Dosimetry, biodistribution, and safety of flurpiridaz F 18 in healthy subjects undergoing rest and exercise or pharmacological stress PET myocardial perfusion imaging.

The objectives of this study were to evaluate radiation dosimetry, biodistribution, human safety, and tolerability of 18F-labeled flurpiridaz (Flurpiridaz) in normal subjects undergoing rest and separate-day exercise or adenosine pharmacological stress PET imaging. METHODS: 12 normal subjects were injected with 58.5 to 121 MBq (1.58 to 3.27 mCi) of Flurpiridaz intravenously at rest on Day 1 and 57 to 171 MBq (1.54 to 4.61 mCi) during stress on Day 2. Sequential whole-body imaging was performed for 5 hours. Blood samples were collected for up to 8 hours. RESULTS: The heart wall received the largest mean absorbed dose with both exercise and adenosine stresses. The mean effective dose was 0.054 rem/mCi (0.015 mSv/MBq) with exercise and 0.069 rem/mCi (0.019 mSv/MBq) with adenosine pharmacological stress. The maximum dose that may be administered without exceeding 1 rem (10 mSv) effective dose was 19 mCi (685 MBq) for exercise and 15 mCi (539 MBq) for adenosine pharmacological stress. There were no drug-related adverse events, and the tracer was well tolerated in all subjects. CONCLUSION: Based on radiation dosimetry, biodistribution, and safety observations, 18F-labeled flurpiridaz is found suitable for clinical PET myocardial perfusion imaging in conjunction with either exercise or pharmacological stress testing.

First-in-Human Safety, Imaging, and Dosimetry of a Carbonic Anhydrase IX-Targeting Peptide, [68Ga]Ga-DPI-4452, in Patients with Clear Cell Renal Cell Carcinoma.

[68Ga]Ga-DPI-4452, a first-in-class carbonic anhydrase IX-binding radiolabeled peptide, is the imaging agent of a theranostic pair with [177Lu]Lu-DPI-4452, developed for selecting and treating patients with carbonic anhydrase IX-expressing tumors. Here, [68Ga]Ga-DPI-4452 imaging characteristics, dosimetry, pharmacokinetics, and safety were assessed in 3 patients with clear cell renal cell carcinoma. Methods: After [68Ga]Ga-DPI-4452 administration, patients underwent serial full-body PET/CT imaging. Blood and urine were sampled. Safety was monitored for 7 d after injection. Results: Tumor uptake was observed at all time points (15 min to 4 h). Across 36 lesions, the SUVmax at 1 h after administration ranged from 6.8 to 211.6 (mean, 64.6 [SD, 54.8]). The kidneys, liver, and bone marrow demonstrated low activity. [68Ga]Ga-DPI-4452 was rapidly eliminated from blood and urine. No clinically significant toxicity was observed. Conclusion: [68Ga]Ga-DPI-4452 showed exceptional tumor uptake in patients with clear cell renal cell carcinoma, with very high tumor-to-background ratios and no significant adverse events, suggesting potential diagnostic and patient selection applications.

Renal and Multiorgan Safety of 177Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer in the VISION Dosimetry Substudy.

In the VISION trial, [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) plus protocol-permitted standard of care significantly improved overall survival and radiographic progression-free survival compared with standard of care alone in patients with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer. This VISION dosimetry substudy quantified absorbed doses of 177Lu-PSMA-617 in the kidneys and other organs. Methods: Participants were a separate cohort of 30 nonrandomized patients receiving standard of care plus 177Lu-PSMA-617 at 7.4 GBq per cycle for up to 6 cycles. Blood samples, whole-body conjugate planar image scintigraphy, and abdominal SPECT/CT images were collected. SPECT/CT images were collected at 2, 24, 48, and 168 h after administration in cycle 1 and at a single time point 48 h after administration in cycles 2-6. Outcomes were absorbed dose per unit activity per cycle and cumulative absorbed dose over all cycles. Cumulative absorbed doses were predicted by extrapolation from cycle 1, and calculation of observed values was based on measurements of cycle 1 and cycles 2-6. Safety was also assessed. Results: Mean (±SD) absorbed doses per cycle in the kidneys were 0.43 ± 0.16 Gy/GBq in cycle 1 and 0.44 ± 0.21 Gy/GBq in cycles 2-6. The observed and predicted 6-cycle cumulative absorbed doses in the kidneys were 15 ± 6 and 19 ± 7 Gy, respectively. Observed and predicted cumulative absorbed doses were similar in other at-risk organs. Safety findings were consistent with those in the VISION study; no patients experienced renal treatment-emergent adverse events of a grade higher than 3. Conclusion: The renal cumulative absorbed 177Lu-PSMA-617 dose was below the established limit. 177Lu-PSMA-617 had a good overall safety profile, and low renal radiotoxicity was not a safety concern. Cumulative absorbed doses in at-risk organs over multiple cycles can be predicted by extrapolation from cycle 1 data in patients with metastatic castration-resistant prostate cancer receiving 177Lu-PSMA-617.

Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity.

Indoleamine 2,3-dioxygenase-1 (IDO1; IDO) mediates oxidative cleavage of tryptophan, an amino acid essential for cell proliferation and survival. IDO1 inhibition is proposed to have therapeutic potential in immunodeficiency-associated abnormalities, including cancer. Here, we describe INCB024360, a novel IDO1 inhibitor, and investigate its roles in regulating various immune cells and therapeutic potential as an anticancer agent. In cellular assays, INCB024360 selectively inhibits human IDO1 with IC(50) values of approximately 10nM, demonstrating little activity against other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO). In coculture systems of human allogeneic lymphocytes with dendritic cells (DCs) or tumor cells, INCB024360 inhibition of IDO1 promotes T and natural killer (NK)-cell growth, increases IFN-gamma production, and reduces conversion to regulatory T (T(reg))-like cells. IDO1 induction triggers DC apoptosis, whereas INCB024360 reverses this and increases the number of CD86(high) DCs, potentially representing a novel mechanism by which IDO1 inhibition activates T cells. Furthermore, IDO1 regulation differs in DCs versus tumor cells. Consistent with its effects in vitro, administration of INCB024360 to tumor-bearing mice significantly inhibits tumor growth in a lymphocyte-dependent manner. Analysis of plasma kynurenine/tryptophan levels in patients with cancer affirms that the IDO pathway is activated in multiple tumor types. Collectively, the data suggest that selective inhibition of IDO1 may represent an attractive cancer therapeutic strategy via up-regulation of cellular immunity.

Biodistribution and radiation dosimetry of the 18 kDa translocator protein (TSPO) radioligand [18F]FEDAA1106: a human whole-body PET study.

PURPOSE: [(18)F]FEDAA1106 is a recently developed positron emission tomography (PET) radioligand for in vivo quantification of the 18 kDa translocator protein [TSPO or, as earlier called, the peripheral benzodiazepine receptor (PBR)]. TSPO imaging is expected to be useful for the clinical evaluation of neuroinflammatory diseases. The aim of this study was to provide dosimetry estimates for [(18)F]FEDAA1106 based on human whole-body PET measurements. METHODS: PET scans were performed for a total of 6.6 h after the injection of 183.8 ± 9.1 MBq of [(18)F]FEDAA1106 in six healthy subjects. Regions of interest were drawn on coronal images. Estimates of the absorbed doses of radiation were calculated using the OLINDA software. RESULTS: Peak uptake was largest in lungs, followed by liver, small intestine, kidney, spleen and other organs. Peak values of the percent injected dose (%ID) at a time after radioligand injection were calculated for the lungs (27.1%ID at 0.2 h), liver (21.1%ID at 0.6 h), small intestine (10.4%ID at 6.3 h), kidney (4.9%ID at 1.8 h) and spleen (4.6%ID at 0.6 h). The largest absorbed dose was found in the spleen (0.12 mSv/MBq), followed by kidneys (0.094 mSv/MBq). The calculated mean effective dose was 0.036 mSv/MBq. CONCLUSION: Based on the distribution and dose estimates, the estimated radiation burden of [(18)F]FEDAA1106 is moderately higher than that of [(18)F]fluorodeoxyglucose (FDG). In clinical studies, the administered activity of this radioligand ought to be adjusted in line with regional regulations. This result would be helpful for further clinical TSPO imaging studies.

Objective criteria for classification of postsecondary students as learning disabled: effects on prevalence rates and group characteristics.

This study examined the consequences of classifying postsecondary students as learning disabled (LD) using five objective sets of criteria: IQ-achievement discrepancies (1.0 to 1.49 SD, 1.5 to 1.99 SD, and >or= 2.0 SD), DSM-IV criteria, and chronic educational impairment beginning in childhood. The participants were 378 postsecondary students from two universities who had been previously classified as LD and were receiving instructional and/or testing accommodations. The agreement between diagnostic models was often low, both in terms of the proportion of students identified as well as which students were identified by the models. The discrepancy models identified the largest proportions of students as LD (10% to 42%), whereas fewer than 10% of participants met either of the other sets of criteria, and 55% of the participants were not classified as LD by any of the models. Implications for further research and practices in postsecondary settings are discussed.

