Wendy Waddington

EANM-EORTC general recommendations for sentinel node diagnostics in melanoma

The accurate diagnosis of a sentinel node in melanoma includes a sequence of procedures from different medical specialities (nuclear medicine, surgery, oncology, and pathology). The items covered are presented in 11 sections and a reference list: (1) definition of a sentinel node, (2) clinical indications, (3) radiopharmaceuticals and activity injected, (4) dosimetry, (5) injection technique, (6) image acquisition and interpretation, (7) report and display, (8) use of dye, (9) gamma probe detection, (10) surgical techniques in sentinel node biopsy, and (11) pathological evaluation of melanoma-draining sentinel lymph nodes. If specific recommendations given cannot be based on evidence from original, scientific studies, referral is given to “general consensus” and similar expressions. The recommendations are designed to assist in the practice of referral to, performance, interpretation and reporting of all steps of the sentinel node procedure in the hope of setting state-of-the-art standards for good-quality evaluation of possible spread to the lymphatic system in intermediate-to-high risk melanoma without clinical signs of dissemination.

Radiation safety of the sentinel lymph node technique in breast cancer

Abstract.Many publications attest to the potential of the sentinel lymph node technique in advancing the clinical management of melanoma and, more recently, breast cancer. Whilst not yet universally regarded as the standard of care, the technique is gaining wide acceptance. Use of a radiolabelled colloidal tracer is central to optimising sensitivity, and this brings with it the need to address radiation safety issues relating to the use of radioactive materials in the operating theatre and pathology laboratory, and the generation of radioactive waste. The radiation dose to the patient should also be determined if the professional is to reassure the patient by placing this in its proper context. For the purpose of this investigation, biodistribution data were obtained from patient studies to quantify the migration of tracer beyond the injection site, thereby permitting a detailed assessment of the internal dosimetry of the tracer and the resulting radiation dose to the patient. Uptake of tracer in the sentinel nodes, reticulo-endothelial system and circulating blood was investigated. The radiation dose to surgical staff was recorded using whole-body monitors and extremity dosimeters worn at the fingers. Clinical waste in the operating theatre was monitored and the radioactive content of significantly contaminated items determined. The radiation dose to pathology staff was estimated from knowledge of the radioactive content of the specimens obtained and a study of work practices. Migration of tracer was found to be minimal, with greater than 95% retention at the injection site. The effective dose resulting to the patient was 2.1×10–2 mSv/MBq, with a mean breast dose of 7.2×10–1 mGy/MBq. A mean whole-body dose of 0.34 µSv was received by surgical staff per procedure, with a mean finger dose of 0.09 mSv (90 µSv). Radiation doses received by pathology staff will be predominantly below measurable levels and are likely to be negligible unless primary specimens from a large number of studies are analysed promptly upon their excision. At operation, surgical swabs can become significantly contaminated and have been found to contain up to 22% of the administered activity, dependent upon the surgical procedure performed. It is concluded that moderate activities of technetium-99m labelled tracer are administered to the patient, and the radiation risk to the patient is consequently low relative to that from many other medical exposures. The radiation doses to staff groups involved in all aspects of the technique are low, and under normal circumstances and levels of workload, routine radiation monitoring will not be required. Standard biohazard precautions prevent direct intake of radioactive contamination. Radioactive waste is created in the operating theatre, and may be generated in the pathology laboratory if specimens are not routinely stored until fully decayed. This will require special handling if the disposal of radioactive material is not permitted.

The Effect of Polyethylene Glycol 400 on Gastrointestinal Transit: Implications for the Formulation of Poorly-Water Soluble Drugs

