Individualization of Radionuclide Therapies: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Hanna Piwowarska-Bilska.

Evidence shows that better and more predictable outcomes can be achieved with patient-individualized dose assessment. Therefore, the incorporation of individual planning into radionuclide therapies is a high priority for nuclear medicine physicians and medical physicists alike. Internal dosimetry is used in tumor therapy to optimize the absorbed dose to the target tissue.  For a nuclear medicine therapy to be considered personalized, treatment planning is essential, including the activity chosen individually for a given patient. The first step in individual planning of radioisotope therapy is to perform a series of diagnostic images, which allows visualizing the distribution and measuring how the activity decreased in time in different organs. The next step is to perform dosimetric measurements. It provides information on the degree of uptake of an administered radiopharmaceutical in pathological tissues and critical organs. The obtained dosimetric report is the foundation for planning the maximum activity on tumors, with a safe level of irradiation of critical organs in a given patient. The last step is to obtain a series of images of the patient recorded after the administration of the therapeutic radiopharmaceutical. 

  • internal dosimetry
  • radiopharmaceuticals
  • radionuclide therapy

1. Introduction

Nuclear medicine uses radiopharmaceuticals, which are various molecules labeled with radioactive isotopes, for diagnosis and therapy. Radiopharmaceuticals are sources of radiation, and when introduced into the patient’s body (by injection, oral administration, or inhalation), they target specific organs, tissues, or cells. Subsequently, the activity of radiopharmaceuticals in tissues decreases due to their elimination from the body and radioactive decay. Administration of the same activity of a given radiopharmaceutical to different patients can distribute in their bodies differently, and therefore it is important to consider each patient individually. The determination of the total number of nuclear disintegrations that occur in a particular organ allows calculating the mean energy absorbed per kilogram of tissue. This parameter is known as the mean absorbed dose.
The knowledge of the absorbed ionizing radiation dose after administration of a radioactive preparation is of great importance both for the patient’s safety and for the proper course of diagnostics or radioisotope therapy. The activity of radioisotopes, administered to patients for diagnostic imaging studies, must ensure the correct image quality while minimizing the dose that will be absorbed. Due to the increase in sensitivity of modern gamma cameras, the reported diagnostic activities are low. However, in the case of radioisotope therapy, the activity of the therapeutic radioisotope should be as high as possible to effectively destroy tumor cells, and at the same time, low enough not to damage critical organs. Therapy using radioactive isotopes is an extremely important and rapidly developing part of nuclear medicine. Modern radioisotope treatments are based on the idea of theranostics [1], according to which a diagnostic examination should be performed with the use of a radiopharmaceutical with the same distribution as the therapeutic radiopharmaceutical. Only when the result of the primary examination shows a sufficiently high accumulation of diagnostic radiopharmaceutical is the patient eligible for the treatment procedure.
In every clinical situation that requires the administration of a radioactive substance to the patient, it is important to know the absorbed dose. Moreover, it is of special importance when the activity is very high, as is the case with radioisotope therapies. Individualized therapy plans, created based on images of a given patient, allow for the optimization of therapy and the minimization of toxic effects [2][3][4][5][6].
Both nuclear medicine and external beam radiotherapy (EBRT) use ionizing radiation to treat malignant tissue. EBRT requires advanced equipment that shapes the external beam to conform to the tumor, and nuclear medicine uses radiopharmaceuticals that are introduced directly into the body. Both treatment techniques should follow the guidelines contained in COUNCIL DIRECTIVE 2013/5/EURATOM from 5 December 2013, concerning the safety of patients diagnosed and treated with ionizing radiation [7]. In Article 56 of the Directive, the following is written: “For all medical exposure of patients for radiotherapeutic purposes, exposures of target volumes shall be individually planned, and their delivery appropriately verified taking into account that doses to non-target volumes and tissues shall be as low as reasonably achievable and consistent with the intended radiotherapeutic purpose of the exposure.” This implies the necessity to personalize the treatment, i.e., the selection of the suitable pharmaceutical, in the right dosage and time. Individual EBRT planning is a common practice that has been developed and used for many years. Teams of physicists involved in treatment planning and clinical dosimetry for each and every patient are the standard in radiotherapy centers. Radiation treatment planning is performed with the use of advanced computer programs using computed tomography (CT), magnetic resonance (MR), or positron emission tomography (PET) images. Modern planning methods include the three-dimensional (3D) technique, which allows for the spatial shaping of radiation beams and the protection of critical organs [8][9].
The situation in nuclear medicine is completely different. Few physicists work in nuclear medicine departments, and radioisotope therapies are usually performed according to standard clinical procedures. Individual calculations of radiopharmaceutical doses for patients are not routinely performed in most nuclear medicine facilities across the world. Nuclear medicine specialists most often use standard activities of radiopharmaceuticals during therapy, considering the patient’s weight or body surface area.
In some cases, administration of standard radiopharmaceutical activities does not provide a sufficiently high dose per tumor to destroy it. On the other hand, giving too much activity could have harmful effects on critical organs. A small fraction of patients receives optimal activity, while the vast majority receive lower doses. This conservative approach provides “radiation safety” to healthy tissues, but also delivers a lower dose than indicated to the neoplastic tissue, resulting in a low response rate and a higher rate of disease relapse. Individualized treatment planning would provide higher absorbed doses to most patients without risking toxicity. “Personalized dosimetry is a must for appropriate molecular radiotherapy”—this is the title of the article by Stabin (one of the pioneers of internal dosimetry) et al. published in 2019 in the Medical Physics journal [10].
 

