of considerations in adopting biosimilars into oncology practice. SUMMARY: Biosimilars are biologic agents that are highly similar to and have no clinically meaningful differences from an approved reference product in terms of safety, purity, and potency. There is a large market for cancer biologics, and approval of biosimilars has the potential to increase access to care and reduce costs. An abbreviated regulatory pathway for the development and approval of biosimilars defines a stepwise approach to demonstrating biosimilarity and conducting clinical comparative trials to confirm equivalent pharmacokinetics, efficacy, safety, and immunogenicity to the reference product. Three therapeutic biologics (bevacizumab, trastuzumab, and rituximab) have been used extensively in the treatment of a variety of cancers and are targets for biosimilar product development. Preclinical and clinical experience with 2 recently approved biosimilars to bevacizumab and trastuzumab is reviewed. Challenges faced by pharmacy and therapeutics committees when considering oncology biosimilars for formulary inclusion are discussed. CONCLUSION: Increased adoption of biosimilars could potentially lower treatment costs and improve access to biologics for patients with cancer. Key considerations in formulary review of biosimilars include the quality and quantity of data from comparative clinical trials, economic factors, manufacturer reliability, and challenges associated with incorporating biosimilars into practice.

Clinical pharmacology of oncology agents in older adults: A comprehensive review of how chronologic and functional age can influence treatment-related effects.

Unique challenges exist when managing older adults with cancer. Associations between cancer and age-related physiologic changes have a direct impact on pharmacokinetics and pharmacodynamics of cancer therapies and can affect drug dosing, dose intensity, efficacy, safety and quality of life. The breadth and depth of these issues, however, have not been fully evaluated because the majority of clinical trials have focused on a younger and healthier population. As a consequence, little information is available to support clinicians in making evidence-based decisions regarding treatment with cancer therapies in older adults, especially those over age 75. Prior clinical pharmacology reviews summarized the literature on how age-related physiologic changes can influence and affect conventional and targeted anti-cancer treatments. Our article provides an updated review with expanded information that includes small molecule kinase inhibitors, monoclonal antibodies, immunotherapies, hormonal, conventional, and miscellaneous agents. Additionally, our article integrates how functional age, determined by the geriatric assessment (GA), can also influence treatment-related effects and health outcomes. Broadening cancer therapy trials to capture not only chronologic age but also functional age would allow clinicians to better identify subsets of older adults who benefit from treatment versus those most vulnerable to morbidity and/or mortality.

Systemic hypersensitivity to fosaprepitant - A report of two cases.

Fosaprepitant is a widely administered antiemetic used mainly for moderately to highly emetogenic chemotherapy. Local injection site reactions are the most common type of infusion reaction reported from fosaprepitant. At our institution, two separate patients have experienced systemic hypersensitivity reactions to their infusions of fosaprepitant. We report a review of the literature and the details of these reactions.

Transcriptome profiling of aging Drosophila photoreceptors reveals gene expression trends that correlate with visual senescence.

BACKGROUND: Aging is associated with functional decline of neurons and increased incidence of both neurodegenerative and ocular disease. Photoreceptor neurons in Drosophila melanogaster provide a powerful model for studying the molecular changes involved in functional senescence of neurons since decreased visual behavior precedes retinal degeneration. Here, we sought to identify gene expression changes and the genomic features of differentially regulated genes in photoreceptors that contribute to visual senescence. RESULTS: To identify gene expression changes that could lead to visual senescence, we characterized the aging transcriptome of Drosophila sensory neurons highly enriched for photoreceptors. We profiled the nuclear transcriptome of genetically-labeled photoreceptors over a 40 day time course and identified increased expression of genes involved in stress and DNA damage response, and decreased expression of genes required for neuronal function. We further show that combinations of promoter motifs robustly identify age-regulated genes, suggesting that transcription factors are important in driving expression changes in aging photoreceptors. However, long, highly expressed and heavily spliced genes are also more likely to be downregulated with age, indicating that other mechanisms could contribute to expression changes at these genes. Lastly, we identify that circular RNAs (circRNAs) strongly increase during aging in photoreceptors. CONCLUSIONS: Overall, we identified changes in gene expression in aging Drosophila photoreceptors that could account for visual senescence. Further, we show that genomic features predict these age-related changes, suggesting potential mechanisms that could be targeted to slow the rate of age-associated visual decline.

