Full report on a survey of adverse reactions to radiopharmaceuticals from 1975 to 2017 in Japan.

OBJECTIVE: This pharmacovigilance-based survey was aimed at determining the prevalence of, and association between, radiopharmaceuticals and adverse reactions to radiopharmaceuticals from 1975 to 2017 in Japan. METHODS: The Subcommittee for Safety Issues of Radiopharmaceuticals of the Japan Radioisotope Association's Medical Science and Pharmaceutical Committee mailed a form for reporting adverse reactions to radiopharmaceuticals to all institutes performing nuclear medicine examinations in Japan. This investigation included adverse reactions to diagnostic radiopharmaceuticals labeled with both single-photon- and positron-emitting radionuclides and therapeutic sodium iodide labeled with 131I. Each institute returned the reporting form to the subcommittee each time an adverse reaction occurred. RESULTS: Replies were obtained from 75% of the institutions. In total, 1099 adverse reactions were reported from 46,645,580 radiopharmaceutical administrations, giving a prevalence of 2.4 adverse reactions per 100,000 administrations (95% confidence interval 2.2-2.5). Adverse reactions were most frequently observed for 131I-iodomethylnorcholesterol (230.1/105 administrations), followed by 131I-HSA (76.3/105 administrations), 131I-sodium iodohippurate (31.2/105 administrations), and 99mTc-DTPA (12.0/105 administrations). Comparison of adverse reactions between before and after 1997 revealed that prevalence dropped from 3.7/105 administrations (95% confidence interval 3.5-4.1) to 1.5/105 administrations (95% confidence interval 1.4-1.6). During the study period, vasovagal reactions accounted for 50.3% of adverse reactions, fever for 7.5%, allergic reactions for 25.7%, and other for 16.5%; 3.7% of all adverse reactions were considered severe but none were lethal. A definite, probable, possible, less likely, and uncertain causal relationship with radiopharmaceuticals was observed in 13.1%, 33.7%, 39.9%, 6.2%, and 7.1% of adverse reactions, respectively. CONCLUSIONS: These results suggest that nuclear medicine staff must be aware of the possibility of adverse reactions from radiopharmaceuticals, despite their rarity.

Comparison of Post-injection Site Pain Between Technetium Sulfur Colloid and Technetium Tilmanocept in Breast Cancer Patients Undergoing Sentinel Lymph Node Biopsy.

BACKGROUND: No prior studies have examined injection pain associated with Technetium-99m Tilmanocept (TcTM). METHODS: This was a randomized, double-blinded study comparing postinjection site pain between filtered Technetium Sulfur Colloid (fTcSC) and TcTM in breast cancer lymphoscintigraphy. Pain was evaluated with a visual analogue scale (VAS) (0-100 mm) and the short-form McGill Pain Questionnaire (SF-MPQ). The primary endpoint was mean difference in VAS scores at 1-min postinjection between fTcSC and TcTM. Secondary endpoints included a comparison of SF-MPQ scores between the groups at 5 min postinjection and construction of a linear mixed effects model to evaluate the changes in pain during the 5-min postinjection period. RESULTS: Fifty-two patients underwent injection (27-fTcSC, 25-TcTM). At 1-min postinjection, patients who received fTcSC experienced a mean change in pain of 16.8 mm (standard deviation (SD) 19.5) compared with 0.2 mm (SD 7.3) in TcTM (p = 0.0002). At 5 min postinjection, the mean total score on the SF-MPQ was 2.8 (SD 3.0) for fTcSC versus 2.1 (SD 2.5) for TcTM (p = 0.36). In the mixed effects model, injection agent (p < 0.001), time (p < 0.001) and their interaction (p < 0.001) were associated with change in pain during the 5-min postinjection period. The model found fTcSC resulted in significantly more pain of 15.2 mm (p < 0.001), 11.3 mm (p = 0.001), and 7.5 mm (p = 0.013) at 1, 2, and 3 min postinjection, respectively. CONCLUSIONS: Injection with fTcSC causes significantly more pain during the first 3 min postinjection compared with TcTM in women undergoing lymphoscintigraphy for breast cancer.

Sentinel lymph node status in vulval cancer: systematic reviews of test accuracy and decision-analytic model-based economic evaluation.