2. Radionuclides for Therapies

Due to the intensive development of pharmacology, the number of new radiopharmaceuticals that can be used in therapy is increasing every year. A particular advantage of radioisotope therapies is that they can be used in situations where all other forms of treatment have failed. Most radionuclides used in therapy emit β− particles, and rarely α particles, which are highly potent. Table 1 contains information on the radionuclides used in radioisotope therapies. Table 2, on the contrary, presents the radionuclides currently being tested, which provides the evidence of the intensive development of this method of treatment.
Table 1.
 Radionuclides used in particular types of radioisotope therapies.
Radionuclide Basic Radiation

Type for

Therapy		 Chemical and Dosage Form Indications Administration Route References
Type for Therapy Indications References
Iodine 131I β− Sodium iodide Thyroid carcinoma Oral  
Hyperthyroidism [
Yttrium 90Y β− Breast cancer [34]
11][12]
Lutetium 177Lu β− Pancreatic cancer [35] Iodine 131I β−   Pheochromocytoma
Iodine 131I β− Neuroblastoma Central Nervous System/Leptomeningeal MetastasesIntravenous [36 
] Iobenguane Paraganglioma
Phosphorus 32P[13 β−][14][15][16]
Pancreatic cancer [37]   Neuroblastoma

Carcinoid		  
Copper 67Cu β− Radioimmunotherapy [38] Iodine 131I β− Apamistamab Leukemia Intravenous [17]
Holmium 166Ho β− HCC, liver metastasis [39] Iodine 131I β− Tositumomab non-Hodgkin’s lymphoma Intravenous [18]
Indium 111In[19 Auger e−]
GEP-NETs, lung and bladder cancer [40][41][42] Iodine 131I β− Lipiodol HCC, liver metastasis Intra-arterial

infusion		 [20][21]
Samarium 153Sm β− Lexidronam Painful skeletal metastases Intravenous [22]
Strontium 89Sr β− Strontium chloride APainful skeletal metastases Lung cancer, glioblastoma, radioimmunotherapy [47][48][49Intravenous ][50][23]
Yttrium 90Y β− Ibritumomabtiuxetan non-Hodgkin’s lymphoma Intravenous [24 β− 90Y resin spheres Unresectable HCC

Liver metastasis		 Intra-arterial

infusion		 [26]
Lutetium 177Lu or

Yttrium 90Y		 β− [177Lu]Lu-DOTATATE

[90Y]Y or [177Lu]Lu-DOTATOC
Tin 117mSn Internal conversion e− Painful skeletal metastases [43]
Bismuth 213Bi α Glioblastoma, prostate and bladder cancer [44][45][46] ]
Yttrium 90Y

Therasphere		 β− 90Y glass spheres Unresectable HCC

Liver metastasis		 Intra-arterial

infusion		 [25]
Yttrium  Unresectable or metastasized NETs Intravenous [27][28]
Lutetium 177Lu or Actinium225Ac β−

α		 [177Lu]Lu-PSMA Prostate cancer Intravenous  
[225Ac]Ac-PSMA (mCRPC) [29
Astatine 21190Y

][30]
At Phosphorus 32P

Yttrium 90Y

Rhenium 186Re		 β− Colloids Radiosynovectomy Intra-articular

injection		 [31]
SIR-Spheres Radium 223Ra A Radium dichloride Painful skeletal metastases Intravenous [32][33]
HCC: hepatocellular carcinoma; SSTR2: Somatostatin receptor type 2; PSMA: prostate-specific membrane antigen; NET: neuroendocrine tumor; mCRPC: metastatic castration-resistant prostate cancer.
Table 2.
 Radionuclides currently introduced into radioisotope therapies, at the stage of research.
Radionuclide Basic Radiation
GEP-NET: gastroenteropancreatic neuroendocrine tumor; EC: electron capture.

3. Trends in Personalized Internal Dosimetry

Most of the listed dosimetric problems should be solved within the next few years, and intensive work is currently being undertaken on simplifying the internal dosimetry techniques. The first simplification concerns the number of necessary scans performed on one patient. The question arises if performing multiple patient acquisitions is necessary and how many of them should be carried out for individual dosimetric calculations. Freedman et al. [51] propose to decrease the series of four standard acquisitions to two post-treatment scans for PRRT with [177Lu]Lu-DOTATATE. However, the authors emphasize the need for further research, as they are concerned that the methods of estimating absorbed doses based on only two scans would be even more user-dependent and require careful analysis of the volumes of interest (VOIs) in images. In a number of papers, published both many years ago and recently [52][53][54][55][56][57][58][59][60][61][62], the authors propose to limit the number of imaging tests performed for dosimetric purposes to one single SPECT/CT acquisition. It is under debate if such simplified dosimetry, based on one measurement, could work properly at all. From a mathematical point of view, there is a lack of measured data to estimate the dose absorbed in a patient’s tissue. However, missing data can be filled with empiric data on the biokinetics of used radiopharmaceuticals. The single time-point dosimetry method requires knowledge about population averages for tracer kinetic parameters. If the biokinetics of the radiopharmaceutical in the analyzed organ and the shape of the TAC have been previously determined based on studies of a given patient population, only one quantitative measurement of the activity at the time corresponding to approximately 1.5 Teff is sufficient (where Teff is the effective elimination half-life of the radiopharmaceutical from the organ) [55][58]. Accuracy analysis of the absorbed dose estimation showed that, for the vast majority of patients, measurement errors were less than 10% [63]. The solution to underestimated or overestimated measurement results could be the creation of databases on the biokinetics of the radiopharmaceutical used in the population. Therefore, in addition to using results of clinical dosimetry measurements to optimize the treatment of individual patients, the obtained data on the biodistribution of used radiopharmaceuticals should also be used to build pharmacokinetic databases on the biokinetics of various radiopharmaceuticals. This population biodistribution should soon become an integral part of programs for simplified, individual internal dosimetry. The second simplification aims to overcome the difficulties of accurately segmenting organs in SPECT images. Since they have significantly limited resolution, the VOI containing all the accumulated activity is difficult to outline. Moreover, since it is generally larger than the organ itself, the determination of the VOI based on CT images cannot be used because it would not contain all the activity accumulated in the organ. Based on the assumption that the activity in the critical organ is relatively evenly distributed, it has been proposed to evaluate the cumulative dose in the organ based on a “small” VOI placed inside the organ itself [64][65][66]. Since the positioning of this VOI can be difficult and cause differences in dose assessment, an automatic segmentation method has been proposed that eliminates these difficulties [67]. Computer scientists and physicists are developing more and more universal and accessible software for internal dosimetry [68][69][70][71][72]. Due to the rapid development of radiopharmacy, new radiopharmaceutical surrogates can be expected for therapeutic radiopharmaceuticals, which cannot be imaged with the gamma camera [73][74][75]. Radiation dosimetry assessment is often initiated with measuring biodistribution of new radiopharmaceuticals in small animals. To study the biological distribution of radiopharmaceuticals in the human body, it is necessary to find the biological distribution in the rodent body and then the results can be generalized to humans. Preclinical dosimetry studies using small animals are an indispensable step in the pathway from in vitro experiments to clinical implementation of new radioisotope therapies. A lot of studies have shown the practicality of using animal distribution as a model for estimating the absorbed dose in humans [76][77][78][79][80]. Due to the growing awareness of the importance of dosimetry, the Internal Atomic Energy Agency conducts training in that field for doctors and medical physicists. For several years, The European School of Multimodality Imaging and Therapy (ESMIT) has been operating within EANM, the aim of which is to educate specialists at three educational levels, both online and in-person [81][82]. The Dosimetry Project Group, operating within ESMIT, organizes advanced courses for the practical application of clinical dosimetry in radioisotope therapy. The courses enable direct contact with dosimetry experts, exchange of experiences, and cooperation of clinicians, implementing individual internal dosimetry in nuclear medicine facilities around the world. These activities are also related to the existing need for standardization and harmonization of internal clinical dosimetry tools.

