Marcus Ferrone

Metabolic imaging of patients with prostate cancer using hyperpolarized [1-¹³C]pyruvate.

Metabolic imaging with hyperpolarized pyruvate was used to safely and noninvasively visualize prostate tumors in patients. The Hyperpolarized Prostate Cancer cells have a different metabolism than healthy cells. Specifically, they consume more pyruvate—a key component in glycolysis—than their normal counterparts. Nelson and colleagues therefore used a hyperpolarized form of pyruvate ([1-13C]pyruvate) to sensitively image increased levels of its product, [1-13C]lactate, as well as the flux of pyruvate to lactate. The [1-13C]pyruvate agent was used here in a first-in-human study in men with prostate cancer. Patients received varying doses of [1-13C]pyruvate that were found to be safe. These patients were then rapidly imaged with hyperpolarized 13C magnetic resonance (MR), which was able to provide dynamic (time course) information as well as three-dimensional (3D) (spatial) data at a single time point. Tumors were detected in all patients with biopsy-proven cancer. And, importantly, with 13C MR imaging (MRI), Nelson et al. were able to see cancer in regions of the prostate that were previously considered to be tumor-free upon inspection with other conventional anatomic imaging methods. With the ability to safely image tumor location and also follow tumor metabolism over time, hyperpolarized 13C MRI may be useful both for initial diagnosis and for monitoring therapy. Although the patients in this study had early-stage disease, the authors believe that [1-13C]lactate/[1-13C]pyruvate flux will only increase with tumor grade, making this imaging technology amenable to more advanced and aggressive cancers. Future studies will focus on optimizing agent preparation and delivery to ensure that this imaging technology can benefit patients in all clinical settings. This first-in-man imaging study evaluated the safety and feasibility of hyperpolarized [1-13C]pyruvate as an agent for noninvasively characterizing alterations in tumor metabolism for patients with prostate cancer. Imaging living systems with hyperpolarized agents can result in more than 10,000-fold enhancement in signal relative to conventional magnetic resonance (MR) imaging. When combined with the rapid acquisition of in vivo 13C MR data, it is possible to evaluate the distribution of agents such as [1-13C]pyruvate and its metabolic products lactate, alanine, and bicarbonate in a matter of seconds. Preclinical studies in cancer models have detected elevated levels of hyperpolarized [1-13C]lactate in tumor, with the ratio of [1-13C]lactate/[1-13C]pyruvate being increased in high-grade tumors and decreased after successful treatment. Translation of this technology into humans was achieved by modifying the instrument that generates the hyperpolarized agent, constructing specialized radio frequency coils to detect 13C nuclei, and developing new pulse sequences to efficiently capture the signal. The study population comprised patients with biopsy-proven prostate cancer, with 31 subjects being injected with hyperpolarized [1-13C]pyruvate. The median time to deliver the agent was 66 s, and uptake was observed about 20 s after injection. No dose-limiting toxicities were observed, and the highest dose (0.43 ml/kg of 230 mM agent) gave the best signal-to-noise ratio for hyperpolarized [1-13C]pyruvate. The results were extremely promising in not only confirming the safety of the agent but also showing elevated [1-13C]lactate/[1-13C]pyruvate in regions of biopsy-proven cancer. These findings will be valuable for noninvasive cancer diagnosis and treatment monitoring in future clinical trials.

Pancreatic Enzyme Pharmacotherapy

Supplemental pancreatic enzyme preparations are provided to patients with conditions of pancreatic exocrine deficiency such as chronic pancreatitis and cystic fibrosis. These patients frequently experience steatorrhea, which occurs from inadequate fat absorption. The delivery of sufficient enzyme concentrations into the duodenal lumen simultaneously with meals can reduce nutrient malabsorption, improve the symptoms of steatorrhea, and in some cases alleviate the pain associated with chronic pancreatitis. Current clinical practices dictate administration of lipase 25,000–40,000 units/meal by using pH‐sensitive pancrelipase microspheres, along with dosage increases, compliance checks, and differential diagnosis in cases of treatment failure. Despite the large number of specialty enzyme replacements available commercially, many patients remain dissatisfied with standard therapy, and future developments are needed to optimize treatment in these individuals.

Fentanyl HCl Patient-Controlled Lontophoretic Transdermal System for the Management of Acute Postoperative Pain