INCB050465 (Parsaclisib), a Novel Next-Generation Inhibitor of Phosphoinositide 3-Kinase Delta (PI3Kδ).

A medicinal chemistry effort focused on identifying a structurally diverse candidate for phosphoinositide 3-kinase delta (PI3Kδ) led to the discovery of clinical candidate INCB050465 (20, parsaclisib). The unique structure of 20 contains a pyrazolopyrimidine hinge-binder in place of a purine motif that is present in other PI3Kδ inhibitors, such as idelalisib (1), duvelisib (2), and INCB040093 (3, dezapelisib). Parsaclisib (20) is a potent and highly selective inhibitor of PI3Kδ with drug-like ADME properties that exhibited an excellent in vivo profile as demonstrated through pharmacokinetic studies in rats, dogs, and monkeys and through pharmacodynamic and efficacy studies in a mouse Pfeiffer xenograft model.

The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies.

PURPOSE: Bromodomain and extraterminal domain (BET) proteins regulate the expression of many cancer-associated genes and pathways; BET inhibitors have demonstrated activity in diverse models of hematologic and solid tumors. We report the preclinical characterization of INCB054329, a structurally distinct BET inhibitor that has been investigated in phase I clinical trials. EXPERIMENTAL DESIGN: We used multiple myeloma models to investigate vulnerabilities created by INCB054329 treatment that could inform rational combinations. RESULTS: In addition to c-MYC, INCB054329 decreased expression of oncogenes FGFR3 and NSD2/MMSET/WHSC1, which are deregulated in t(4;14)-rearranged cell lines. The profound suppression of FGFR3 sensitized the t(4;14)-positive cell line OPM-2 to combined treatment with a fibroblast growth factor receptor inhibitor in vivo. In addition, we show that BET inhibition across multiple myeloma cell lines resulted in suppressed interleukin (IL)-6 Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling. INCB054329 displaced binding of BRD4 to the promoter of IL6 receptor (IL6R) leading to reduced levels of IL6R and diminished signaling through STAT3. Combination with JAK inhibitors (ruxolitinib or itacitinib) further reduced JAK-STAT signaling and synergized to inhibit myeloma cell growth in vitro and in vivo. This combination potentiated tumor growth inhibition in vivo, even in the MM1.S model of myeloma that is not intrinsically sensitive to JAK inhibition alone. CONCLUSIONS: Preclinical data reveal insights into vulnerabilities created in myeloma cells by BET protein inhibition and potential strategies that can be leveraged in clinical studies to enhance the activity of INCB054329.

How Many U.S. High School Students Have a Foreign Language Reading "Disability"? Reading Without Meaning and the Simple View.

Conventional wisdom suggests that students classified as learning disabled will exhibit difficulties with foreign language (FL) learning, but evidence has not supported a relationship between FL learning problems and learning disabilities. The simple view of reading model posits that reading comprehension is the product of word decoding and language comprehension and that there are good readers and 3 types of poor readers-dyslexic, hyperlexic, and garden variety-who exhibit different profiles of strengths and/or deficits in word decoding and language comprehension. In this study, a random sample of U.S. high school students completing first-, second-, and third-year Spanish courses were administered standardized measures of Spanish word decoding and reading comprehension, compared with monolingual Spanish readers from first to eleventh grades, and classified into reader types according to the simple view of reading. The majority of students fit the hyperlexic profile, and no participants fit the good reader profile until they were compared with first- and second-grade monolingual Spanish readers. Findings call into question the practice of diagnosing an FL "disability" before a student engages in FL study.

Design considerations for incorporating sodium iodide symporter reporter gene imaging into prostate cancer gene therapy trials.