This entry is adapted from 10.3390/cancers14143418

References

  1. Ken Herrmann; Steven M. Larson; Wolfgang A. Weber; Theranostic Concepts: More Than Just a Fashion Trend—Introduction and Overview. Journal of Nuclear Medicine 2017, 58, 1S-2S, 10.2967/jnumed.117.199570.
  2. Lidia Strigari; Mark Konijnenberg; Carlo Chiesa; Manuel Bardies; Yong Du; Katarina Sjögreen Gleisner; Michael Lassmann; Glenn Flux; The evidence base for the use of internal dosimetry in the clinical practice of molecular radiotherapy. European Journal of Pediatrics 2014, 41, 1976-1988, 10.1007/s00259-014-2824-5.
  3. Sofie Van Binnebeek; Kristof Baete; Bert Vanbilloen; Christelle Terwinghe; Michel Koole; Felix M. Mottaghy; Paul M. Clement; Luc Mortelmans; Karin Haustermans; Eric Van Cutsem; et al.Alfons VerbruggenKris BogaertsChris VerslypeChristophe Deroose Individualized dosimetry-based activity reduction of 90Y-DOTATOC prevents severe and rapid kidney function deterioration from peptide receptor radionuclide therapy. European Journal of Nuclear Medicine and Molecular Imaging 2014, 41, 1141-1157, 10.1007/s00259-013-2670-x.
  4. K. Reichmann; C. Yong-Hing; M. Damm; J. Risse; H. Ahmadzadehfar; T. Logvinski; S. Guhlke; H.-J. Biersack; A. Sabet; S. Ezziddin; et al. Early prediction of tumour response to PRRT. Nuklearmedizin - NuclearMedicine 2013, 52, 170-177, 10.3413/nukmed-0581-13-05.
  5. Anna Sundlöv; Katarina Sjögreen-Gleisner; Johanna Svensson; Michael Ljungberg; Tomas Olsson; Peter Bernhardt; Jan Tennvall; Individualised 177Lu-DOTATATE treatment of neuroendocrine tumours based on kidney dosimetry. European Journal of Pediatrics 2017, 44, 1480-1489, 10.1007/s00259-017-3678-4.
  6. Raffaella Barone; Françoise Borson-Chazot; Roelf Valkema; Stéphan Walrand; Franck Chauvin; Lida Gogou; Larry K Kvols; Eric P Krenning; François Jamar; Stanislas Pauwels; et al. Patient-specific dosimetry in predicting renal toxicity with (90)Y-DOTATOC: relevance of kidney volume and dose rate in finding a dose-effect relationship.. Journal of Nuclear Medicine 2005, 46, 99S-106S.
  7. Mark Konijnenberg; Ken Herrmann; Carsten Kobe; Frederik Verburg; Cecilia Hindorf; Roland Hustinx; Michael Lassmann; EANM position paper on article 56 of the Council Directive 2013/59/Euratom (basic safety standards) for nuclear medicine therapy. null 2020, 48, 67-72.
  8. Ravi A Chandra; Florence K Keane; Francine E M Voncken; Charles R Thomas; Contemporary radiotherapy: present and future. The Lancet 2021, 398, 171-184, 10.1016/s0140-6736(21)00233-6.
  9. Mareike K Thompson; Philip Poortmans; Anthony J Chalmers; Corinne Faivre-Finn; Emma Hall; Robert A Huddart; Yolande Lievens; David Sebag-Montefiore; Charlotte Coles; Practice-changing radiation therapy trials for the treatment of cancer: where are we 150 years after the birth of Marie Curie?. Br. J. Cancer 2018, 119, 389-407, 10.17863/cam.31556.
  10. Michael G. Stabin; Mark T. Madsen; Habib Zaidi; Personalized dosimetry is a must for appropriate molecular radiotherapy. Medical Physics 2019, 46, 4713-4716, 10.1002/mp.13820.
  11. H R Maxon; E E Englaro; S R Thomas; V S Hertzberg; J D Hinnefeld; L S Chen; H Smith; D Cummings; M D Aden; Radioiodine-131 therapy for well-differentiated thyroid cancer--a quantitative radiation dosimetric approach: outcome and validation in 85 patients.. Journal of Nuclear Medicine 1992, 33, 1132-6.
  12. R S Benua; N R Cicale; M Sonenberg; R W Rawson; The relation of radioiodine dosimetry to results and complications in the treatment of metastatic thyroid cancer.. The American journal of roentgenology, radium therapy, and nuclear medicine 1962, 87, 171-82.
  13. P. A Fitzgerald; R. E Goldsby; J. P Huberty; D. C Price; R. A Hawkins; J. J Veatch; F. D. Cruz; T. M Jahan; C. A Linker; L. Damon; et al.K. K Matthay Malignant Pheochromocytomas and Paragangliomas: A Phase II Study of Therapy with High-Dose 131I-Metaiodobenzylguanidine (131I-MIBG). Annals of the New York Academy of Sciences 2006, 1073, 465-490, 10.1196/annals.1353.050.
  14. Richard B Noto; Daniel A Pryma; Jessica Jensen; Tess Lin; Nancy Stambler; Thomas Strack; Vivien Wong; Stanley J Goldsmith; Phase 1 Study of High-Specific-Activity I-131 MIBG for Metastatic and/or Recurrent Pheochromocytoma or Paraganglioma. The Journal of Clinical Endocrinology & Metabolism 2017, 103, 213-220, 10.1210/jc.2017-02030.
  15. Sally L. George; Nadia Falzone; Sarah Chittenden; Stephanie J. Kirk; Donna Lancaster; Sucheta J. Vaidya; Henry Mandeville; Frank Saran; Andrew D.J. Pearson; Yong Du; et al.Simon T. MellerAna M. Denis-BacelarGlenn D. Flux Individualized 131I-mIBG therapy in the management of refractory and relapsed neuroblastoma. Nuclear Medicine Communications 2016, 37, 466-472, 10.1097/mnm.0000000000000470.