Objective: To summarize the pharmaceutics, pharmacokinetics, development, and clinical application of IONSYS, the fentanyl HCl patient-controlled iontophoretic transdermal system for the management of acute postoperative pain. Data Sources: Clinical literature including both primary sources and review articles was accessed through a search of the MEDLINE databases (1980–October 2006). Key search terms included cutaneous analgesia, fentanyl, IONSYS, opioid, postoperative pain, and patient-controlled analgesia (PCA). Additional clinical trial and drug data were supplied by the manufacturer, the ALZA Corporation. Study Selection and Data Extraction: Review articles, abstracts, and clinical studies related to patient-controlled iontophoretic transdermal fentanyl and postoperative pain management were analyzed. An evaluation of the research exploring IONSYS for the management of acute postoperative pain was conducted. Relevant information was then selected and is provided in this article. Data Synthesis: IONSYS is the first iontophoretic transdermal drug delivery system that utilizes low-level electrical energy to actively transport ionized fentanyl HCl through intact skin. Research has revealed that use of IONSYS for patients with acute postoperative pain is safe, effective, and well tolerated. Phase I–III trials have demonstrated an appropriate dosing range leading to effective analgesia, with minimal adverse effects. The analgesia provided by this system was found to be superior to that of analgesia placebo and equivalent to that of an intravenous morphine PCA. Conclusions: Data from clinical trials indicated that IONSYS is successful in controlling acute postoperative pain that circumvents the limitations of intravenous patient-controlled analgesia. The use of this system may serve as an alternative modality for the management of acute pain without increasing such adverse effects as bleeding, intravenous catheter infiltration, or manual pump malfunction.

A Review of the Relationship Between Parenteral Nutrition and Metabolic Bone Disease

Metabolic bone disease (MBD) refers to the conditions that produce a diffuse decrease in bone density and strength because of an imbalance between bone resorption and bone formation. MBD can be a potential complication in patients receiving chronic parenteral nutrition (PN) therapy and the management of this condition presents a challenge for many clinicians. The etiology of PN-associated MBD is poorly understood, but traditional risk factors can include malnutrition, vitamin and mineral deficiencies, toxic contaminants in the PN solution, concomitant medications, and presence of certain disease states. Although additional studies are warranted to further elucidate the development and management of this condition, the following review discusses some of the important factors that may play a role in the genesis of PN-associated MBD and evaluates some potential strategies for the diagnosis and treatment of this complication.

Teduglutide for the Treatment of Short Bowel Syndrome

Objective: To summarize the pharmacology, development, and clinical application of teduglutide (ALX-0600), a glucagon-like peptide-2 (GLP-2) analog for the treatment of short bowel syndrome (SBS). Data Sources: Clinical literature, including both primary sources and review articles, was accessed through a search of the MEDLINE databases (1980–March 2006). Key search terms included teduglutide, ALX-0600, glucagon-like peptide-2, short bowel syndrome, short gut, and intestinal adaptation. Clinical trial and drug data were supplied by the manufacturer, NPS Pharmaceuticals. Study Selection and Data Extraction: Review articles, abstracts, and clinical studies related to GLP-2 and its analog, teduglutide, were analyzed. An evaluation of the research exploring teduglutide for the management of SBS was conducted. Relevant information was then selected. Data Synthesis: Research has revealed that administration of GLP-2 to patients following major small bowel resection improves intestinal adaptation and nutrient absorption. Teduglutide is an enzyme-resistant GLP-2 analog that shows promise in preventing intestinal injury, restoring mucosal integrity, and enhancing intestinal absorptive function. Conclusions: Data from ongoing clinical trials indicate that teduglutide may have the ability to enhance intestinal absorptive capacity in patients with SBS. Further studies and the completion of Phase III trials are necessary to determine the appropriate dosage and length of treatment for patients with SBS to gain optimal therapeutic benefit from this drug.

Assessing Prostate Cancer Aggressiveness with Hyperpolarized Dual-Agent 3D Dynamic Imaging of Metabolism and Perfusion

New magnetic resonance (MR) molecular imaging techniques offer the potential for noninvasive, simultaneous quantification of metabolic and perfusion parameters in tumors. This study applied a three-dimensional dynamic dual-agent hyperpolarized 13C magnetic resonance spectroscopic imaging approach with 13C-pyruvate and 13C-urea to investigate differences in perfusion and metabolism between low- and high-grade tumors in the transgenic adenocarcinoma of mouse prostate (TRAMP) transgenic mouse model of prostate cancer. Dynamic MR data were corrected for T1 relaxation and RF excitation and modeled to provide quantitative measures of pyruvate to lactate flux (kPL ) and urea perfusion (urea AUC) that correlated with TRAMP tumor histologic grade. kPL values were relatively higher for high-grade TRAMP tumors. The increase in kPL flux correlated significantly with higher lactate dehydrogenase activity and mRNA expression of Ldha, Mct1, and Mct4 as well as with more proliferative disease. There was a significant reduction in perfusion in high-grade tumors that associated with increased hypoxia and mRNA expression of Hif1α and Vegf and increased ktrans , attributed to increased blood vessel permeability. In 90% of the high-grade TRAMP tumors, a mismatch in perfusion and metabolism measurements was observed, with low perfusion being associated with increased kPL This perfusion-metabolism mismatch was also associated with metastasis. The molecular imaging approach we developed could be translated to investigate these imaging biomarkers for their diagnostic and prognostic power in future prostate cancer clinical trials. Cancer Res; 77(12); 3207-16. ©2017 AACR.