This study was done to aid in the design of a phase I gene therapy trial in patients with prostate cancer. We determined the dosimetric characteristics of our reporter gene system when coupled with intravenous administration of radioactive sodium pertechnetate (Na(99m) TcO(4)) and determined the feasibility of using human sodium iodide symporter (hNIS) as a reporter gene to study the dynamics of adenoviral transgene expression in a large animal tumor. A replication-competent Ad5-yCD/mutTK(SR39) rep-hNIS adenovirus was injected into the prostate gland of dogs for dosimetry purposes, and into a canine soft tissue sarcoma (STS) for imaging purposes. After resection of the prostate, the amount of (99m)TcO(4)() sequestered in the prostate was determined, the radiation dose absorbed by the prostate and nontarget critical organs was calculated, and hNIS reporter gene expression was imaged in the STS by single-photon emission computed tomography (SPECT). On the basis of the findings from 25 dogs, the amount of (99m)TcO (4)() sequestered in the prostate ranged from 13 to 276 muCi. Using the highest value observed, absorbed radiation dose to critical organs was calculated and found to be below U.S. Food and Drug Administration limits for diagnostic imaging. Also, (99m)TcO (4)() uptake was readily detected by SPECT and found to persist in vivo for at least 4 days. On the basis of our dosimetry calculations, up to five imaging procedures can be safely performed in humans after intraprostatic injection of the Ad5-yCD/mutTK(SR39)rep-hNIS adenovirus and the hNIS reporter gene system can be used to study the dynamics of adenoviral gene therapy vectors in large animal tumors.

INCB24360 (Epacadostat), a Highly Potent and Selective Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitor for Immuno-oncology.

A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 inhibitor 4f, INCB24360 (epacadostat). The molecular structure of INCB24360 contains several previously unknown or underutilized functional groups in drug substances, including a hydroxyamidine, furazan, bromide, and sulfamide. These moieties taken together in a single structure afford a compound that falls outside of "drug-like" space. Nevertheless, the in vitro ADME data is consistent with the good cell permeability and oral bioavailability observed in all species (rat, dog, monkey) tested. The extensive intramolecular hydrogen bonding observed in the small molecule crystal structure of 4f is believed to significantly contribute to the observed permeability and PK. Epacadostat in combination with anti-PD1 mAb pembrolizumab is currently being studied in a phase 3 clinical trial in patients with unresectable or metastatic melanoma.

Potent benzimidazole sulfonamide protein tyrosine phosphatase 1B inhibitors containing the heterocyclic (S)-isothiazolidinone phosphotyrosine mimetic.

Potent nonpeptidic benzimidazole sulfonamide inhibitors of protein tyrosine phosphatase 1B (PTP1B) were derived from the optimization of a tripeptide containing the novel (S)-isothiazolidinone ((S)-IZD) phosphotyrosine (pTyr) mimetic. An X-ray cocrystal structure of inhibitor 46/PTP1B at 1.8 A resolution demonstrated that the benzimidazole sulfonamides form a bidentate H bond to Asp48 as designed, although the aryl group of the sulfonamide unexpectedly interacts intramolecularly in a pi-stacking manner with the benzimidazole. The ortho substitution to the (S)-IZD on the aryl ring afforded low nanomolar enzyme inhibitors of PTP1B that also displayed low caco-2 permeability and cellular activity in an insulin receptor (IR) phosphorylation assay and an Akt phosphorylation assay. The design, synthesis, and SAR of this novel series of benzimidazole sulfonamide containing (S)-IZD inhibitors of PTP1B are presented herein.

Weak and strong novice readers of English as a foreign language: effects of first language and socioeconomic status.

This study examined individual differences among beginning readers of English as a foreign language (EFL). The study concentrated on the effects of underlying first language (L1) knowledge as well as EFL letter and vocabulary knowledge. Phonological and morphological awareness, spelling, vocabulary knowledge, and word reading in Hebrew L1, in addition to knowledge of EFL letters and EFL vocabulary, were measured. The study also investigated the effect of socioeconomic background (SES) on beginning EFL readers. Participants included 145 fourth graders from three schools representing two socioeconomic backgrounds in the north of Israel. The results indicate that knowledge of English letters played a more prominent role than knowledge of Hebrew L1 components in differentiating between strong and weak EFL readers. The Linguistic Coding Differences Hypothesis was supported by L1 phonological awareness, word reading, and vocabulary knowledge appearing as part of discriminating functions. The presence of English vocabulary knowledge as part of the discriminant functions provides support for English word reading being more than just a decoding task for EFL beginner readers. Socioeconomic status differentiated the groups for EFL word recognition but not for EFL reading comprehension.

Native language predictors of foreign language proficiency and foreign language aptitude.

Fifty-four students were tested at specific time intervals over 10 years to determine best native language (NL) predictors of oral and written foreign language (FL) proficiency and FL aptitude. All participants completed two years of Spanish, French, or German. Each was administered measures of NL literacy, oral language, and cognitive ability in elementary school. A measure of FL aptitude was administered at the beginning of ninth grade and FL proficiency was evaluated at the end of the 10th grade. Among the variables, NL literacy measures were the best predictors of FL proficiency, and NL achievement and general (verbal) intelligence were strong predictors of FL aptitude. Results suggest that indices of NL literacy as early as first grade are related to FL proficiency and FL aptitude nine and 10 years later. Findings provide strong support for connections between L1 and L2 skills, and for speculation that "lower level" skills in phonological processing are important for written language development and oral proficiency in a FL.