  16. R. Edward Coleman; James B. Stubbs; John A. Barrett; Miguel De La Guardia; Norman Lafrance; John W. Babich; Radiation Dosimetry, Pharmacokinetics, and Safety of Ultratrace™ Iobenguane I-131 in Patients with Malignant Pheochromocytoma/Paraganglioma or Metastatic Carcinoid. Cancer Biotherapy and Radiopharmaceuticals 2009, 24, 469-475, 10.1089/cbr.2008.0584.
  17. Benjamin K. Tomlinson; Vijay Reddy; Mark S. Berger; Jennifer Spross; Renee Lichtenstein; Boglarka Gyurkocza; Rapid Reduction of Peripheral Blasts in Older Patients with Refractory Acute Myeloid Leukemia (AML) Using Re-Induction with Single Agent Anti-CD45 Targeted Iodine (131I) Apamistamab [Iomab-B] Radioimmunotherapy in the Phase III SIERRA Trial. Clinical Lymphoma Myeloma and Leukemia 2019, 19, S232, 10.1016/j.clml.2019.07.117.
  18. Julie M. Vose; Richard L. Wahl; Mansoor Saleh; Ama Z. Rohatiner; Susan J. Knox; John A. Radford; Andrew D. Zelenetz; George F. Tidmarsh; Robert J. Stagg; Mark S. Kaminski; et al. Multicenter Phase II Study of Iodine-131 Tositumomab for Chemotherapy-Relapsed/Refractory Low-Grade and Transformed Low-Grade B-Cell Non-Hodgkin’s Lymphomas. Journal of Clinical Oncology 2000, 18, 1316-1323, 10.1200/jco.2000.18.6.1316.
  19. Sandra J. Horning; Anas Younes; Vinay Jain; Stewart Kroll; Jennifer Lucas; Donald Podoloff; Michael Goris; Efficacy and Safety of Tositumomab and Iodine-131 Tositumomab (Bexxar) in B-Cell Lymphoma, Progressive After Rituximab. Journal of Clinical Oncology 2005, 23, 712-719, 10.1200/jco.2005.07.040.
  20. Hyung Sik Yoo; Chan Hee Park; Jong Tae Lee; Ki Whang Kim; Chun Sik Yoon; Jung Ho Suh; Chang Yun Park; Byung Soo Kim; Heung Jai Choi; Kyong Sik Lee; et al. Small hepatocellular carcinoma: high dose internal radiation therapy with superselective intra-arterial injection of I-131-labeled Lipiodol. Cancer Chemotherapy and Pharmacology 1994, 33, S128-S133, 10.1007/bf00686684.
  21. J L Raoul; D Guyader; J F Bretagne; R Duvauferrier; P Bourguet; D Bekhechi; Y M Deugnier; M Gosselin; Randomized controlled trial for hepatocellular carcinoma with portal vein thrombosis: intra-arterial iodine-131-iodized oil versus medical support.. Journal of Nuclear Medicine 1994, 35, 1782-7.
  22. J F Eary; C Collins; M Stabin; C Vernon; S Petersdorf; M Baker; S Hartnett; S Ferency; S J Addison; F Appelbaum; et al. Samarium-153-EDTMP biodistribution and dosimetry estimation.. Journal of Nuclear Medicine 1993, 34, 1031-6.
  23. R G Robinson; D F Preston; M Schiefelbein; K G Baxter; Strontium 89 therapy for the palliation of pain due to osseous metastases.. JAMA 1995, 274, 420–424.
  24. Thomas E. Witzig; Ian W. Flinn; Leo I. Gordon; Christos Emmanouilides; Myron S. Czuczman; Mansoor N. Saleh; Larry Cripe; Gregory Wiseman; Teresa Olejnik; Pratik S. Multani; et al.Christine A. White Treatment With Ibritumomab Tiuxetan Radioimmunotherapy in Patients With Rituximab-Refractory Follicular Non-Hodgkin’s Lymphoma. Journal of Clinical Oncology 2002, 20, 3262-3269, 10.1200/jco.2002.11.017.
  25. Riad Salem; Robert Lewandowski; Carol Roberts; James Goin; Kenneth Thurston; Marwan Abouljoud; Angi Courtney; Use of Yttrium-90 Glass Microspheres (TheraSphere) for the Treatment of Unresectable Hepatocellular Carcinoma in Patients with Portal Vein Thrombosis. Journal of Vascular and Interventional Radiology 2004, 15, 335-345, 10.1097/01.rvi.0000123319.20705.92.
  26. W.Y. Lau; S. Ho; T.W.T. Leung; M. Chan; R. Ho; P.J. Johnson; A.K.C. Li; Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90yttrium microspheres. International Journal of Radiation Oncology*Biology*Physics 1998, 40, 583-592, 10.1016/s0360-3016(97)00818-3.
  27. Jonathan Strosberg; Ghassan El-Haddad; Edward Wolin; Andrew Hendifar; James Yao; Beth Chasen; Erik Mittra; Pamela L. Kunz; Matthew H. Kulke; Heather Jacene; et al.David BushnellThomas M. O’DorisioRichard P. BaumHarshad R. KulkarniMartyn CaplinRachida LebtahiTimothy HobdayEbrahim DelpassandEric Van CutsemAl BensonRajaventhan SrirajaskanthanMarianne PavelJaime MoraJordan BerlinEnrique GrandeNicholas ReedEttore SeregniKjell ÖbergMaribel Lopera SierraPaola SantoroThomas ThevenetJack L. ErionPhilippe RuszniewskiDik KwekkeboomEric Krenning Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. New England Journal of Medicine 2017, 376, 125-135, 10.1056/nejmoa1607427.
  28. A. Otte; R. Herrmann; A. Heppeler; M. Behe; E. Jermann; P. Powell; H. R. Maecke; J. Muller; Yttrium-90 DOTATOC: first clinical results. European Journal of Pediatrics 1999, 26, 1439-1447, 10.1007/s002590050476.