AbstractPurpose. To assess the effect of polyethylene glycol 400 (PEG 400), a pharmaceutical excipient frequently employed to enhance the solubility and bioavailability of poorly water-soluble drugs, on the gastrointestinal transit of liquid and pellet preparations in human subjects using gamma scintigraphy. Methods. Ten, healthy male volunteers each received, on separate occasions, a liquid preparation consisting of 150 ml orange juice (control) or 150 ml orange juice containing 10 g PEG 400 (test). Non-disintegrating pellets of size 1.4-1.7 mm, encapsulated within a hard gelatin capsule, were simultaneously administered on both occasions to act as a marker for solid dosage form transit. The liquid and pellet preparations were radiolabelled with 111In and 99mTc respectively thus enabling their positions within the gastrointestinal tract to be followed using a gamma camera. Results. Rapid liquid emptying from the stomach was observed, with no significant difference noted in the gastric residence times of the two preparations. Caecum arrival times for the liquid preparations were significantly different by virtue of their differential rates of transit through the small intestine. The mean small intestinal liquid transit time for the control preparation was 236 min whereas the corresponding value for the PEG 400-containing test preparation was 153 min. This 35% reduction in transit time was attributed to the presence of PEG 400. Pellet transit was largely unaffected by the presence of PEG 400. Conclusions. These findings clearly demonstrate that PEG 400 has a marked accelerating effect on small intestinal liquid transit, which in turn has implications for the formulation of poorly water-soluble drugs with PEG 400.

Influence of Polyethylene Glycol 400 on the Gastrointestinal Absorption of Ranitidine

AbstractPurpose. To investigate the effect of co-administered polyethylene glycol 400 (PEG 400), a pharmaceutical excipient previously shown to accelerate small intestinal transit, on the absorption characteristics of ranitidine from the gastrointestinal tract. Methods. Ten healthy male volunteers each received, on two separate occasions, an immediate-release pellet formulation of ranitidine (150 mg) encapsulated within a hard gelatin capsule and a liquid preparation consisting of 150 ml orange juice (control) or 150 ml orange juice containing 10 g PEG 400 (test). The liquid preparations were also radiolabelled with indium-111 to allow their transit through the gastrointestinal tract to be followed using a gamma camera. On a further occasion an intravenous injection of ranitidine (50 mg) was administered. Blood samples were taken over a 12 h period on each study day to allow a ranitidine plasma and subsequent absorption rate profile to be generated for each oral formulation. Urine was collected for 24 h and assessed for PEG 400 concentration. Results. The absolute bioavailability of ranitidine from the pellet formulation was significantly reduced by 31% (from 51% to 35%) and small intestinal liquid transit time was significantly shortened by 37% (from 226 min to 143 min) as a consequence of PEG 400 in the test preparation. PEG 400 also affected the rate of ranitidine absorption, with major differences noted in the mean absorption time and Cmax parameters. The appearance of double peaks were less evident in the ranitidine pharmacokinetic profiles in the presence of PEG 400, and little or no correlation was observed between the absorption of ranitidine and PEG 400. Conclusions. These results clearly demonstrate that PEG 400 adversely influences the gastrointestinal absorption of ranitidine. This in turn has ramifications for the use of PEG 400 as a pharmaceutical excipient in oral formulations.

177Lu-DOTATATE Molecular Radiotherapy for Childhood Neuroblastoma

This study tested the principle that 68Ga-DOTATATE PET/CT may be used to select children with primary refractory or relapsed high-risk neuroblastoma for treatment with 177Lu-DOTATATE and evaluated whether this is a viable therapeutic option for those children. Methods: Between 2008 and 2010, 8 children with relapsed or refractory high-risk neuroblastoma were studied with 68Ga-DOTATATE PET/CT. The criterion of eligibility for 177Lu-DOTATATE therapy was uptake on the diagnostic scan equal to or higher than that of the liver. Results: Of the 8 children imaged, 6 had abnormally high uptake on the 68Ga-DOTATATE PET/CT scan and proceeded to treatment. Patients received 2 or 3 administrations of 177Lu-DOTATATE at a median interval of 9 wk and a median administered activity of 7.3 GBq. Of the 6 children treated, 5 had stable disease by the response evaluation criteria in solid tumors (RECIST). Of these 5 children, 2 had an initial metabolic response and reduction in the size of their lesions, and 1 patient had a persistent partial metabolic response and reduction in size of the lesions on CT, although the disease was stable by RECIST. One had progressive disease. Three children had grade 3 and 1 child had grade 4 thrombocytopenia. No significant renal toxicity has been seen. Conclusion: 68Ga-DOTATATE can be used to image children with neuroblastoma and identify those suitable for molecular radiotherapy with 177Lu-DOTATATE. We have shown, for what is to our knowledge the first time, that treatment with 177Lu-DOTATATE is safe and feasible in children with relapsed or primary refractory high-risk neuroblastoma. We plan to evaluate this approach formally in a phase I–II clinical trial.