Is there a "disability" for learning a foreign language?

Recently, talk of a new type of learning disability (LD)--a foreign language learning disability, or FLLD--has made its way into the LD and foreign language (FL) literature. However, no empirical evidence has been published to support the concept of a "disability" for FL learning by those professionals who use the term. In this article, the author takes the position that there is not a distinct "disability" that can be called an FLLD. He reviews several years of research evidence indicating that any proposal for such a distinct entity is problematic. To support his position, he reviews problems with the current definition and diagnostic criteria for LD. He then cites the many difficulties inherent in the development and use of (a) a logically consistent, easily operationalized, and empirically valid definition of and (b) diagnostic criteria for the FLLD concept. The author then discusses how FL learning problems occur along a continuum of very strong to very poor language learners, and he explains how the proponents of an FLLD misuse the concept of FL aptitude. Finally, the author cites implications resulting from the research evidence on FL learning problems and use of the term FLLD.

Structure-based design and discovery of protein tyrosine phosphatase inhibitors incorporating novel isothiazolidinone heterocyclic phosphotyrosine mimetics.

Structure-based design led to the discovery of novel (S)-isothiazolidinone ((S)-IZD) heterocyclic phosphotyrosine (pTyr) mimetics that when incorporated into dipeptides are exceptionally potent, competitive, and reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B). The crystal structure of PTP1B in complex with our most potent inhibitor 12 revealed that the (S)-IZD heterocycle interacts extensively with the phosphate binding loop precisely as designed in silico. Our data provide strong evidence that the (S)-IZD is the most potent pTyr mimetic reported to date.

OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine.

UNLABELLED: The OLINDA/EXM version 1.0 personal computer code was created as a replacement for the widely used MIRDOSE3.1 code. This paper documents the basic function of the code and how it is similar to and different from the MIRDOSE software. METHODS: After creation of the code and alpha- and beta-testing phases, a premarket notification submission (510(k)) was filed with the Food and Drug Administration to permit marketing of the code. Permission was granted in June 2004, and the code is currently being distributed through Vanderbilt University. Not all of the technical details of the dosimetry methods have been shown here, as they have been previously documented. RESULTS: Agreement of doses between the MIRDOSE3.1 and OLINDA/EXM codes was good, within 1%-2% in most cases. CONCLUSION: The extensive testing of the OLINDA/EXM code, based on comparison with literature-established dose calculations and with the widely tested and accepted MIRDOSE3.1 code, should give users confidence in its output. The OLINDA/EXM code should be easy for MIRDOSE users to adopt and for new users to understand. It will be useful in standardizing and automating internal dose calculations, assessing doses in clinical trials with radiopharmaceuticals, making theoretic calculations for existing pharmaceuticals, teaching, and other purposes.

A Phase I-II, Open-Label, Multicenter Trial to Determine the Dosimetry and Safety of 99mTc-Sestamibi in Pediatric Subjects.

UNLABELLED: Myocardial perfusion imaging has long been used off label by practitioners attending for children with cardiac aliments. To provide clinicians with evidence-based dosage recommendation, a phase I-II, open-label, nonrandomized, multicenter trial was therefore designed using (99m)Tc-sestamibi in pediatric subjects (registered under www.clinicaltrials.gov identifier no. NCT00162045). METHODS: Safety and pharmacokinetic data were collected from 78 subjects using either a 1-d imaging protocol (3.7-7.4 MBq/kg, followed by 11.1 MBq/kg) or a 2-d protocol (7.4 MBq/kg for both rest and stress). Anterior and posterior planar images were collected at 15 min, 1.5 h, 4 h, and 8 h. Blood and urine samples were collected at predetermined times. RESULTS: Subjects included 39 children (mean age ± SD, 8.5 ± 2.04 y) and 39 adolescents (mean age ± SD, 13.6 ± 1.39 y). Mean estimated organ-absorbed doses to the upper large intestine, small intestine, gallbladder wall, and lower large intestines were 0.082, 0.043, 0.042, and 0.035 mSv/MBq, respectively. All patients tolerated the radiotracer without serious adverse effects. Significant differences were observed in the liver, upper large intestine contents, and small intestine contents between rest and stress imaging. The effective dose equivalent and effective dose averages were lower in adolescents than younger children (0.011 and 0.019 mSv/MBq, respectively; P < 0.0001). Percentage injected doses (%IDs) corrected for radioactive decay in all dosimetry-evaluable subjects at 15 min and 4 h were 1.9% and 1.2% in the myocardium. Similarly in the lungs, the %ID for all dosimetry-evaluable subjects was 4.9% at 15 min after injection. At rest, the %ID in the liver decreased from a maximum of about 26% at 15 min to less than 9% at 90 min. With stress, values decreased from 15% to 7%, respectively. CONCLUSION: The estimates of radiation dosimetry, pharmacokinetic parameters, and safety profile in this study population are similar to published studies based on body-mass extrapolations from studies in adults. As such, applying current (99m)Tc-sestamibi dosing regimens for 1- and 2-d protocols based on those extrapolations will result in the expected radiation dose in children and adolescents.