Inverse-collimated proton radiography for imaging thin materials.

Relativistic, magnetically focused proton radiography was invented at Los Alamos National Laboratory using the 800 MeV LANSCE beam and is inherently well-suited to imaging dense objects, at areal densities >20 g cm-2. However, if the unscattered portion of the transmitted beam is removed at the Fourier plane through inverse-collimation, this system becomes highly sensitive to very thin media, of areal densities <100 mg cm-2. Here, this inverse-collimation scheme is described in detail and demonstrated by imaging Xe gas with a shockwave generated by an aluminum plate compressing the gas at Mach 8.8. With a 5-mrad inverse collimator, an areal density change of just 49 mg cm-2 across the shock front is discernible with a contrast-to-noise ratio of 3. Geant4 modeling of idealized and realistic proton transports can guide the design of inverse-collimators optimized for specific experimental conditions and show that this technique performs better for thin targets with reduced incident proton beam emittance. This work increases the range of areal densities to which the system is sensitive to span from ∼25 mg cm-2 to 100 g cm-2, exceeding three orders of magnitude. This enables the simultaneous imaging of a dense system as well as thin jets and ejecta material that are otherwise difficult to characterize with high-energy proton radiography.

Board-Certified Oncology Pharmacists: Their Potential Contribution to Reducing a Shortfall in Oncology Patient Visits.

PURPOSE: With an aging US population, the number of patients who need cancer treatment will increase significantly by 2020. On the basis of a predicted shortage of oncology physicians, nonphysician health care practitioners will need to fill the shortfall in oncology patient visits, and nurse practitioners and physician assistants have already been identified for this purpose. This study proposes that appropriately trained oncology pharmacists can also contribute. The purpose of this study is to estimate the supply of Board of Pharmacy Specialties-certified oncology pharmacists (BCOPs) and their potential contribution to the care of patients with cancer through 2020. METHODS: Data regarding accredited oncology pharmacy residencies, new BCOPs, and total BCOPs were used to estimate oncology residencies, new BCOPs, and total BCOPs through 2020. A Delphi panel process was used to estimate patient visits, identify patient care services that BCOPs could provide, and study limitations. RESULTS: By 2020, there will be an estimated 3,639 BCOPs, and approximately 62% of BCOPs will have completed accredited oncology pharmacy residencies. Delphi panelists came to consensus (at least 80% agreement) on eight patient care services that BCOPs could provide. Although the estimates given by our model indicate that BCOPs could provide 5 to 7 million 30-minute patient visits annually, sensitivity analysis, based on factors that could reduce potential visit availability resulted in 2.5 to 3.5 million visits by 2020 with the addition of BCOPs to the health care team. CONCLUSION: BCOPs can contribute to a projected shortfall in needed patient visits for cancer treatment. BCOPs, along with nurse practitioners and physician assistants could substantially reduce, but likely not eliminate, the shortfall of providers needed for oncology patient visits.

PD-1 Pathway Inhibitors: Immuno-Oncology Agents for Restoring Antitumor Immune Responses.