BACKGROUND: Vulval cancer causes 3-5% of all gynaecological malignancies and requires surgical removal and inguinofemoral lymphadenectomy (IFL). Complications affect > 50% of patients, including groin wound infection, lymphoedema and cellulitis. A sentinel lymph node (SLN) is the first groin node with the highest probability of malignancy. SLN biopsy would be useful if it could accurately identify patients in whom cancer has spread to the groin, without removing all groin nodes. SLNs can be identified by isosulfan blue dye and/or technetium-99 ((99m)Tc) radioactive tracer during lymphoscintigraphy. The blue dye/(99m)Tc procedure only detects SLN, not metastases - this requires histological examination, which can include ultrastaging and staining with conventional haematoxylin and eosin (H&E) or immunohistochemistry. OBJECTIVES: To determine the test accuracy and cost-effectiveness of the SLN biopsy with (99m)Tc and/or blue dye compared with IFL or clinical follow-up for test negatives in vulval cancer, through systematic reviews and economic evaluation. DATA SOURCES: Standard medical databases, including MEDLINE, EMBASE, Science Citation Index and The Cochrane Library, medical search gateways, reference lists of review articles and included studies were searched to January 2011. METHODS: For accuracy and effectiveness, standard methods were used and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Searches were to January 2011, with no language restrictions. Meta-analyses were carried out with Meta-Disc version 1.4 (Javier Zamora, Madrid, Spain) for accuracy; none was appropriate for effectiveness. The economic evaluation from a NHS perspective used a decision-tree model in DATA TreeAge Pro Healthcare 2001 (TreeAge Software, Inc., Williamstown, MA, USA). Six options (blue dye with H&E, blue dye with ultrastaging, (99m)Tc with H&E, (99m)Tc with ultrastaging, blue dye/(99m)Tc with H&E, blue dye/(99m)Tc with ultrastaging) were compared with IFL. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: For accuracy, of the 26 included studies, most evaluated (99m)Tc/blue dye combined. Four studies had clinical follow-up only for test negatives and five had clinical follow-up for all and IFL for test negatives. Numbers with no SLN found were difficult to distinguish from those with negative SLN biopsies. The largest group of 11 studies using (99m)Tc/blue dye, ultrastaging and immunohistochemistry had a pooled sensitivity of 95.6% [95% confidence interval (CI) 91.5% to 98.1%] and a specificity of 100% (95% CI 99.0% to 100%). Mean SLN detection rates were 94.6% for (99m)Tc, 68.7% for blue dye and 97.7% for both. One study measured global health status quality of life (QoL) and found no difference between SLN biopsy and IFL. One patient preference evaluation showed that 66% preferred IFL rather than a 5% false-negative rate from SLN biopsy. For effectiveness, of 14,038 references, one randomised controlled trial, three case-control studies and 13 case series were found. Approximately 50% died from vulval cancer and 50% from other causes during follow-ups. Recurrences were in the ratio of approximately 4 : 2 : 1 vulval, groin and distant, with more recurrences in node-positive patients. No studies reported QoL. For cost per death averted, IFL was less costly and more effective than strategies using SLN biopsy. For morbidity-free survival and long-term morbidity-free survival, (99m)Tc with ultrastaging was most cost-effective. Strategies with blue dye only and H&E only were never cost-effective. The incremental cost-effectiveness ratio for (99m)Tc with ultrastaging compared with IFL was £4300 per case of morbidity-free survival and £7100 per long-term morbidity-free survival. LIMITATIONS: The main limitations of this study include the lack of good-quality evidence on accuracy, effectiveness and QoL. A large project such as this takes time to publish, so the most recent studies are not included. CONCLUSIONS: A sensitive and specific combined metastatic SLN detection test and information on generic QoL in vulval cancer is urgently required. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Comparative evaluation of [(99m)tc]tilmanocept for sentinel lymph node mapping in breast cancer patients: results of two phase 3 trials.