  29. Oliver Sartor; Johann de Bono; Kim N. Chi; Karim Fizazi; Ken Herrmann; Kambiz Rahbar; Scott T. Tagawa; Luke T. Nordquist; Nitin Vaishampayan; Ghassan El-Haddad; et al.Chandler H. ParkTomasz M. BeerAlison ArmourWendy J. Pérez-ContrerasMichelle DeSilvioEuloge KpameganGermo GerickeRichard A. MessmannMichael J. MorrisBernd J. Krause Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. New England Journal of Medicine 2021, 385, 1091-1103, 10.1056/nejmoa2107322.
  30. Benedikt Feuerecker; Robert Tauber; Karina Knorr; Matthias Heck; Ali Beheshti; Christof Seidl; Frank Bruchertseifer; Anja Pickhard; Andrei Gafita; Clemens Kratochwil; et al.Margitta RetzJürgen E. GschwendWolfgang A. WeberCalogero D’AlessandriaAlfred MorgensternMatthias Eiber Activity and Adverse Events of Actinium-225-PSMA-617 in Advanced Metastatic Castration-resistant Prostate Cancer After Failure of Lutetium-177-PSMA. European Urology 2020, 79, 343-350, 10.1016/j.eururo.2020.11.013.
  31. Knut Liepe; John J. Zaknun; Ajit Padhy; Emerita Barrenechea; Victoria Soroa; Solav Shrikant; Paijit Asavatanabodee; Ming J. Jeong; Maurizio Dondi; Radiosynovectomy using yttrium-90, phosphorus-32 or rhenium-188 radiocolloids versus corticoid instillation for rheumatoid arthritis of the knee. Annals of Nuclear Medicine 2011, 25, 317-323, 10.1007/s12149-011-0467-1.
  32. S. Nilsson; P. Strang; A.K. Aksnes; L. Franzèn; P. Olivier; A. Pecking; J. Staffurth; S. Vasanthan; C. Andersson; Ø.S. Bruland; et al. A randomized, dose–response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer. European Journal of Cancer 2012, 48, 678-686, 10.1016/j.ejca.2011.12.023.
  33. Christopher C. Parker; Robert E. Coleman; Oliver Sartor; Nicholas J. Vogelzang; David Bottomley; Daniel Heinrich; Svein I. Helle; Joe M. O'Sullivan; Sophie D. Fosså; Aleš Chodacki; et al.Paweł WiechnoJohn LogueMihalj SekeAnders WidmarkDag Clement JohannessenPeter HoskinNicholas D. JamesArne SolbergIsabel SyndikusJan KlimentSteffen WedelSibylle BoehmerMarcos Dall’OglioLars FranzénØyvind S. BrulandOana PetrenciucKarin StaudacherRui LiSten Nilsson Three-year Safety of Radium-223 Dichloride in Patients with Castration-resistant Prostate Cancer and Symptomatic Bone Metastases from Phase 3 Randomized Alpharadin in Symptomatic Prostate Cancer Trial. European Urology 2017, 73, 427-435, 10.1016/j.eururo.2017.06.021.
  34. Thomas Lindner; Anastasia Loktev; Annette Altmann; Frederik Giesel; Clemens Kratochwil; Jürgen Debus; Dirk Jäger; Walter Mier; Uwe Haberkorn; Development of Quinoline-Based Theranostic Ligands for the Targeting of Fibroblast Activation Protein. Journal of Nuclear Medicine 2018, 59, 1415-1422, 10.2967/jnumed.118.210443.
  35. Richard P. Baum; Aviral Singh; Christiane Schuchardt; Harshad Rajaram Kulkarni; Ingo Klette; Stefan Wiessalla; Frank Osterkamp; Ulrich Reineke; Christiane Smerling; 177Lu-3BP-227 for Neurotensin Receptor 1–Targeted Therapy of Metastatic Pancreatic Adenocarcinoma: First Clinical Results. Journal of Nuclear Medicine 2017, 59, 809-814, 10.2967/jnumed.117.193847.
  36. 131I-Omburtamab Radioimmunotherapy for Neuroblastoma Central Nervous System/Leptomeningeal Metastases. . https://clinicaltrials.gov. Retrieved 2022-8-4
  37. Manoop S. Bhutani; Irina M. Cazacu; Alexandra A. Luzuriaga Chavez; Ben S. Singh; Franklin C.L. Wong; William D. Erwin; Eric P. Tamm; Geena G. Mathew; Dao B. Le; Eugene J. Koay; et al.Cullen M. TaniguchiBruce D. MinskyShubham PantChing-Wei D. TzengAlbert C. KoongGauri R. VaradhacharyMatthew H.G. KatzRobert A. WolffDavid R. FogelmanJoseph M. Herman Novel EUS-guided brachytherapy treatment of pancreatic cancer with phosphorus-32 microparticles: first United States experience. VideoGIE 2019, 4, 223-225, 10.1016/j.vgie.2019.02.009.
  38. DeNardo, S.; DeNardo, G.; Kukis, D.; Shen, S.; Kroger, L.; DeNardo, D.; Goldstein, D.S.; Mirick, G.R.; Salako, Q.; Mausner, L.F.; et al.et al. 67Cu-21T-BAT-Lym-1 pharmacokinetics, radiation dosimetry, toxicity and tumor regression in patients with lymphoma. J. Nucl. Med. 1999, 40, 302–310.
  39. Maarten Lj Smits; Johannes Fw Nijsen; Maurice Aaj Van Den Bosch; Marnix Geh Lam; Maarten Ad Vente; Willem Ptm Mali; Alfred D Van Het Schip; Bernard A Zonnenberg; Holmium-166 radioembolisation in patients with unresectable, chemorefractory liver metastases (HEPAR trial): a phase 1, dose-escalation study. The Lancet Oncology 2012, 13, 1025-1034, 10.1016/s1470-2045(12)70334-0.
  40. Andrey Rosenkranz; Tatiana A. Slastnikova; Tatiana A. Karmakova; Maria S. Vorontsova; Natalya Morozova; Vasiliy M. Petriev; Alexey S. Abrosimov; Yuri V. Khramtsov; Tatiana N. Lupanova; Alexey V. Ulasov; et al.Raisa I. YakubovskayaGeorgii P. GeorgievAlexander Sobolev Antitumor Activity of Auger Electron Emitter 111In Delivered by Modular Nanotransporter for Treatment of Bladder Cancer With EGFR Overexpression. Frontiers in Pharmacology 2018, 9, 1331, 10.3389/fphar.2018.01331.