Calculating the absorbed dose from radioactive patients: the line-source versus point-source model.

UNLABELLED: In calculations of absorbed doses from radioactive patients, the activity distribution in such patients is generally assumed to be an unattenuated point source and the dose to exposed individuals at a given distance is therefore calculated using the inverse square law. In many nuclear medicine patients, the activity distribution is widely dispersed and does not simulate a point source. In these cases, a line-source model is proposed to more accurately reflect this extended activity distribution. METHODS: Calculations of dose rate per unit activity were performed for a point source and for line sources of lengths of 20, 50, 70, 100, and 174 cm, and the ratios of line-source values to point-source values were calculated. In addition, radionuclide-independent conversion factors, to convert exposure rate constants to dose rates per unit activity, for these line-source lengths at various distances were determined. RESULTS: The calculated values, substantiated by published data, indicate that the inverse square law approximation is not valid for a line source until a certain distance is reached, dependent on the length of the line source. For the 20-, 50-, 70-, 100-, and 174-cm line sources, the dose rate values estimated by the inverse square law approximation are within approximately 10% of the values estimated using the line-source approach at distances of 20, 45, 60, 85, and 145 cm, respectively. At closer distances, use of the point-source model for a patient with an extended activity distribution will overestimate the radiation absorbed dose to exposed individuals, sometimes by a very significant amount. CONCLUSION: The line-source model is a more realistic and practical approach than the traditional point-source model for determining the dose to individuals exposed to radioactive patients with widespread activity distributions.

Radiation dose distributions in normal tissue adjacent to tumors containing (131)I or (90)Y: the potential for toxicity.

UNLABELLED: Given the relatively large tumor-absorbed doses reported for patients receiving radionuclide therapy, particularly radioimmunotherapy, and the relatively long pathlength of the nonpenetrating emissions of some radionuclides being used for these therapies, there exists the possibility of large absorbed doses to tissues adjacent to, surrounded by, or surrounding these tumors. Because tumors can occur adjacent to critical organs or tissues, such as arteries, nerves, pericardium, and the walls of the organs of the gastrointestinal tract, large absorbed doses to these normal tissues can lead to acute complications. METHODS: In this study, the Monte Carlo radiation transport code MCNP4b was used to simulate the deposition of energy from emissions of 2 radionuclides of interest, (131)I and (90)Y, to assess the possible magnitude of the absorbed doses in tissues adjacent to tumors. Mathematic models were constructed to simulate situations that might occur, such as tumor wrapped around a small cylinder (e.g., a nerve or artery), tumor against a tissue (e.g., the pericardium or wall of any gastrointestinal tract organ), and tumor surrounded by any soft tissue. Tumor masses of 10, 20, and 40 g were used in each model. Depth dose distributions were calculated using Monte Carlo simulations of the radiation transport in these geometric models. RESULTS: For tissues close to tumors containing (90)Y, the absorbed dose ranged from 24% of the absorbed dose in the tumor, for the case of tissues 1 mm from the tumor, to 103% of the absorbed dose in the tumor, for the case of small structures such as nerves or arteries surrounded by tumor. For tissues close to tumors containing (131)I, the absorbed dose ranged from 4% of the absorbed dose in the tumor, for the case of tissues 1 mm from the tumor, to 46% of the absorbed dose in the tumor, for the case of small structures such as nerves or arteries surrounded by tumor. CONCLUSION: This study showed that when absorbed doses to tumors are large, the absorbed dose to adjacent tissues can also be large, potentially causing unexpected toxicities.