Immune checkpoint inhibitors are designed to restore a patient's own antitumor immune response that has been suppressed during tumor development. The first monoclonal antibodies against the immune checkpoint programmed death 1 (PD-1) receptor, nivolumab and pembrolizumab, are now approved for clinical use. Both agents are indicated for the treatment of advanced melanoma, as well as for the treatment of metastatic non-small cell lung cancer (NSCLC). Nivolumab is also approved for the treatment of advanced renal cell carcinoma. In patients with melanoma, these agents result in objective response rates of ~25-40%, with durable responses lasting more than 2 years in some cases. Results from phase III trials have shown improved survival with nivolumab versus standard-of-care chemotherapy in both patients with advanced melanoma and those with advanced NSCLC. In patients with advanced melanoma, both PD-1 inhibitors (nivolumab and pembrolizumab) have shown improved survival versus ipilimumab. PD-1 inhibitors are associated with adverse events that have immune etiologies, with grade greater than 3 adverse events typically reported in 16% or less of patients. However, most immune-mediated adverse events (including grade 3-4 adverse events) can be managed by using published management algorithms without permanent discontinuation of the agent. As nivolumab and pembrolizumab enter the clinic, and with more PD-1 pathway agents in development for a range of tumor types, this review aims to provide pharmacists with a basic understanding of the role of PD-1 in modulating the immune system and their use in the cancer treatment. The most recent clinical efficacy and safety data are discussed, highlighting the response characteristics distinctive to immune checkpoint inhibitors, along with pharmacokinetic and pharmacodynamic data and cost considerations.

Cetuximab hypersensitivity infusion reactions: Incidence and risk factors.

INTRODUCTION: Cetuximab is a chimeric mouse-human (30:70) IgG1 monoclonal antibody that competitively inhibits the binding of epidermal growth factor. Cetuximab is generally well tolerated; however, hypersensitivity infusion reactions have been reported. The incidence at the University of Oklahoma was currently unknown, though anecdotally high. The purpose of this study was to determine the incidence of severe HIRs and secondarily to determine risk factors for cetuximab-induced hypersensitivity infusion reactions. METHODS AND RESULTS: A retrospective chart review was conducted and included all patients that received cetuximab from 2005 to 2010 at the outpatient clinics of the Oklahoma University Health Sciences Center. A total of 153 patients were included in the analysis. The overall incidence proportion of severe hypersensitivity infusion reactions was 12.4%. Male patients had an increased incidence of severe hypersensitivity infusion reactions compared to female patients (20.6% vs. 5%, p = 0.0036). Current smokers had an increased incidence of severe hypersensitivity infusion reactions of 23.6% when compared to never smokers or former smokers, p = 0.0012. Cervical cancer had a significantly decreased risk of severe hypersensitivity infusion reactions when compared to other tumor types (5.3% vs. 16.7%, p = 0.0387). Multivariate analysis identified risk factors associated with severe HIRs to be: male gender, RR = 3.9, p = 0.01 and current smokers, RR = 3.98, p = 0.0048. CONCLUSION: Patients at the University of Oklahoma had an increased incidence of severe hypersensitivity infusion reactions when compared to the national average. Male patients and current smokers were found to be at increased risk for severe hypersensitivity infusion reactions in our study. Further investigation is warranted.

Severe infusion reactions to brentuximab vedotin in two patients with Hodgkin lymphoma previously treated with allogeneic stem cell transplantation.

Brentuximab vendotin is a monoclonal antibody approved in August 2011 for use in patients with Hodgkin disease and a rare systemic lymphoma known as anaplastic large cell lymphoma. Brentuximab is approved in patients with Hodgkin disease who have failed autologous transplantation or after failure of at least two prior multi-agent chemotherapy regimens but has not been studied following allogeneic transplantation. Four patients with relapsed Hodgkin disease have been treated at our institution with at least two doses of brentuximab vendotin. Two patients have experienced significant infusion reactions on multiple occasions, and two patients have tolerated the infusions well. During phase 2 trials, there were no reports of Grade 3 or 4 infusion-related reactions. Both patients with reactions had relapsed following allogeneic stem cell transplants, while neither of the patients who tolerated the infusions had undergone transplantation. We report our experience with brentuximab vendotin-treated patients at our institution, focusing on the two post-allogeneic patients who experienced multiple significant infusion reactions. This report evaluates possible mechanisms behind their reactions, including previous allogeneic stem cell transplantation as a likely precipitating factor.

Mammalian target of rapamycin: biological function and target for novel anticancer agents.

