Interventional Pain Management for Sacroiliac Tumors in the Oncologic Population: A Case Series and Paradigm Approach.

Introduction: Tumors invading the sacrum and/or ilium often represent incurable metastatic disease, and treatment is targeted toward palliation of symptoms and control of pain. As systemic opioid therapy is frequently inadequate and limited by side effects, a variety of interventional techniques are available to better optimize analgesia. Using six patients as a paradigm for interventional approaches to pain relief, we present a therapeutic algorithm for treating sacroiliac tumor-related pain in the oncologic population. Methods: We describe the use of ultrasound-guided proximal sacroiliac joint corticosteroid injection, sacroiliac lateral branch radiofrequency ablation, percutaneous sacroplasty, and implantable neuraxial drug delivery devices to treat malignant sacroiliac pain in six patients. Pre- and postprocedure numerical rating scale (NRS) pain scores, duration of pain relief, and postprocedure pain medication requirements were studied for each patient. Results: Each patient had marked improvement in their pain based on an average postprocedure NRS difference of six points. The average duration of pain relief was eight months. In all cases, opioid requirements decreased after the intervention. Discussion: Depending on tumor location, burden of disease, and patient preference, patients suffering from metastatic disease to the sacrum may find benefit from use of ultrasound-guided proximal sacroiliac joint corticosteroid injection, sacroiliac lateral branch radiofrequency ablation, percutaneous sacroplasty, dorsal column stimulator leads, and/or implantable neuraxial drug delivery devices. We provide a paradigm for treatment in this patient population.

Ultrasound-Guided Serratus Plane Block for Treatment of Postmastectomy Pain Syndromes in Breast Cancer Patients: A Case Series.

Postmastectomy pain syndrome is common after surgical treatment for breast cancer and may be challenging to manage. Currently, there are a wide variety of approaches to treat this type of pain, including medications, physical therapy, and interventional procedures. However, because of the complexity of innervation of the breast, the serratus plane block may better target the web of nerves innervating the anterior chest wall including the breast. We present a case series of 8 patients who were successfully treated with serratus plane block for pain after treatment for breast cancer. We feel that this particular application for the serratus plane block deserves further investigation, as it is relatively easy to perform and has good clinical utility for this type of pain.

A retrospective review and treatment paradigm of interventional therapies for patients suffering from intractable thoracic chest wall pain in the oncologic population.

INTRODUCTION: Tumors invading the chest wall and pleura are often incurable, and treatment is targeted toward palliation of symptoms and control of pain. When patients develop tolerance or side effects to systemic opioid therapy, interventional techniques can better optimize a patient's pain. We performed a retrospective review of 146 patients from April 2004 to January 2014 who underwent diagnostic and therapeutic procedures for pain relief. Using four patients as a paradigm for neurolytic approaches to pain relief, we present a therapeutic algorithm for treating patients with intractable thoracic chest wall pain in the oncologic population. MATERIAL AND METHODS: For each patient, we describe the use of intercostal/paravertebral nerve blocks and neurolysis, pulsed radiofrequency ablation (PRFA) of the thoracic nerve roots, or intrathecal pump placement to successfully treat the patient's chest wall pain. Analysis of 146 patient charts is also performed to assess effectiveness of therapy. RESULTS: Seventy-nine percent of patients undergoing an intercostal nerve diagnostic blockade (with local anesthetic and steroid) stated that they had improved pain relief with 22% having prolonged pain relief (average of 21.5 days). Only 32% of successful diagnostic blockade patients elected to proceed to neurolysis, with a 62% success rate. Seven patients elected to proceed to intrathecal drug delivery. DISCUSSION: Intercostal nerve diagnostic blockade with local anesthetic and steroid may lead to prolonged pain relief in this population. Furthermore, depending on tumor location, we have developed a paradigm for the treatment of thoracic chest wall pain in the oncologic population.