  41. Ebrahim S. Delpassand; Jennifer Sims-Mourtada; Hitomi Saso; Ali Azhdarinia; Faramarz Ashoori; Farzad Torabi; Gregory Espenan; Warren H. Moore; Eugene Woltering; Lowell Anthony; et al. Safety and Efficacy of Radionuclide Therapy with High-Activity In-111 Pentetreotide in Patients with Progressive Neuroendocrine Tumors. Cancer Biotherapy and Radiopharmaceuticals 2008, 23, 292-300, 10.1089/cbr.2007.0448.
  42. C. R. Divgi; S. Welt; M. Kris; Francisco X Real; S. D. J. Yeh; R. Gralla; B. Merchant; S. Schweighart; M. Unger; S. M. Larson; et al.J. Mendelsohn Phase I and Imaging Trial of Indium 111-Labeled Anti-Epidermal Growth Factor Receptor Monoclonal Antibody 225 in Patients With Squamous Cell Lung Carcinoma. JNCI: Journal of the National Cancer Institute 1991, 83, 97-104, 10.1093/jnci/83.2.97.
  43. Treatment of Cancer-Related Bone Pain by Using Bone-Targeted Radiation-Based Therapy (Sn-117m-DTPA) in Patients With Prostate Cancer That Has Spread to Bones . Clinical Trials. Retrieved 2022-8-4
  44. Clemens Kratochwil; Karl Schmidt; Ali Afshar-Oromieh; Frank Bruchertseifer; Hendrik Rathke; Alfred Morgenstern; Uwe Haberkorn; Frederik L. Giesel; Targeted alpha therapy of mCRPC: Dosimetry estimate of 213Bismuth-PSMA-617. Eur J Nucl Med Mol Imaging 2017, 45, 31-37, 10.1007/s00259-017-3817-y.
  45. Leszek Krolicki; Frank Bruchertseifer; Jolanta Kunikowska; Henryk Koziara; Bartosz Królicki; Maciej Jakuciński; Dariusz Pawlak; Christos Apostolidis; Saed Mirzadeh; Rafał Rola; et al.Adrian MerloAlfred Morgenstern Prolonged survival in secondary glioblastoma following local injection of targeted alpha therapy with 213Bi-substance P analogue. European Journal of Nuclear Medicine and Molecular Imaging 2018, 45, 1636-1644, 10.1007/s00259-018-4015-2.
  46. Michael E. Autenrieth; Christof Seidl; Frank Bruchertseifer; Thomas Horn; Florian Kurtz; Benedikt Feuerecker; Calogero D’Alessandria; Christian Pfob; Stephan Nekolla; Christos Apostolidis; et al.Saed MirzadehJürgen E. GschwendMarkus SchwaigerKlemens ScheidhauerAlfred Morgenstern Treatment of carcinoma in situ of the urinary bladder with an alpha-emitter immunoconjugate targeting the epidermal growth factor receptor: a pilot study. European Journal of Nuclear Medicine and Molecular Imaging 2018, 45, 1364-1371, 10.1007/s00259-018-4003-6.
  47. Kazuko Kaneda‐Nakashima; Zijian Zhang; Yoshiyuki Manabe; Atsushi Shimoyama; Kazuya Kabayama; Tadashi Watabe; Yoshikatsu Kanai; Kazuhiro Ooe; Atsushi Toyoshima; Yoshifumi Shirakami; et al.Takashi YoshimuraMitsuhiro FukudaJun HatazawaTakashi NakanoKoichi FukaseAtsushi Shinohara α‐Emitting cancer therapy using 211 At‐AAMT targeting LAT1. Cancer Science 2020, 112, 1132-1140, 10.1111/cas.14761.
  48. Huizi Keiko Li; Yukie Morokoshi; Satoshi Kodaira; Tamon Kusumoto; Katsuyuki Minegishi; Hiroaki Kanda; Kotaro Nagatsu; Sumitaka Hasegawa; Utility of 211At-Trastuzumab for the Treatment of Metastatic Gastric Cancer in the Liver: Evaluation of a Preclinical α-Radioimmunotherapy Approach in a Clinically Relevant Mouse Model. Journal of Nuclear Medicine 2021, 62, 1468-1474, 10.2967/jnumed.120.249300.
  49. Michael R. Zalutsky; David A. Reardon; Gamal Akabani; R. Edward Coleman; Allan H. Friedman; Henry S. Friedman; Roger E. McLendon; Terence Z. Wong; Darell D. Bigner; Clinical Experience with α-Particle–Emitting 211At: Treatment of Recurrent Brain Tumor Patients with 211At-Labeled Chimeric Antitenascin Monoclonal Antibody 81C6. Journal of Nuclear Medicine 2007, 49, 30-38, 10.2967/jnumed.107.046938.
  50. Håkan Andersson; Elin Cederkrantz; Tom Bäck; Chaitanya Divgi; Jörgen Elgqvist; Jakob Himmelman; György Horvath; Lars Jacobsson; Holger Jensen; Sture Lindegren; et al.Stig PalmRagnar Hultborn Intraperitoneal α-Particle Radioimmunotherapy of Ovarian Cancer Patients: Pharmacokinetics and Dosimetry of 211At-MX35 F(ab′)2—A Phase I Study. Journal of Nuclear Medicine 2009, 50, 1153-1160, 10.2967/jnumed.109.062604.
  51. Clemens Kratochwil; Karl Schmidt; Ali Afshar-Oromieh; Frank Bruchertseifer; Hendrik Rathke; Alfred Morgenstern; Uwe Haberkorn; Frederik L. Giesel; Targeted alpha therapy of mCRPC: Dosimetry estimate of 213Bismuth-PSMA-617. European Journal of Pediatrics 2017, 45, 31-37, 10.1007/s00259-017-3817-y.
  52. Nanette Freedman; Mattias Sandström; Jonathan Kuten; Natan Shtraus; Inna Ospovat; Albert Schlocker; Einat Even-Sapir; Personalized radiation dosimetry for PRRT—how many scans are really required?. EJNMMI Physics 2020, 7, 1-15, 10.1186/s40658-020-00293-z.
  53. Ernesto Amato; Alfredo Campennì; Rosaria M. Ruggeri; Lucrezia Auditore; Sergio Baldari; Comment on: “Technical note: Single time point dose estimate for exponential clearance” [Med. Phys. 45(5), 2318‐2324 (2018)]. Medical Physics 2019, 46, 2776-2779, 10.1002/mp.13540.