PURPOSE: The biological function of the mammalian target of rapamycin (mTOR) and mechanisms of action of mTOR inhibitors currently available for clinical use are described. SUMMARY: mTOR is a target for anticancer agents due to its role in cancer development, progression, and resistance to other antineoplastic agents. Currently, two mTOR inhibitors, temsirolimus and everolimus, are approved for the treatment of patients with advanced renal cell carcinoma (RCC). Clinical trials comparing single-agent temsirolimus with interferon alfa-2a demonstrated an improvement in overall survival and progression-free survival (PFS) in patients with metastatic RCC. Clinical studies comparing everolimus with placebo indicated improved PFS in advanced RCC patients whose disease had progressed on or after vascular endothelial growth factor (VEGF) inhibitor therapy. Due to its role in the phosphatidylinositol 3-kinase (PI3K) signaling pathway, mTOR is a rational target for inhibition in combination with other agents, including traditional chemotherapy and agents that are affected by or target the PI3K pathway. Data from these studies review the use of mTOR inhibitors in non-Hodgkin's lymphoma and endometrial, breast, and neuroendocrine tumors. Common toxicities of mTOR inhibitors include mucositis, stomatitis, rash, asthenia, fatigue, and myelosuppression. Additional toxicities requiring monitoring include hyperglycemia, hyperlipidemia, and pneumonitis. CONCLUSION: The mTOR signaling pathway is upregulated in a variety of solid and hematologic tumors. Two inhibitors of this pathway, temsirolimus and everolimus, have been approved for use in metastatic RCC. Although relatively safe, these drugs are associated with some unique adverse effects, such as hyperlipidemia, hyperglycemia, and pneumonitis, that require monitoring and may require clinical intervention.

Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases.

BACKGROUND: Lapatinib, the first dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinases, was approved by the US Food and Drug Administration (FDA) in 2007. It is indicated for use in combination with capecitabine for the treatment of patients with advanced breast cancer or metastatic breast cancer (MBC) whose tumors overexpress HER2 (ErbB2) and who have received previous treatment that included an anthracycline, a taxane, and trastuzumab. OBJECTIVE: This review summarizes the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of lapatinib, and its current and potential role in the treatment of breast cancer and other malignancies. METHODS: Relevant English-language publications were identified through searches of MEDLINE (1966-May 2008),the American Society of Clinical Oncology abstracts database (2000-2007), abstracts from the San Antonio Breast Cancer Symposium (2005-2007), and the FDA Web site (January 2008). Search terms included lapatinib, GW572016, HER2, EGFR, receptor tyrosine kinase, dual-receptor blockade, adverse events, and clinical trials. RESULTS: The T(max) of lapatinib after oral administration is 3 to 4 hours. Dividing the dose or administering it with food, particularly a high-fat meal, increases the AUC >2-fold. Lapatinib is metabolized primarily by the cytochrome P450 3A4 isozyme, with 1 metabolite remaining active against EGFR but not HER2. Due to drug accumulation, the t(1/2) of lapatinib is 24 hours with continuous dosing. In a Phase III trial comparing lapatinib and capecitabine with capecitabine alone in women with HER2-positive, locally advanced breast cancer or MBC that had progressed after treatment with an anthracycline, a taxane, and trastuzumab, the combination of lapatinib and capecitabine was associated with a numeric improvement in response rate compared with capecitabine alone (22% vs 14%, respectively; P = NS) and a significant increase in time to progression (6.2 vs 4.3 months; hazard ratio = 0.57; 95% CI, 0.43-0.77; P < 0.001). Lapatinib has been reported to have antitumor activity in Phase II trials when used as first-line therapy for MBC, in patients with inflammatory breast cancer, and in patients with central nervous system metastases. Phase II trials in other solid tumor types found modest activity. The approved dosing of lapatinib is 1,250 mg PO QD given continuously in combination with capecitabine 2,000 mg/m(2) daily administered in 2 divided doses on days 1 to 14 of a 21-day cycle. The most common clinical toxicities of all grades associated with lapatinib used in combination with capecitabine in the pivotal clinical trial were diarrhea (65%), hand-foot syndrome (53%), nausea (44%), rash (29%), and fatigue (24%). Cardiac toxicity appears to be less frequent with lapatinib than with trastuzumab. CONCLUSIONS: Lapatinib is a dual inhibitor of the EGFR and HER2 tyrosine kinases. It is approved by the FDA for use in combination with capecitabine for the treatment of HER2-positive MBC that has progressed with standard treatment. In clinical trials, this combination was associated with a significant improvement in the time to progression in patients with MBC. Lapatinib's efficacy in other malignancies that overexpress EGFR and/or HER2 is under evaluation.