BACKGROUND: Sentinel lymph node (SLN) surgery is used worldwide for staging breast cancer patients and helps limit axillary lymph node dissection. [(99m)Tc]Tilmanocept is a novel receptor-targeted radiopharmaceutical evaluated in 2 open-label, nonrandomized, within-patient, phase 3 trials designed to assess the lymphatic mapping performance. METHODS: A total of 13 centers contributed 148 patients with breast cancer. Each patient received [(99m)Tc]tilmanocept and vital blue dye (VBD). Lymph nodes identified intraoperatively as radioactive and/or blue stained were excised and histologically examined. The primary endpoint, concordance (lower boundary set point at 90 %), was the proportion of nodes detected by VBD and [(99m)Tc]tilmanocept. RESULTS: A total of 13 centers contributed 148 patients who were injected with both agents. Intraoperatively, 207 of 209 nodes detected by VBD were also detected by [(99m)Tc]tilmanocept for a concordance rate of 99.04 % (p < 0.0001). [(99m)Tc]tilmanocept detected a total of 320 nodes, of which 207 (64.7 %) were detected by VBD. [(99m)Tc]Tilmanocept detected at least 1 SLN in more patients (146) than did VBD (131, p < 0.0001). In 129 of 131 patients with ≥1 blue node, all blue nodes were radioactive. Of 33 pathology-positive nodes (18.2 % patient pathology rate), [(99m)Tc]tilmanocept detected 31 of 33, whereas VBD detected only 25 of 33 (p = 0.0312). No pathology-positive SLNs were detected exclusively by VBD. No serious adverse events were attributed to [(99m)Tc]tilmanocept. CONCLUSION: [(99m)Tc]Tilmanocept demonstrated success in detecting a SLN while meeting the primary endpoint. Interestingly, [(99m)Tc]tilmanocept was additionally noted to identify more SLNs in more patients. This localization represented a higher number of metastatic breast cancer lymph nodes than that of VBD.

Modification of Diet in Renal Disease equation in the risk stratification of contrast induced acute kidney injury in hospital in patients

Antecedentes: Varios organismos recomiendan el uso de la tasa de filtrado glomerular estimada (TFGe) en la monitorización de la función renal, calculada preferentemente con la fórmula de Modificación de la Dieta en la Enfermedad Renal (MDRD). El papel de esta fórmula no está claro en la estratificación del riesgo de la lesión renal aguda inducida por contraste en pacientes no estables. Objetivo: Evaluación comparativa de la TFGe de la MDRD en la estratificación del riesgo de lesión renal aguda inducida por contraste. Método: La tasa de filtrado glomerular (TFG) se midió dos veces (pre- y posexamen) mediante Tc-99m-DTPA, junto con los niveles de nitrógeno ureico en suero y creatinina en 32 pacientes (edad media ± DE; 60,1 ± 13,2 años) que precisaban de cuidados hospitalarios por diversas razones y que se sometieron a rayos-x mediante contraste (mediana; 90,2 ± 16,8 ml). La TFGe se calculó mediante la fórmula correspondiente. Se evaluó la concordancia entre la TFG medida (TFGm) y la TFGe de la MDRD, asignando a los pacientes un baremo de estratificación para la lesión renal aguda inducida por contraste, usando primero la TFGm y posteriormente TFGe, comparando los resultados. Resultados: Se obtuvo una correlación moderada entre la TFGm y la TFGe (r =0,47, p <0,001), con una diferencia no significativa. Sin embargo, el análisis de Bland& Altman reveló grandes límites de concordancia entre la TFGm y la TFGe (-80,3 a 55,2), con una diferencia media de -12,5 ml/min/1,73 m2. En el análisis por método ROC, cuando los valores de la TFGm se catalogaron como normales(>60 ml/min/1,73 m2) y disminuidos (< 60 ml/min/1,73 m2), el área bajo la curva fue 0.80 (CI 95%; 0,62-0,92) para TFGe, con una sensibilidad del (..) (AU)

Background: Several organizations recommend using estimated glomerular filtration rate (eGFR) in kidney function monitoring, preferably calculated with Modification of Diet in Renal Disease (MDRD) formula. The role of this formula is not clear in the risk stratification of contrast induced acute kidney injury (CIAKI) in non steady state patients. Aim Comparative evaluation of the MDRD eGFR in risk stratification of CIAKI. Method: GFR was measured twice (pre and post-examination) by Tc-99m-DTPA, along with serum levels of urea nitrogen and creatinine in 32 patients (mean age ± SD; 60.1 ± 13.2 years) needing hospital care for various reasons and underwent to x-ray examination with contrast media (mean; 90.2 ± 16.8 ml). eGFR was calculated by the dedicated formula. Agreement between measured GFR(mGFR) and MDRD eGFR was assessed and patients were scored and stratified for CIAKI by using first mGFR, then eGFR and results were compared. Results: A moderate correlation was obtained between mGFR and eGFR (r = 0.47, p <0.001)and the difference was not significant. However, Bland&Altman analysis revealed large limits of agreement between mGFR and eGFR (-80.3 to 55.2) with a mean difference of -12.5 ml/min/1.73m2. In ROC analysis, when mGFR values were classified as normal (>60 ml/min/1.73m2)and decreased (<60ml/min/1.73m2), AUC was 0.80 (95%CI;0.62-0.92) for eGFR, with a sensitivity of 29% and specificity of 100%. Furthermore, the risk group categorization, using eGFR instead of mGFR was resulted in a group change for four patients (13%); from moderate to low risk group. Conclusion: It seems that MDRD eGFR differs from mGFR. In non steadystate patients CIAKI classification using eGFR should be considered with caution (AU)

Special safety considerations in preparation of technetium Tc-99m DTPA for cerebrospinal fluid-related imaging procedures.