Concentration-Dependent Effects of Polyethylene Glycol 400 on Gastrointestinal Transit and Drug Absorption

AbstractPurpose. The aim of the study was to investigate the effect of different concentrations of polyethylene glycol 400 (PEG 400) on liquid transit through, and ranitidine absorption from, the gastrointestinal tract. Methods. Six healthy male volunteers received, on four separate occasions, 150 mL water containing 150 mg ranitidine and either 0 (control), 1, 2.5, or 5 g PEG 400. The solutions were radiolabeled with technetium-99m to allow their gastrointestinal transit to be followed using a gamma camera. Urine samples were collected over a 24-h period to assess the amount of ranitidine excreted and hence absorbed. Results. No significant differences in gastric emptying were noted between the four solutions. In contrast, the presence of 1, 2.5, and 5 g PEG 400 reduced the mean small intestinal transit times of the solutions by 9, 20, and 23%, respectively, against the control. In terms of drug absorption, the mean cumulative amount of ranitidine excreted was reduced by 38% in the presence of both 2.5 and 5 g PEG 400, although it was significantly increased by 41% in the presence of 1 g PEG 400. Conclusions. The results show that low concentrations of PEG 400 enhance the absorption of ranitidine possibly via modulation of intestinal permeability, while high concentrations have a detrimental effect on ranitidine absorption presumably via a reduction in the small intestinal transit time.

The sentinel node in surgical oncology

This book, a comprehensive review on sentinel node detection, is geared toward nuclear medicine physicians, pathologists, surgeons, technologists, and health care providers interested in the growing field of tumor detection and removal. The foreword explains how sentinel node detection can alter our perception of cancer treatment and potentially influence treatment algorithms significantly, and the preface explains the importance of a multidisciplinary team approach to this method of treatment. Well-presented, well-illustrated chapters are included on probe selection, radiopharmaceuticals, pathology, imaging techniques, dosimetry, radiation protection, and cost-effectiveness. Three chapters were previously published in the European Journal of Nuclear Medicine , and these are particularly well illustrated and have many tables. The main focus is on breast cancer and malignant melanoma, but penile carcinoma and colon cancer are also mentioned. A brief discussion on the use of blue dye in sentinel node localization contributes to the broad appeal and uniqueness of the book. Techniques, surgical imaging, and pathology are discussed well, and a useful chapter is included on dosimetry and radiation protection for health care providers. Inclusion of this chapter is interesting because many health care providers, especially those not used to dealing with radiation, are concerned about exposure. The issue is adequately addressed, including details on radiation protection. A final strong point is that the book is replete with peerreviewed references. Among the shortcomings of the book is its repetitiveness. For example, probe selection is discussed in chapter 1 and again in chapter 4. With 4 authors, and with 2 chapters edited by other contributors, the book is a compilation of efforts and reads as such. Other deficiencies are the superficial discussion of patient preparation and the lack of information on pain management. In addition, the subject index is incomplete and often does not direct one to all pertinent pages. Another shortcoming is that the book was written mainly for Europeans. The authors describe the European practice in sentinel node detection and lymphoscintigraphy and include a chapter on malignant melanoma detection in Europe. They use many terms familiar to European physicians, such as the term “theater” for operating room. In the chapter on clinical cases, the radiopharmaceuticals discussed are used mainly in Europe, and for U.S. readers a more detailed discussion on radiopharmaceuticals available in the United States and on the size of colloid particle doses would have been useful. Besides this shortcoming, other weak points in the chapter include the similarity among the cases, the simplism of the teaching points, and the inadequacy of the information on radiopharmaceuticals, doses, patient preparation, and other complementary studies. Some discussion on pearls and pitfalls should also have been included. Overall, I consider this text a primer for beginners in the field of sentinel node detection. It is useful for a multidisciplinary approach to this method of treatment and is written in a manner that all can understand. The clarity of the text and the high-quality figures and tables provide newcomers with fundamentals on the technique and information on the usefulness of sentinel node detection.