  54. Heribert Hänscheid; Michael Lassmann; Will SPECT/CT Cameras Soon Be Able to Display Absorbed Doses? Dosimetry from Single-Activity-Concentration Measurements. Journal of Nuclear Medicine 2020, 61, 1028-1029, 10.2967/jnumed.119.239970.
  55. Xinchi Hou; Julia Brosch; Carlos Uribe; Alessandro Desy; Guido Boning; Jean-Mathieu Beauregard; Anna Celler; Arman Rahmim; Feasibility of single-time-point dosimetry for radiopharmaceutical therapies. Journal of Nuclear Medicine 2020, 62, 1006-1011, 10.2967/jnumed.120.254656.
  56. Price A. Jackson; Michael S. Hofman; Rodney J. Hicks; Mark Scalzo; John A Violet; Radiation Dosimetry in 177Lu-PSMA-617 Therapy Using a Single Posttreatment SPECT/CT Scan: A Novel Methodology to Generate Time- and Tissue-Specific Dose Factors. Journal of Nuclear Medicine 2019, 61, 1030-1036, 10.2967/jnumed.119.233411.
  57. A Bockisch; T Jamitzky; R Derwanz; H J Biersack; Optimized dose planning of radioiodine therapy of benign thyroidal diseases.. Journal of Nuclear Medicine 1993, 34, 1632-1638.
  58. Heribert Hänscheid; Michael Laßmann; Christoph Reiners; Dosimetry prior to I-131-therapy of benign thyroid disease. Zeitschrift für Medizinische Physik 2011, 21, 250-257, 10.1016/j.zemedi.2011.01.006.
  59. Heribert Hänscheid; Constantin Lapa; Andreas K. Buck; Michael Lassmann; Rudolf A. Werner; Dose Mapping After Endoradiotherapy with 177Lu-DOTATATE/DOTATOC by a Single Measurement After 4 Days. Journal of Nuclear Medicine 2017, 59, 75-81, 10.2967/jnumed.117.193706.
  60. Mark T. Madsen; Yusuf Menda; Thomas M. O'dorisio; M. Sue O'dorisio; Technical Note: Single time point dose estimate for exponential clearance.. Medical Physics 2018, 45, 2318-2324, 10.1002/mp.12886.
  61. Pedro L. Esquinas; Ajit Shinto; Koramadai K. Kamaleshwaran; Jephy Joseph; Anna Celler; Biodistribution, pharmacokinetics, and organ-level dosimetry for 188Re-AHDD-Lipiodol radioembolization based on quantitative post-treatment SPECT/CT scans. EJNMMI Physics 2018, 5, 30, 10.1186/s40658-018-0227-6.
  62. Alexandre Chicheportiche; Simona Ben-Haim; Simona Grozinsky-Glasberg; Kira Oleinikov; Amichay Meirovitz; David J. Gross; Jeremy Godefroy; Dosimetry after peptide receptor radionuclide therapy: impact of reduced number of post-treatment studies on absorbed dose calculation and on patient management.. EJNMMI Physics 2020, 7, 5-15, 10.1186/s40658-020-0273-8.
  63. Wei Zhao; Pedro Luis Esquinas; Andrea Frezza; Xinchi Hou; Jean-Mathieu Beauregard; Anna Celler; Accuracy of kidney dosimetry performed using simplified time activity curve modelling methods: a 177Lu-DOTATATE patient study. Physics in Medicine & Biology 2019, 64, 175006, 10.1088/1361-6560/ab3039.
  64. Michela Del Prete; Frédéric Arsenault; Nassim Saighi; Wei Zhao; François-Alexandre Buteau; Anna Celler; Jean-Mathieu Beauregard; Accuracy and reproducibility of simplified QSPECT dosimetry for personalized 177Lu-octreotate PRRT. EJNMMI Physics 2018, 5, 25, 10.1186/s40658-018-0224-9.
  65. Mattias Sandström; Ulrike Garske-Román; Dan Granberg; Silvia Johansson; Charles Widström; Barbro Eriksson; Anders Sundin; Hans Lundqvist; Mark Lubberink; Individualized Dosimetry of Kidney and Bone Marrow in Patients Undergoing 177Lu-DOTA-Octreotate Treatment. Journal of Nuclear Medicine 2012, 54, 33-41, 10.2967/jnumed.112.107524.
  66. Mattias Sandström; Ezgi Ilan; Anna Karlberg; Silvia Johansson; Nanette Freedman; Ulrike Garske-Román; Method dependence, observer variability and kidney volumes in radiation dosimetry of (177)Lu-DOTATATE therapy in patients with neuroendocrine tumours.. EJNMMI Physics 2015, 2, 24, 10.1186/s40658-015-0127-y.
  67. Jorma Heikkonen; Hanna Mäenpää; Eero Hippeläinen; Vappu Reijonen; Mikko Tenhunen; Effect of calculation method on kidney dosimetry in 177Lu-octreotate treatment. Acta Oncologica 2016, 55, 1069-1076, 10.1080/0284186x.2016.1182642.
  68. Xinchi Hou; Wei Zhao; Jean-Mathieu Beauregard; Anna Celler; Personalized kidney dosimetry in 177Lu-octreotate treatment of neuroendocrine tumours: a comparison of kidney dosimetry estimates based on a whole organ and small volume segmentations. Physics in Medicine and Biology 2019, 64, 175004, 10.1088/1361-6560/ab32a1.
  69. Lore Santoro; Laurine Pitalot; Dorian Trauchessec; Erick Mora-Ramirez; Pierre-Olivier Kotzki; Manuel Bardiès; Emmanuel Deshayes; Clinical implementation of PLANET®Dose for dosimetric assessment after [177Lu]Lu-DOTA-TATE : comparison with Dosimetry Toolkit® and OLINDA/EXM® V1.0. EJNMMI Res. 2021, 11, 1, 10.21203/rs.3.rs-36998/v2.