Use of prescription and nonprescription medications and supplements by cancer patients during chemotherapy: questionnaire validation.

BACKGROUND: Cancer patients take medications for coexisting disease and self-medicate with over-the-counter drugs (OTCs). A complete analysis of the use of prescription drugs, OTCs, and supplements during cancer treatment has never been done. METHODS: The study developed and validated a self-administered questionnaire on the use of concomitant medications by patients undergoing treatment with chemotherapy. The questionnaire listed 510 prescription medications, OTCs, and supplements (including vitamins, minerals, and herbs). Fifty-two subjects completed the questionnaire while visiting the infusion clinic to receive chemotherapy. On a subsequent visit the subjects brought their medications to the clinic and a pharmacist reviewed their completed questionnaire. RESULTS: Ninety-six percent of the subjects reported taking prescription medications within 3 days prior to chemotherapy, 71% reported taking OTCs and 69% reported use of supplements. The subjects took an average of 5.5 (range 0-13) prescription drugs, 2.2 (0-20) OTCs, and 1.9 (0-11) supplements. Twenty-one drugs were each taken by at least 10% of the subjects. Acetaminophen was taken by 59.6% of the subjects. One subject reported taking five acetaminophen-containing drugs. The questionnaire's sensitivity was 92.0%, specificity 99.9%. CONCLUSION: Within 3 days prior to chemotherapy, subjects took an average of 9.6 concomitant medications, many of which alter drug metabolism and or disposition. In clinical trials, multivariate analysis of all concomitant medications could add to clinically relevant data to identify drug interactions that negate or potentiate the efficacy of cancer treatment regimens. In some instances, apparent resistance of tumors to chemotherapy may be the result of drug interactions.

Use of an audience response system (ARS) in a dual-campus classroom environment.

OBJECTIVES: To implement an audience response system in a dual-campus classroom that aggregated data during graded (attendance and quizzes) and non-graded classroom activities (formative quizzes, case discussions, examination reviews, and team activities) and explore its strengths, weaknesses, and impact on active learning. DESIGN: After extensive research, an appropriate audience response system was selected and implemented in a dual-classroom setting for a third-year required PharmD course. Students were assigned a clicker and training and policies regarding clicker use were reviewed. Activities involving clicker use were carefully planned to simultaneously engage students in both classrooms in real time. Focus groups were conducted with students to gather outcomes data. ASSESSMENT: Students and faculty members felt that the immediate feedback the automated response system (ARS) provided was most beneficial during non-graded activities. Student anxiety increased with use of ARS during graded activities due to fears regarding technology failure, user error, and academic integrity. SUMMARY: ARS is a viable tool for increasing active learning in a doctor of pharmacy (PharmD) program, especially when used for non-graded class activities. Faculty members should proceed cautiously with using ARS for graded classroom activities and develop detailed and documented policies for ARS use.

Clinical and biological activity of soy protein powder supplementation in healthy male volunteers.

