Evaluation of Dose Distribution to Organs-at-Risk in a Prospective Phase 1 Trial of Pembrolizumab and Multisite Stereotactic Body Radiation Therapy (SBRT).

PURPOSE: Our purpose was to characterize the radiation doses to organs-at-risk (OAR) in the phase I trial (NCT02608385) that established safety/efficacy of stereotactic body radiation therapy (SBRT) using NRG-BR001 dose constraints combined with programmed cell death protein 1 blockade for metastatic disease. METHODS AND MATERIALS: Between January 2016 and May 2018, 73 patients with advanced solid tumors were treated with SBRT followed by pembrolizumab. Tumor volumes (gross tumor volume/internal tumor volume) were delineated for each metastasis, with planning target volume contraction to limit OAR dose per protocol (n = 54) or when gross tumor volume/internal tumor volume > 65 cm3 (n = 19). For 20 OAR, doses were compared with NRG-BR001 constraints. Protocol constraints were considered challenged when the minimum of the highest dose received by ≥6 patients without dose-limiting toxicities (DLTs) (Dmax6th) was ≥70% of the protocol constraint. RESULTS: A total of 151 metastases were irradiated including 32 peripheral lung, 23 central lung, 13 mediastinal/cervical, 24 liver, 28 abdominal-pelvic, 16 osseous, and 15 spinal metastases. A median of 2 metastases (range, 2-4) with mean volumes of 33.5 cm3 (range, 0.4-391 cm3) were treated using average planning target volumes of 50.7 cm3 (range, 3.2-161 cm3). At least 1 dose constraint from NRG-BR001 was exceeded in 38 of 73 (52%) patients. OAR constraints were challenged in 10 serial organs (gastrointestinal, cardio-pulmonary, musculoskeletal, and nervous systems) and 1 parallel OAR (lung). Grade 3 DLTs occurred in 6 patients, including pneumonitis (n = 3), colitis (n = 2), and hepatic failure (n = 1). In 4 patients, the toxicity could be directly attributed to the planned dose to OAR (ie, pneumonitis due to high lung dose or colitis due to high bowel dose). CONCLUSIONS: Multisite SBRT in combination with programmed cell death protein 1 blockade was safely tolerated when treating critical central, abdominal-pelvic, and peripheral OAR nearing NRG-BR001 constraints with clinically acceptable toxicity in the corresponding organ systems. The observed relationship between dose and DLTs in 4 of 6 patients indicates that NRG-BR001 dose constraints should be respected in subsequent trials to maintain clinical safety.

Cataracts in congenital toxoplasmosis.

PURPOSE: To determine the incidence and natural history of cataracts in children with congenital toxoplasmosis. METHODS: Children referred to the National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS) between 1981 and 2005 were examined by ophthalmologists at predetermined times according to a specific protocol. The clinical course and treatment of patients who developed cataracts were reviewed. RESULTS: In the first year of life, 134 of 173 children examined were treated with pyrimethamine, sulfadiazine, and leukovorin, while the remaining 39 were not treated. Cataracts occurred in 27 eyes of 20 patients (11.6%, 95% confidence interval [7.2%, 17.3%]). Fourteen cataracts were present at birth and 13 developed postnatally. Locations of the cataracts included anterior polar (three eyes), anterior subcapsular (six eyes), nuclear (five eyes), posterior subcapsular (seven eyes), and unknown (six eyes). Thirteen cataracts were partial, nine total, and five with unknown complexity. Twelve cataracts remained stable, 12 progressed, and progression was not known for 3. Five of 27 eyes had cataract surgery, with 2 of these developing glaucoma. Sixteen eyes of 11 patients had retinal detachment and cataract. All eyes with cataracts had additional ocular lesions. CONCLUSIONS: In the NCCCTS cohort, 11.6% of patients were diagnosed with cataracts. There was considerable variability in the presentation, morphology, and progression of the cataracts. Associated intraocular pathology was an important cause of morbidity.

Quantitative real-time RT-PCR monitoring of BCR-ABL in chronic myelogenous leukemia shows lack of agreement in blood and bone marrow samples.

Molecular monitoring of the BCR-ABL transcript in chronic myelogenous leukemia (CML) using quantitative RT-PCR provides clinicians with important diagnostic and prognostic information. To determine whether molecular detection and monitoring of CML is comparable using peripheral blood (PB) and bone marrow (BM) aspirate samples, we performed a prospective study using quantitative real-time RT-PCR (QRT-PCR) of paired PB and BM samples from 41 patients with CML entered onto a single Cancer and Leukemia Group B (CALGB) treatment study. QRT-PCR analysis of PB and BM samples was performed prior to initiation of, and during, treatment with homoharringtonine and cytarabine on a CALGB study for previously untreated CML. Statistical analyses demonstrated good agreement of PB and BM pre-treatment samples. However, using the Bland-Altman statistical method that measures true agreement between PB and BM values, we found that there was only modest agreement of BCR-ABL measurements in PB and BM for samples obtained during treatment. PB values obtained during treatment tended to be lower than the corresponding BM values [average difference = -0.37 (p<0.001) in 36 paired samples] and the 95% limits of agreement ranged from -1.23 to 0.48. Nevertheless, our study demonstrates that BM and PB QRT-PCR values followed a similar trend during treatment (Spearman correlation coefficient, 0.83; 95% CI, 0.70, 0.96). Our data suggest that, quantitatively, PB and BM measurements of BCR-ABL are frequently disparate. Since BM values tended to be higher than PB values, BM sampling provides the most accurate assessment of minimal residual disease (MRD). Based on these results, we caution against interchanging BM with PB sampling for MRD monitoring during treatment of CML since this may lead to misinterpretation of treatment results.