Pharmacokinetics of penciclovir in healthy cats following oral administration of famciclovir or intravenous infusion of penciclovir

OBJECTIVE To investigate the pharmacokinetics of penciclovir in healthy cats following oral administration of famciclovir or IV infusion of penciclovir. ANIMALS 6 cats. PROCEDURES Cats received famciclovir (40 [n = 3] or 90 [3] mg/kg, PO, once) in a balanced crossover-design study; the alternate dose was administered after a ≥ 2-week washout period. After another washout period (≥ 4 weeks), cats received an IV infusion of penciclovir (10 mg/kg delivered over 1 hour). Plasma penciclovir concentrations were analyzed via liquid chromatography-mass spectrometry at fixed time points after drug administration. RESULTS Mean ± SD maximum plasma concentration (C(max)) of penciclovir following oral administration of 40 and 90 mg of famciclovir/kg was 1.34 ± 0.33 μg/mL and 1.28 ± 0.42 μg/mL and occurred at 2.8 ± 1.8 hours and 3.0 ± 1.1 hours, respectively; penciclovir elimination half-life was 4.2 ± 0.6 hours and 4.8 ± 1.4 hours, respectively; and penciclovir bioavailability was 12.5 ± 3.0% and 7.0 ± 1.8%, respectively. Following IV infusion of penciclovir (10 mg/kg), mean ± SD penciclovir clearance, volume of distribution, and elimination half-life were 4.3 ± 0.8 mL/min/kg, 0.6 ± 0.1 L/kg, and 1.9 ± 0.4 hours, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Penciclovir pharmacokinetics following oral administration of famciclovir were nonlinear within the dosage range studied, likely because of saturation of famciclovir metabolism. Oral administration of famciclovir at 40 or 90 mg/kg produced similar C(max) and time to C(max) values. Therefore, the lower dose may have similar antiviral efficacy to that proven for the higher dose.

Development of methods and feasibility of using hyperpolarized carbon-13 imaging data for evaluating brain metabolism in patient studies.

Hyperpolarized carbon‐13 (13C) metabolic imaging is a noninvasive imaging modality for evaluating real‐time metabolism. The purpose of this study was to develop and implement experimental strategies for using [1‐13C]pyruvate to probe in vivo metabolism for patients with brain tumors and other neurological diseases.

Trastuzumab for the Treatment of Non—Small-Cell Lung Cancer:

OBJECTIVE: To evaluate trastuzumab for the treatment of advanced non—small-cell lung cancer (NSCLC). DATA SOURCES: Clinical literature was accessed through MEDLINE (1966–January 2003), EMBASE (1974–January 2003), International Pharmaceutical Abstracts (1970–January 2003), Proceedings of the American Society of Clinical Oncology (1995–January 2003), and Genentech. Key search terms included trastuzumab, lung cancer, Herceptin, and NSCLC. DATA SYNTHESIS: Research has revealed that NSCLC specimens may express the protein HER-2/neu. The monoclonal antibody against HER-2/neu, trastuzumab, could prove valuable for patients. An evaluation of the studies exploring trastuzumab for management of NSCLC was conducted. Phase II clinical trials reveal variable response rates from no improvement to a partial response rate of 42%. Due to a lack of clinical trials and deficiencies in the literature, the ultimate benefit of this agent remains to be proven. CONCLUSIONS: Clinical data from ongoing trials indicate potential synergy when trastuzumab is added to standard chemotherapy. The ultimate benefit in NSCLC remains to be proven.

The LGBTQI health forum: an innovative interprofessional initiative to support curriculum reform

ABSTRACT Lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI) individuals continue to face barriers to accessing appropriate and comprehensive healthcare. Compounding this problem, healthcare trainees report few training opportunities and low levels of preparedness to care for LGBTQI patients. In 2009, an interprofessional group of students and a faculty advisor at the University of California, San Francisco, developed a novel student-organized LGBTQI Health Forum for medical, dental, pharmacy, nursing, and physical therapy students to deliver LGBTQI health content that was otherwise absent from the formal curriculum. This elective course has evolved based upon participant feedback, emerging educational strategies, and the existing curricula infrastructure at our institution. After eight years of growth, this 10-contact hour weekend elective attracts over 250 participants each year. Plenary sessions deliver foundational terminology and skills to all attendees. Learners then select breakout sessions to attend, allowing for an individualized curriculum based upon specific interests and knowledge gaps. Breakout session topics prioritize traditionally underrepresented aspects of LGBTQI health in professional school curricula. This Forum serves as a model in which to supplement LGBTQI content into existing school curricula and offers an opportunity for interprofessional education. Next steps include conducting a formal evaluation of the curriculum, expanding our performance-based assessments, and potentially implementing a continuing education program for licensed practitioners. With a core group of interprofessional student organizers and a faculty champion, other institutions may view this course architecture as a potential way to offer learners not only LGBTQI content, but other underrepresented subjects into their own educational programs.