OBJECTIVE: To review special safety considerations in the preparation of technetium 99m (Tc-99m) diethylenetriaminepentaacetic acid (DTPA; generic name, pentetate) for cerebrospinal fluid (CSF)-related imaging procedures. DATA SOURCES: Review of practices and results at one institution supplemented with findings and recommendations from the literature. Literature searches were conducted via Medline/PubMed using the following terms: Tc-99m DTPA/pentetate, CSF, cisternography, intrathecal, and adverse reactions. The author's own files were also searched for articles (e.g., in newsletters) not indexed by Medline/PubMed. STUDY SELECTION: Articles considered appropriate for review included all human research studies, reviews, case reports, abstracts, and letters published in English on Tc-99m DTPA use in CSF-related imaging procedures, especially with regard to safety or adverse reactions. DATA EXTRACTION: All information related to safety precautions and adverse reactions associated with Tc-99m DTPA injected intrathecally or otherwise used for CSF-related imaging procedures were considered. DATA SYNTHESIS: 18 years' experience in one institution was reviewed with the added perspective of literature findings and recommendations. CONCLUSION: With proper attention to safety considerations, Tc-99m DTPA can be safely used in CSF-related imaging procedures.

Predictive value of 99Tcm-DTPA captopril scintigraphy in patients with a solitary kidney and reduced kidney function.

The aim of this study was to determine if the qualitative 99Tcm-DTPA captopril radionuclide test (CRT) can help predict the acute detrimental effect of angiotensin-converting enzyme (ACE) inhibitors on renal function in hypertensive patients with solitary kidneys and chronic renal failure. Between 1991 and 1996, eight consecutive patients (6 males, 2 females) aged 27-73 years (mean 49.8 years) with known chronic renal failure and a solitary kidney referred for ACE treatment were included. 99Tcm-DTPA renography was performed at baseline and 1 h after the administration of 25 mg captopril within 1 week of each other. The CRT was performed in accordance with the criteria of the Working Party on the Diagnostic Criteria of Renovascular Hypertension with Captopril Renography. A beneficial or detrimental effect of subsequent ACE inhibitor treatment on renal function was determined by long-term follow-up (> or = 2 years). The CRT accurately predicted outcome in all eight patients subsequently treated with ACE inhibitors. In conclusion, our results suggest a role for qualitative 99Tcm-DTPA CRT in the prediction of renal function in patients with a solitary kidney and chronic renal failure subsequently treated with ACE inhibitors.

Quantitative assessment of hepatocellular function through in vivo radioreceptor imaging with technetium 99m galactosyl human serum albumin.

Technetium 99m diethylenetriaminepentaacetic acid-galactosyl human serum albumin is a newly developed analog ligand to asialoglycoprotein receptor, which is a hepatic cell surface receptor specific for galactose-terminated glycoproteins. Hepatic functional imaging, which yields estimates of asialoglycoprotein receptor concentration, was performed after intravenous injection of 3 mg technetium 99m diethylenetriaminepentaacetic acid-galactosyl human serum albumin. A total of 75 human subjects were studied: 6 controls without liver diseases, 51 patients with chronic liver diseases and 18 patients with acute liver diseases. In chronic liver disease the asialoglycoprotein receptor concentration significantly correlated with the clinical severity based on the criteria of the Liver Cancer Study Group of Japan (rs = -0.890, p = 0.0001). Good correlations between the asialoglycoprotein receptor concentration and conventional liver function tests were also observed. In acute liver disease the asialoglycoprotein receptor concentration correlated well with the normotest (r = 0.796, p = 0.0001), prothrombin time (r = 0.701, p = 0.0002) and total serum bilirubin (r = -0.642, p = 0.0007). We conclude that the parameter, asialoglycoprotein receptor concentration, obtained from the kinetic analysis of technetium 99m diethylenetriaminepentaacetic acid-galactosyl human serum albumin time-activity data, is a sensitive measure of functioning hepatocyte mass in acute and chronic liver disease.