PURPOSE: To determine if a commonly used soy protein supplement exhibits biological activity in vivo and in vitro, we evaluated an over-the-counter soy protein powder supplement using blood from healthy male volunteers and in an estrogen receptor in vitro assay. SUBJECTS AND METHODS: We recruited healthy male volunteers 18 years of age or older that were in good health. Treatment consisted of consuming two scoops (56 g) of pure soy protein powder (Puritan's Pride, Oakdale, NY) daily for 28 days. Serum testosterone and luteinizing hormone (LH) levels were collected on days -7, 0, 14, and 28 of therapy, and day 42. A reporter estrogen receptor (ER) assay was used to determine the effect on ER-beta and ER-alpha in vitro. RESULTS: Twelve subjects were enrolled with a mean age of 32.25 years (range 25 to 47). Serum testosterone decreased 19%(+/-22%) during the 4-week use of soy protein powder (P = 0.021) and increased within 2 weeks after we discontinued soy protein powder. Serum LH concentrations decreased during the 4-week use of soy protein powder then increased within 2 weeks after we stopped the soy protein powder, but the changes did not reach statistical significance (P = 0.20). Soy protein powder was found to induce agonist activity to ER-beta using a reporter estrogen receptor assay in yeast. CONCLUSION: Soy protein powder decreases serum testosterone levels in healthy men and acts as an ER-beta agonist; the significance of this biological effect with respect to cancer prevention needs further study.

Effect of docetaxel in patients with hormone-dependent prostate-specific antigen progression after local therapy for prostate cancer.

PURPOSE: To evaluate docetaxel in the treatment of patients with early-stage prostate cancer with prostate-specific antigen (PSA) progression after local therapy without androgen ablation therapy. PATIENTS AND METHODS: Twenty-five patients with adenocarcinoma of the prostate with PSA progression despite local therapy were treated with 70 mg/m2 docetaxel every 21 days. Treatment was planned for eight cycles. Patients were followed up for effects on PSA, testosterone, and toxicity. RESULTS: Twenty-three of 25 patients completed at least one full cycle of therapy. Ten (43%) of 23 patients demonstrated a decrease in PSA by > or = 50% for at least 4 weeks. The nadir decrease in PSA occurred beyond 150 days of therapy in most patients. Therapy was well tolerated. Grade 4 neutropenia with fever occurred in only six cycles (4.5%). Two patients required 25% dose reductions, both occurring with cycle 6, secondary to increased transaminases in one patient, and grade 3 lacrimation in the other patient. Two patients were removed after the first cycle of therapy due to toxicity (deep venous thrombosis, chest palpitations). Mean testosterone levels were not reduced in 17 patients assessed before and during therapy (P = .12). CONCLUSION: This study demonstrated the activity of docetaxel alone, without androgen ablation, in patients with PSA progression after completion of local therapy. Treatment with docetaxel in this population with early disease progression was well tolerated, biochemically active, and was not androgen ablative. Accrual to national phase III studies in early disease is now critical and should be strongly encouraged to determine the ability of early chemotherapy to improve survival.

Bevacizumab: an angiogenesis inhibitor with efficacy in colorectal and other malignancies.

OBJECTIVE: To review the pharmacology, pharmacokinetics, and pivotal clinical trials for bevacizumab, emphasizing its use in colorectal cancer. DATA SOURCES: A PubMed/MEDLINE search was conducted (1966-April 2004) using the following terms: bevacizumab, Avastin, anti-VEGF, anti-angiogenesis, and colorectal cancer. Additional data sources included meeting abstracts, bibliographies from identified articles, and information from the manufacturer. STUDY SELECTION AND DATA EXTRACTION: Preclinical and clinical trials that used bevacizumab for the treatment of colorectal cancer and other malignancies were selected from the data sources. All published, randomized clinical trials evaluating bevacizumab in colorectal cancer were included in this review. DATA SYNTHESIS: Despite advances in chemotherapy, current therapeutic options for metastatic disease provide only temporary benefit for most patients. Bevacizumab is the first anti-cancer agent shown to provide benefit for patients with cancer by inhibiting angiogenesis. Bevacizumab has shown significant activity in the treatment of many cancers, including metastatic colorectal cancer. When used in combination with fluorouracil-based chemotherapy, bevacizumab improves overall response rates, time to progression, and survival in patients with metastatic colorectal cancer. Common toxicities associated with bevacizumab include hypertension, bleeding episodes, and thrombotic events. CONCLUSIONS: Although clinical knowledge on the effectiveness of bevacizumab is limited, early data indicate that it is a promising agent, with a novel mechanism of action, for patients with metastatic cancer, including colorectal cancer.