Operational characteristics of (11)c-choline positron emission tomography/computerized tomography for prostate cancer with biochemical recurrence after initial treatment.

PURPOSE: We examined the performance of (11)C-choline positron emission tomography/computerized tomography for its ability to delineate prostate cancer distribution and extent after initial therapy. MATERIALS AND METHODS: A consecutive series retrospective review was performed of all patients with prostate cancer who were evaluated using (11)C-choline positron emission tomography/computerized tomography from September 2007 to November 2010 at the Mayo Clinic. Statistical analysis was performed to determine the sensitivity, specificity, positive predictive value, negative predictive value and prostate specific antigen threshold for the detection of recurrent lesions. RESULTS: In the study period 176 patients with biochemical recurrence after primary treatment failure underwent (11)C-choline positron emission tomography/computerized tomography. Using patient based analysis (11)C-choline positron emission tomography yielded a sensitivity, specificity, positive predictive value and negative predictive value of 93%, 76%, 91% and 81%, respectively. Of the 176 positron emission tomography/computerized tomography scans performed 56 (32%) were deemed clinically useful as defined by the ability to identify lesions not delineated using conventional imaging, thereby prompting changes in clinical management. The optimal prostate specific antigen for lesion detection was 2.0 ng/ml. On multivariate analysis prostate specific antigen at positron emission tomography (HR 1.37, p = 0.04) and clinical stage at initial diagnosis of prostate cancer (HR 5.19, p = 0.0035) were significant predictors of positive (11)C-choline positron emission tomography/computerized tomography. CONCLUSIONS: (11)C-choline positron emission tomography/computerized tomography performs well in men with biochemical recurrence after primary treatment failure. The optimal prostate specific antigen value for lesion detection is approximately 2.0 ng/ml. We found that (11)C-choline positron emission tomography/computerized tomography substantially enhances the rate of prostate cancer lesion detection by approximately 32% beyond what can be garnered using conventional imaging techniques and at a lower prostate specific antigen value.

Influential Factors in the Preparation of 68Ga-DOTATATE.

Acceptable and reproducible radiochemical purity (RP) for 68Ga-DOTATATE was difficult to obtain with the NETSPOT kit because the manufacturer instructions lacked details on the heater or needles used. Methods: The drug was prepared in an International Organization for Standardization (ISO) 5 environment. Multiple dry baths and needle types were used to investigate the effects of reaction temperature and metal contamination, respectively. Temperature curves were obtained with a calibrated thermocouple. The influence of the accuracy of the NETSPOT reagent volume and its effect on outcome were investigated. Results: The AccuBlock dry bath required recalibration for the ISO 5 environment; after calibration, the temperature was stable (only ±0.1°C from the set point). When we followed package insert recommendations (dry bath temperature set to 98°C, reaction time of 8 min), the reaction temperature was 90.6°C. When Becton Dickinson needles were used for reconstitution, 15 of 18 runs (83%) did not meet the RP specification. However, B. Braun Medical needles achieved satisfactory and stable RP. When the 68Ga generator was eluted with 5.0 mL of 0.1 M hydrochloric acid (HCl), only 3.8-3.9 mL of eluate reached the reaction vial; this volume did not impact labeling (final pH was 3.8). The labeling success rate increased markedly if the 68Ga eluate was passed through a conditioned silica gel cartridge or if no cartridge was used; then, RP was more than 99%. HCl contact with the septum of the labeling vial reduced RP. Conclusion: The needle type and the temperature setting of the dry bath have critical roles in 68Ga-DOTATATE preparation. The AccuBlock dry bath has excellent stability and accuracy and can be used for reliable preparation. By using a conditioned silica gel cartridge or by eliminating the cartridge altogether, the RP is reliably high and stable.

Mayo Clinic approaches to meet United States Pharmacopeia <797> requirements for facility design and environmental controls of nuclear pharmacy.

UNLABELLED: According to the United States Pharmacopeia (USP) General Chapter <797> (USP <797>), "Pharmaceutical Compounding-Sterile Preparations," the compounding facility must be physically designed and environmentally controlled to minimize airborne contamination from contacting critical sites. The goal of the project was to evaluate the appropriateness and effectiveness of our approaches in meeting <797> requirements. METHODS: USP <797> standards, radiation safety concerns, and work-flow patterns were the focal points in our assessment of 4 laboratories: 2 nuclear pharmacy laboratories that engage in preparing sterile (low-, medium-, and high-risk levels), nonsterile, or possible hazardous radioactive drugs and 2 other laboratories in which only low-risk-level preparations are involved. RESULTS: Each laboratory was constructed with a physically separated International Organization for Standardization Class 7 anteroom and clean room to allow us to maintain an appropriate air quality, a consistent operation, and a desirable flexibility. An isolated area within the laboratory was designated for preparing nonsterile products. Higher air change per hour was used in the areas with higher traffic or smaller space. Lead-lined biological safety cabinets (BSCs) were segregated and used depending on the risk category of the preparations. In 1 laboratory, the exhaust flow for the BSC was too great, and a lead-lined compounding aseptic containment isolator (CACI) was installed. Air in the BSC and CACI was 100% exhausted to the atmosphere. 99Mo/99mTc generators were placed in the negative-pressure clean room to ensure a more efficient operation and cleaner air environment. Clean-room equipment (i.e., keyboards, printers, and telephones) was installed, and refrigerators or freezers and the central-processing unit of each computer were placed outside clean room. CONCLUSION: Our wide-range preparations of sterile, nonsterile, or potential hazardous radiopharmaceuticals, coupled with the limited space of each laboratory and existing antiquated mechanical systems, presented a challenge. Nevertheless, we successfully remodeled each nuclear pharmacy laboratory to meet USP <797> requirements for facility design and environmental controls.

Comparison of the EZ-Cap recapper with the Mayo recapper for the prevention of needlesticks.

UNLABELLED: The purpose of this project was the development of a device that improves the design of our current capping block, the Mayo recapper. The major challenges for design and improvement included creating a device that is simple to use and can be applied throughout our department. We wanted a recapper device that increased safety and minimized the potential for needlesticks. Simplicity was another important factor, along with versatility and low cost. A new recapper, called EZ-Cap, was developed, and a comparison study was conducted to evaluate the pros and cons of the EZ-Cap recapper and the Mayo recapper. METHODS: Nuclear medicine technologists (n = 10) in our department used each device when administering patient injections. At the conclusion of their patient injection rotation, they recorded on a survey sheet the pros and cons of each device. The results of this survey were used to evaluate the effectiveness, comfort level during use, and safety of each recapping device. We used a 2-level scoring system to help determine which device was more favorable. The first level focused on comfort and convenience and was given a score of +1 or -1. The second level focused on safety and was given a score of +2 or -2. Because we believed that safety was a high priority for our capping blocks, this level received a higher score than the first level. RESULTS: The Mayo recapper was the device preferred by 9 of 10 technologists surveyed. The EZ-Cap recapper had several technical issues that made it difficult to use and that could potentially lead to safety concerns. According to our scoring system, the Mayo recapper received a score of +9 for its pros and -4 for its cons. By comparison, the EZ-Cap recapper received a score of +7 for its pros and -16 for its cons. CONCLUSION: Our results show that the Mayo recapper was the device of choice because its pros outweighed its cons. However, we will continually improve the effectiveness of the Mayo recapper to prevent needlesticks.

Safety devices for delivery of radioactive iodine.

For clinical applications, liquid 131I is more cost-effective and flexible than capsules for diagnostic and therapeutic dosing of the thyroid gland. However, the liquid is potentially a contamination hazard because of possible spilling by a patient or staff member. The objective of this study was to design a safety system for delivering therapeutic doses of liquid 131I that would not only minimize potential contamination spill hazards but also reduce radiation exposure to patients and staff during the therapeutic dosing process. A plastic vial with a secured top and tube to allow drinking was placed in a lead container with a screw-on lid. A dosing tray holds the lead-encased vial directly in front of the patient, further reducing the risk of spillage. The tray has a peripheral lip to contain any liquid that might spill. This height-adjustable tray is temporarily fastened to the chair's armrest. After the dose is administered, 20 mL of distilled water is injected into the shielded vial through a 1.5-mm orifice in the cap. The orifice is a vent to eliminate any vacuum created while drinking. The water rinses the vial so the patient receives the entire dose after the second drink. Our shielded spill-proof safety cup effectively seals the contents, reducing the risk of spillage and minimizing radiation exposure to patients and staff. Impact testing demonstrated only minimal leakage when the cup was dropped from a 1-m height. Our shielded cup and tray assembly could be implemented efficiently and economically into the clinical setting with minimal expense.

A performance evaluation of 90Y dose-calibrator measurements in nuclear pharmacies and clinics in the United States.

A blind performance test was conducted to evaluate dose-calibrator measurements at nuclear pharmacies in the United States (US). Two test-sample geometries were chosen to represent those used for measurements of 90Y-ibritumomab tiuxetan (ZEVALIN). The radioactivity concentration of test-samples was verified by the US National Institute of Standards and Technology. Forty-five results were reported by 10 participants. Eighty percent of reported values were within the US Pharmacopoeia content standard (+/-10%) for 90Y-ZEVALIN. All results were within US Nuclear Regulatory Commission conformance limits (+/-20%) for defining therapeutic misadministrations.

Rapid Instant Thin-Layer Chromatography System for Determining the Radiochemical Purity of 68Ga-DOTATATE.

The objective of this study was to develop instant thin-layer chromatography (ITLC) conditions for the determination of radiochemical purity of 68Ga-DOTATATE in a shorter time period than those stated in the NETSPOT (Advanced Accelerator Applications, Saint-Genis-Pouilly, France; AAA) kit package insert (PI). A faster ITLC system is needed to reduce the 48- to 50-min development time so that more radioactivity is available for single patient use and wait times are shorter in the event of kit failure. Methods: Variations of the PI mobile system were evaluated with microfiber chromatography paper impregnated with silica gel (ITLC-SG). After a more suitable mobile system was identified, evaluation began by attempting to shorten the 10-cm development distance to 7, 8, and 9 cm. Results: Experiments using variations of PI mobile phase showed that increasing the proportion of methanol in the mobile phase decreased development time. Additionally, if the ratio of 1 M ammonium acetate was reduced to 10% or less, retention factor values fall outside specification. Reducing the development distance shortened development time as expected; however, it also affected the resolution aspect of the radiochromatogram. Conclusion: The fastest developing ITLC system, which maintained resolution and peak shape, was methanol:1 M ammonium acetate (80:20 V/V) with ITLC-SG using a development distance of 8 cm.

Non-invasive visualization of tumor infiltrating lymphocytes in patients with metastatic melanoma undergoing immune checkpoint inhibitor therapy: a pilot study.

Early in the course of immunotherapy there is frequently a transient enlargement of tumor masses (pseudo-progression) due to tumor infiltration by TILs. Current clinical imaging modalities are not able to distinguished pseudo-progression from true tumor progression. Thus, patients often remain on treatment 4-8 weeks longer to confirm disease progression. Nuclear medicine offers the possibility to image immune cells and potentially discriminate pseudo-progression and progression. We conducted a pilot study in patients with metastatic melanoma receiving ipilimumab (IPI) or pembrolizumab (PEMBRO) to assess safety and feasibility of SPECT/CT imaging with 99mTc- interleukin-2 (99mTc-HYNIC-IL2) to detect TILs and distinguish between true progression from pseudo- progression. Scans were performed prior to and after 12w treatment. After labelling,99mTc-HYNIC-IL2 was purified and diluted in 10 mL of 5% glucose with 0.1% human serum albumin. Of the 5 patients (2 treated with IPI and 3 with PEMBRO) enrolled, two failed to complete the second scan as they discontinued IPI due grade 3 colitis (1 patient) or patient refusal after developing multiple toxicities attributed to IPI (1 patient). Following the first scan, one patient reported to have a grade 1 pruritus with grade 1 pain. No other toxicities attributed to the radiopharmaceutical infusion were reported. Metastatic lesions could be visualized by 99mTc-IL2 imaging and there was positive correlation between size and 99mTc-HYNIC-IL2 uptake, both before and after 12 weeks of therapy. The results of this pilot study demonstrate the safety and feasibility of 99mTc-IL2 imaging and has led to a number of hypotheses to be tested in future studies.

Trends of radiopharmaceutical use at Mayo Clinic Rochester.

UNLABELLED: The field of radiology is continuously changing. The purpose of this study was to identify the effect of technologic advances on nuclear medicine during the past 15 y. METHODS: The number of radiopharmaceutical doses dispensed at Mayo Clinic (Rochester, Minnesota) from 1990 through 2004 was tracked. The number of doses was equivalent to the number of scans performed. RESULTS: Since 1990, the number of bone scans decreased by 38%. Brain scans using (99m)Tc have increased by 166%. The number of cardiac doses dispensed increased 184% from 1990 through 1999 but decreased 3% between 2000 and 2004. The number of lung scans decreased 52% from 1992 through 1999 and increased 66% from 1999 through 2004. The number of kidney scans decreased 67% since 1990. Since its introduction in 1993, the use of (111)In-pentetreotide has increased 16-fold. PET data showed a 602% increase in the number of procedures from 2001 through 2004. CONCLUSION: The number of bone, lung, and kidney scans has decreased because of advances in other imaging modalities. Although the number of cardiac imaging scans increased during most of the study period, the recent rate of growth has declined, possibly because of the availability of alternative procedures such as stress echocardiography. The number of brain and lung scans performed has increased, partially because of the development of new protocols. PET and tumor imaging have shown a substantial increase because of increasing numbers of approved indications and Medicare reimbursement.

Potential Ways to Address Shortage Situations of 99Mo/99mTc.

99mTc, the most common radioisotope used in nuclear medicine, is produced in a nuclear reactor from the decay of 99Mo. There are only a few aging nuclear reactors around the world that produce 99Mo, and one of the major contributors, the National Research Universal (Canada), ceased production on October 31, 2016. The National Research Universal produced approximately 40% of the world's 99Mo supply, so with its shut down, shortages of 99Mo/99mTc are expected. Methods: Nuclear pharmacies and nuclear medicine departments throughout the United States were contacted and asked to provide their strategies for coping with a shortage of 99Mo/99mTc. Each of these strategies was evaluated on the basis of its effectiveness for conserving 99mTc while still meeting the needs of the patients. Results: From the responses, the following 6 categories of strategies, in order of importance, were compiled: contractual agreements with commercial nuclear pharmacies, alternative imaging protocols, changes in imaging schedules, software use, generator management, and reduction of ordered doses or elimination of backup doses. Conclusion: The supply chain of 99Mo/99mTc is quite fragile; therefore, being aware of the most appropriate coping strategies is crucial. It is essential to build a strong collaboration between the nuclear pharmacy and nuclear medicine department during a shortage situation. With both nuclear medicine departments and nuclear pharmacies implementing viable strategies, such as the ones proposed, the amount of 99mTc available during a shortage situation can be maximized.

A cost-effective and versatile xenon gas dispenser.

OBJECTIVE: To modify a commercial xenon gas dispenser so that two xenon unit-dose vials could be combined with a modified dispenser to deliver a recommended dose. METHOD: To maintain the same operating mechanism, changes were made only to the vial shield and the needle port of the original gas dispenser. The modified gas dispenser consisted of two puncture needles and two vial holders shielded with the same thickness of lead as the commercial dispenser. RESULTS: Our evaluation showed that the modified gas dispenser operated the same way as the commercial unit, and the average 133Xe residual activity in either one or two xenon unit-dose vials of the modified gas dispenser was not significantly different from that in one vial of the commercial xenon gas dispenser. CONCLUSION: The modified xenon gas dispenser allows the stock of xenon gas vials to be managed cost-effectively. The modified unit can be used to dispense two low-activity xenon gas vials to deliver a standard dose to a patient. Also, the modified gas dispenser can be used to combine different amounts of xenon activity in two unit-dose vials in order to customize the dose delivered to patients with special needs (e.g., obese patients). Our modified device can also function as a single-dose dispenser by placing an empty vial alongside the unit-dose vial of radioactive xenon gas.

Inhibition evaluation for a 20-min endotoxin limit test on FDG.

OBJECTIVES: In chemical quality control tests for 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG), gel time is inversely related to endotoxin concentration. Solutions for positive product control (PPC) and positive water control (PWC) should contain a highly concentrated endotoxin level. The aims of our study were to derive an endotoxin concentration that causes PPC and PWC to gel and to evaluate inhibitory effects caused by FDG on gel formation in PPC and PWC test solutions. METHODS: At expiration, the maximum administered total dose (in millilitres) of FDG should contain fewer than 175 endotoxin units (EU). Our average batch volume of FDG is 15 ml; thus, the minimum endotoxin limit should be 12 EU x ml(-1) . Twelve tubes were tested for each of four concentrations. Inhibition was assessed using Limulus amoebocyte lysate reagent, depyrogenated vials, and pyrogen-free sterile micropipette tips. Each study was performed with four groups of solutions: decayed 18F-FDG, negative control, PPC and PWC. RESULTS: In the study of undiluted FDG, seven of 50 PPC vials at 12 EU x ml(-1) did not gel. The lowest endotoxin concentration that consistently gelled at 20 min was 4 EU x ml(-1) . In the sample tested for inhibition using PPC tubes at 4 EU x ml(-1) , 49 tubes gelled at 20 min, and one did not. CONCLUSION: The inhibition rate improved between undiluted (i.e., 7/50 (14%)) and diluted (i.e., 1/50 (2%)) FDG PPC trials (P=0.03). However, given that 1 of 50 trials failed for diluted FDG PPC, we conclude that inhibition still occurs and there is a 95% chance that the inhibition rate could be as high as 11% or as low as 0% on repetition of the experiment.

Comparison of various requirements of the quality assurance procedures for (18)F-FDG injection.

The quality assurance (QA) requirements (i.e., test procedure, acceptance criteria, and testing schedule) for fludeoxyglucose (18)F ((18)F-FDG) injection listed in the U.S. Pharmacopeia (USP); the draft Chemistry, Manufacturing, and Controls (CMC) issued by the U.S. Food and Drug Administration (FDA); and the European Pharmacopeia (EP) were compared. The FDA Modernization Act of 1997 requires that the QA of compounded PET drug products be in compliance with the PET compounding standards and official monographs included in the USP. However, the "sunset" clause of the PET section within the FDA Modernization Act of 1997 stipulates that all PET drug products, in due course, must meet the requirements for drug approval procedures and current good manufacturing practice, and the FDA has issued a draft CMC that includes QA specifications for (18)F-FDG injection. The purpose of this article is to discuss the pros and cons of each of the QA tests stated in the USP, CMC, and EP and to propose a practical testing method for each required test, thereby helping end users to ensure the quality of the (18)F-FDG injection product. It is hoped that this article will stimulate further cooperation among various countries worldwide in the development of a set of harmonized and sensible QA standards for all PET drug products.

Effects of methylene blue stabilizer on in vitro viability and chemotaxis of 99mTc-exametazime-labeled leukocytes.

UNLABELLED: This study was conducted to evaluate the effects of methylene blue/phosphate buffer stabilizer on the labeling efficiency, cell membrane integrity, chemotaxis, and in vitro stability of leukocytes labeled with 99mTc-exametazime. METHODS: Whole blood (480 mL) was obtained from each of 3 healthy donors and divided equally into eight 60-mL aliquots. Two aliquots from each of the 3 subjects were used as a control (i.e., leukocytes were not labeled with either nonstabilized or stabilized 99mTc-exametazime) in this study. The remaining 6 aliquots from each of the 3 subjects were divided equally into the following formulation groups: (a) leukocytes labeled with nonstabilized 99mTc-exametazime, (b) leukocytes labeled with stabilized 99mTc-exametazime containing 250 microg methylene blue, and (c) leukocytes labeled with stabilized 99mTc-exametazime containing 500 microg methylene blue. Duplicate samples were evaluated to confirm the repeatability of the study. Six samples were studied under each experimental condition (i.e., control, a, b, and c groups). The cell membrane integrity and chemotatic capacity of leukocytes were measured at 1 and 3 h after preparation, whereas a complete blood count was obtained at 3 h after preparation. The labeling efficiency was calculated immediately on conclusion of cell labeling, whereas the in vitro stability of the radiolabeled leukocytes was evaluated at 3 h after radiolabeling. RESULTS: None of the samples showed trypan blue-stained cells. For the chemotactic index, no statistically significant differences were noted between the 3 labeling formulations at 1 h (P = 0.43) or 3 h (P = 0.10) after preparation. None of the labeling formulations differed significantly from the control values of the chemotactic index (all P > 0.25). For the complete blood count, no significant differences were observed between any of the groups, with the exception of platelet number in the control group (P = 0.004). The labeling efficiency (P = 0.10) and in vitro stability (P = 0.33) were also similar in our comparison of the 3 labeling formulations. CONCLUSION: With no major statistically significant difference noted either between the 3 labeling formulations or between the control and the 3 labeling formulations, we concluded that the methylene blue/phosphate buffer stabilizer (250 or 500 microg methylene blue) did not affect the cell membrane integrity, chemotactic capacity, labeling efficiency, in vitro stability, or complete blood count of leukocytes labeled with stabilized 99mTc-exametazime.

A rational regulatory approach for positron emission tomography imaging probes: from "first in man" to NDA approval and reimbursement.

We propose a new regulatory approach for positron emission tomography (PET) molecular imaging probes, essential tools in today's medicine. Even though the focus of this paper is on positron-emitting labeled probes, it is also justified to extend this proposed regulatory approach to other diagnostic nuclear medicine radiopharmaceuticals. Key aspects of this proposal include: (1) PET molecular imaging probes would be placed in a "no significant risk" category, similar to that category for devices in current Food and Drug Administration (FDA) regulations, based on overwhelming scientific evidence that demonstrates their faultless safety profile; (2) the FDA-sanctioned Radioactive Drug Research Committee (RDRC) will oversee all diagnostic research with these probes. The newly defined RDRC should approve "first in man" use; supervise a broader spectrum of diagnostic research protocols, including those looking to demonstrate initial efficacy, as well as multicenter clinical trials and the use of molecular imaging probes as a screening tool in drug discovery. The current investigational new drug (IND) mechanism is thus eliminated for these diagnostic probes; (3) when a molecular imaging probe has demonstrated diagnostic efficacy, FDA approval (i.e., NDA) will be sought. The review will be done by a newly constituted Radioactive Drug Advisory Committee (RDAC) composed of experts chosen by the professional societies, who would provide a binding assessment of the adequacy of the safety and efficacy data. When the RDAC recommends its diagnostic use on scientific and medical grounds, the molecular imaging probe becomes FDA approved. After a molecular imaging probe is approved for a diagnostic indication, the existing mechanism to seek reimbursement will be utilized; and (4) the FDA would retain its direct oversight function for traditional manufacturers engaged in commercial distribution of the approved diagnostic molecular imaging probes (i.e., under NDA) to monitor compliance with existing US Pharmacopeia (USP) requirements. With abbreviated and more appropriate regulations, new PET molecular imaging probes for diagnostic use would be then rapidly incorporated into the mainstream diagnostic medicine. Equally importantly, this approach would facilitate the use of molecular imaging in drug discovery and development, which would substantially reduce the costs and time required to bring new therapeutic drugs to market.

The planning and design of a new PET radiochemistry facility.

The objectives of the Mayo positron emission tomography (PET) radiochemistry facility are the production of PET drugs for clinical service of our in-house patients, commercial distribution of PET drug products, and development of new PET drugs. The factors foremost in the planning and design phases were the current regulatory climate for PET drug production, radiation safety issues, and effective production flow. A medium-energy cyclotron was preferred for its small footprint to allow a compact vault, its high-proton energy to offer a higher product radioactivity; and its research capabilities. A vault installation was chosen instead of a self-shielded machine for improved access and ease of maintenance. Adjacent to the cyclotron is an area that houses the support equipment and a large dedicated workshop to support machine maintenance and targetry development. The total floor area of the PET radiochemistry facility is 344.2 m(2) (3,705.5 ft(2)), of which the radiochemistry laboratory occupies 130.7 m(2) (1,407 ft(2)). To reduce environmental contamination of PET drug products, the laboratory contains a controlled-air environment class 10,000 (M5.5) clean room with access via an interlocking entry change area. A fully shielded isolator (class 100 [M3.5]) is located in the clean room. The PET drugs are delivered via shielded tubing between the synthesizer and isolator. Inside the isolator, there is an automated device for dispensing the PET drug into either a bulk-activity vial or a unit-dose syringe. The dispensed PET radiopharmaceutical then passes through a hatch to a dedicated area where it is packaged for in-house use or commercial distribution. Unit doses for in-house patients are transported via pneumatic tube to the PET imaging area 76.2 m (250 ft) away. There is extensive radiation area monitoring throughout the facility that continuously measures radiation levels. We believe that our new PET radiochemistry facility not only meets overall objectives, but also provides an ergonomic, efficient working environment for the production and development of PET drugs.

Neurolytic transversus abdominal plane block with alcohol for long-term malignancy related pain control.

There have been several case reports in the literature of neurolytic transversus abdominis plane (TAP) blocks being used for malignant abdominal wall pain. However, most used phenol as a neurolytic agent. We found only a single case report by Sakamoto using alcohol for TAP neurolysis. Unfortunately this patient passed away only 5 days after performance of the block. We attempt to extend upon the existing literature by describing neurolytic TAP blockade outcomes using alcohol on 3 cancer patients with metastatic disease to the abdominal wall. Two of our 3 patients had colorectal cancer invading the abdominal musculature. The third patient had a metastatic neuroendocrine nodule in the left rectus muscle. In our case series, all 3 patients had sustained and significant (greater than 50%) relief of abdominal wall pain after performing TAP neurolysis using alcohol. Ultrasound guidance was used for all blocks. The concentration of alcohol used varied from 33% to 77% between patients. Duration of relief lasted between 17 days and 6 months. Opioid use either decreased or remained relatively stable for prolonged periods of time after neurolysis. Other than one patient with transient post-procedure pain related to alcohol injection, there were no significant complications. Addition of a depo steroid for diagnostic TAP blockade prior to neurolysis did not appear to extend or provide additional analgesia. Based on our observations, TAP neurolysis using alcohol also offers a feasible option for long-term control of malignant abdominal wall pain. Further investigation is needed to determine if alcohol offers any significant advantage compared with phenol.