18F-FDG PET/CT and 123I-Metaiodobenzylguanidine Imaging in High-Risk Neuroblastoma: Diagnostic Comparison and Survival Analysis

The aim of our study was to evaluate prospectively the diagnostic performance and prognostic significance of 18F-FDG PET/CT in comparison with 123I-metaiodobenzylguanidine (123I-MIBG) imaging in patients with high-risk neuroblastoma. Methods: Twenty-eight patients with refractory or relapsed high-risk neuroblastoma (16 male and 12 female patients; age range, 2–45 y; median age, 7.5 y) were simultaneously evaluated with 18F-FDG PET/CT and 123I-MIBG imaging before treatment with high-dose 131I-MIBG. We compared the 2 methods in mapping tumor load, according to the extent of disease and intensity of positive lesions identified in each patient. Separate comparisons were performed for the soft-tissue and bone–bone marrow components of tumor burden. Survival analysis was performed to assess the prognostic significance of 18F-FDG and 123I-MIBG imaging parameters. Results: 18F-FDG PET/CT results were positive in 24 of 28 (86%) patients, whereas 123I-MIBG imaging results were positive in all patients. 18F-FDG was superior in mapping tumor load in 4 of 28 (14%) patients, whereas 123I-MIBG was better in 12 of 28 (43%) patients. In the remaining 12 (43%) patients, no major differences were noted between the 2 modalities. 18F-FDG PET/CT missed 5 cases of bone–bone marrow disease, 4 cases of soft-tissue disease, and 6 cases of skull involvement that were positive on 123I-MIBG scans. Cox regression and Kaplan–Meier survival curves showed that the group of patients (4/28) in whom 18F-FDG was superior to 123I-MIBG had a significantly lower survival rate than the others. Tumoral avidity for 18F-FDG (maximum standardized uptake value) and extent of 18F-FDG–avid bone–bone marrow disease were identified as adverse prognostic factors. Conclusion: 123I-MIBG imaging is superior to 18F-FDG PET/CT in the assessment of disease extent in high-risk neuroblastoma. However, 18F-FDG PET/CT has significant prognostic implications in these patients.

Colonic delivery of 4-aminosalicylic acid using amylose–ethylcellulose-coated hydroxypropylmethylcellulose capsules

Background : 4‐Aminosalicylic acid has the potential for use in the treatment of diseases of the colon.

Initial evaluation of123I-5-I-R91150, a selective 5-HT2A ligand for single-photon emission tomography, in healthy human subjects

The mapping of 5-HT2 receptors in the brain using functional imaging techniques has been limited by a relative lack of selective radioligands. Iodine-123 labelled 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide (123I-5-I-R91150 or123I-R93274) is a new ligand for single-photon emission tomography (SPET), with high affinity and selectivity for 5-HT2A receptors. This study reports on preliminary123I-5-I-R91150 SPET, wholebody and blood distribution findings in five healthy human volunteers. Maximal brain uptake was approximately 2% of total body counts at 180 min post injection (p.i.). Dynamic SPET sequences were acquired with the brain-dedicated, single-slice multi-detector system SEM-810 over 200 min p.i. Early peak uptake (at 5 min p.i.) was seen in the cerebellum, a region free from 5HT2A receptors. In contrast, radioligand binding in the frontal cortex increased steadily over time, up to a peak at approximately 100–120 min p.i. Frontal cortex-cerebellum activity ratios reached values of 1.4, and remained stable from approximately 100 min p.i. onwards. Multi-slice SPET sequences showed a pattern of regional variation of binding compatible with the autoradiographic data on the distribution of 5-HT2A receptors in (cerebral cortex>striatum>cerebellum). These findings suggest that123I-5-I-R91150 may be used for the imaging of 5-HT2A receptors in the living human brain with SPET.