  70. Tiantian Li; Licheng Zhu; Zhonglin Lu; Na Song; Ko-Han Lin; Greta S. P. Mok; BIGDOSE: software for 3D personalized targeted radionuclide therapy dosimetry. Quantitative Imaging in Medicine and Surgery 2020, 10, 160-170, 10.21037/qims.2019.10.09.
  71. Daphne M. V. Huizing; Steffie M. B. Peters; Michelle W. J. Versleijen; Esther Martens; Marcel Verheij; Michiel Sinaasappel; Marcel P. M. Stokkel; Berlinda J. De Wit-Van Der Veen; A head-to-head comparison between two commercial software packages for hybrid dosimetry after peptide receptor radionuclide therapy. EJNMMI Physics 2020, 7, 36, 10.1186/s40658-020-00308-9.
  72. Jacek Capala; Stephen A. Graves; Aaron Scott; George Sgouros; Sara St. James; Pat Zanzonico; Brian E. Zimmerman; Dosimetry for Radiopharmaceutical Therapy: Current Practices and Commercial Resources. Journal of Nuclear Medicine 2021, 62, 3S-11S, 10.2967/jnumed.121.262749.
  73. Maxime Chauvin; Damian Borys; Francesca Botta; Pawel Bzowski; Jeremie Dabin; Ana Denis-Bacelar; Aurélie Desbrée; Nadia Falzone; Boon Lee; Andrea Mairiani; et al.Alessandra MalarodaGilles MathieuErin McKayErick Mora-RamirezAndrew P. RobinsonDavid SarrutLara StruelensAlex Vergara GilManuel Bardiès OpenDose: Open-Access Resource for Nuclear Medicine Dosimetry. Journal of Nuclear Medicine 2020, 61, 1514-1519, 10.2967/jnumed.119.240366.
  74. James R Ballinger; Theranostic radiopharmaceuticals: established agents in current use. The British Journal of Radiology 2018, 91, 20170969, 10.1259/bjr.20170969.
  75. George Sgouros; Lisa Bodei; Michael R. McDevitt; Jessie R. Nedrow; Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nature Reviews Drug Discovery 2020, 19, 589-608, 10.1038/s41573-020-0073-9.
  76. Jacek Capala; Charles A. Kunos; A New Generation of “Magic Bullets” for Molecular Targeting of Cancer. Clinical Cancer Research 2021, 27, 377-379, 10.1158/1078-0432.ccr-20-3690.
  77. Francesco Cicone; Silvano Gnesin; Thibaut Denoël; Thierry Stora; Nicholas P. Van Der Meulen; Cristina Müller; Christiaan Vermeulen; Martina Benešová; Ulli Köster; Karl Johnston; et al.Ernesto AmatoLucrezia AuditoreGeorge CoukosMichael StabinNiklaus SchaeferDavid ViertlJohn O. Prior Internal radiation dosimetry of a 152Tb-labeled antibody in tumor-bearing mice. EJNMMI Research 2019, 9, 1-10, 10.1186/s13550-019-0524-7.
  78. Arun Gupta; Min Sun Lee; Joong Hyun Kim; Dong Soo Lee; Jae Sung Lee; Preclinical Voxel-Based Dosimetry in Theranostics: a Review. Nuclear Medicine and Molecular Imaging 2020, 54, 86-97, 10.1007/s13139-020-00640-z.
  79. Naoyuki Ukon; Songji Zhao; Kohshin Washiyama; Noboru Oriuchi; Chengbo Tan; Saki Shimoyama; Miho Aoki; Hitoshi Kubo; Kazuhiro Takahashi; Hiroshi Ito; et al. Human dosimetry of free 211At and meta-[211At]astatobenzylguanidine (211At-MABG) estimated using preclinical biodistribution from normal mice. EJNMMI Physics 2020, 7, 1-14, 10.1186/s40658-020-00326-7.
  80. Sahafi-Pour SA, Shirmardi SP, Saeedzadeh E, Baradaran S, Sadeghi M.; Internal dosimetry studies of 177 Lu-BBN-GABA-DOTA, as a cancer therapy agent, in human tissues based on animal data. Appl Radiat Isot 2022, 186, 110273, 10.1016/j.apradiso.2022.110273.
  81. E Courtney Henry; Matthew Strugari; George Mawko; Kimberly Brewer; David Liu; Andrew C. Gordon; Jeffrey N. Bryan; Charles Maitz; Robert Abraham; S Cheenu Kappadath; et al.Alasdair Syme Precision Dosimetry in Yttrium-90 Radioembolization through CT Imaging of Radiopaque Microspheres in a Rabbit Liver Model. EJNMMI Phys . 2021, 21, 9(1), 10.21203/rs.3.rs-806070/v1.
  82. G. D. Flux; K. Sjogreen Gleisner; C. Chiesa; M. Lassmann; N. Chouin; J. Gear; M. Bardiès; S. Walrand; K. Bacher; U. Eberlein; et al.M. LjungbergLidia StrigariE. VisserM. W. Konijnenberg From fixed activities to personalized treatments in radionuclide therapy: lost in translation?. European Journal of Pediatrics 2017, 45, 152-154, 10.1007/s00259-017-3859-1.
  83. Michael R. Zalutsky; David A. Reardon; Gamal Akabani; R. Edward Coleman; Allan H. Friedman; Henry S. Friedman; Roger E. McLendon; Terence Z. Wong; Darell D. Bigner; Clinical Experience with α-Particle–Emitting 211At: Treatment of Recurrent Brain Tumor Patients with 211At-Labeled Chimeric Antitenascin Monoclonal Antibody 81C6. Journal of Nuclear Medicine 2007, 49, 30-38, 10.2967/jnumed.107.046938.
  84. Håkan Andersson; Elin Cederkrantz; Tom Bäck; Chaitanya Divgi; Jörgen Elgqvist; Jakob Himmelman; György Horvath; Lars Jacobsson; Holger Jensen; Sture Lindegren; et al.Stig PalmRagnar Hultborn Intraperitoneal α-Particle Radioimmunotherapy of Ovarian Cancer Patients: Pharmacokinetics and Dosimetry of 211At-MX35 F(ab′)2—A Phase I Study. Journal of Nuclear Medicine 2009, 50, 1153-1160, 10.2967/jnumed.109.062604.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback