The Value of IgM Memory B-Cells in the Assessment of Splenic Function in Childhood Cancer Survivors at Risk for Splenic Dysfunction: A DCCSS-LATER Study.

Background: Childhood cancer survivors (CCS) who received radiotherapy involving the spleen or total body irradiation (TBI) might be at risk for splenic dysfunction. A comprehensive screening test for examining splenic dysfunction is lacking. Objective: We investigated whether IgM memory B-cells could be used to assess splenic dysfunction in CCS who received a splenectomy, radiotherapy involving the spleen, or TBI. Methods: All CCS were enrolled from the DCCSS-LATER cohort. We analyzed differences in IgM memory B-cells and Howell-Jolly bodies (HJB) in CCS who had a splenectomy (n = 9), received radiotherapy involving the spleen (n = 36), or TBI (n = 15). IgM memory B-cells < 9 cells/µL was defined as abnormal. Results: We observed a higher median number of IgM memory B-cells in CCS who received radiotherapy involving the spleen (31 cells/µL, p=0.06) or TBI (55 cells/µL, p = 0.03) compared to CCS who received splenectomy (20 cells/µL). However, only two CCS had IgM memory B-cells below the lower limit of normal. No difference in IgM memory B-cells was observed between CCS with HJB present and absent (35 cells/µL vs. 44 cells/µL). Conclusion: Although the number of IgM memory B-cells differed between splenectomized CCS and CCS who received radiotherapy involving the spleen or TBI, only two CCS showed abnormal values. Therefore, this assessment cannot be used to screen for splenic dysfunction.

Measuring chronic myeloid leukaemia TKI-related toxic effects in the real world: a systematic review and critical assessment of content validity of patient-reported outcome measures.

Insight into real-world treatment-related toxic effects reported by patients has the potential to improve care, benchmark trials, and fill knowledge gaps, especially in patients with chronic myeloid leukaemia, which is treated in the majority of patients continually with tyrosine-kinase inhibitors (TKIs). The aim of our systematic review was to investigate the content validity of instruments that elicit TKI-related toxic effects reported by patients with chronic myeloid leukaemia in the real world. We searched PubMed and Embase from Jan 1, 2017 to Oct 21, 2022. Studies on instruments used in or developed for patients with chronic myeloid leukaemia that assess a patient's symptoms were eligible. Content validity was assessed according to the Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN): none of the six identified instruments were rated as sufficient. Five instruments (European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire for chronic myeloid leukaemia with 24 items [EORTC QLQ-CML24], EORTC symptom set, Functional Assessment of Cancer Therapy-Leukaemia [FACT-LEU], haematological malignancies patient-reported outcomes [HM-PRO], and MD Anderson Symptom Inventory for chronic myeloid leukaemia [MDASI-CML]) were rated as inconsistent due to not being evaluated by professionals post-development, having very few patients with chronic myeloid leukaemia involved, or missing key symptoms. Moderate-quality to very low-quality evidence underpinned these ratings. The two EORTC instruments were the only ones not to miss key toxic effects (eg, muscle cramps). However, their relevance was rated as inconsistent: the QLQ-CML24 includes questions on health-related quality-of-life, whereas the symptom set includes items sourced from solid cancer treatments. This Review shows the need for an instrument with sufficient content validity to measure toxic effects from TKI treatment in patients with chronic myeloid leukaemia. Until then, stakeholders can make an informed choice from currently used instruments with our assessment.

Early response assessment and prediction of overall survival after peptide receptor radionuclide therapy.

BACKGROUND: Response after peptide receptor radionuclide therapy (PRRT) can be evaluated using anatomical imaging (CT/MRI), somatostatin receptor imaging ([68Ga]Ga-DOTA-TATE PET/CT), and serum Chromogranin-A (CgA). The aim of this retrospective study is to assess the role of these response evaluation methods and their predictive value for overall survival (OS). METHODS: Imaging and CgA levels were acquired prior to start of PRRT, and 3 and 9 months after completion. Tumour size was measured on anatomical imaging and response was categorized according to RECIST 1.1 and Choi criteria. [68Ga]Ga-DOTA-TATE uptake was quantified in both target lesions depicted on anatomical imaging and separately identified PET target lesions, which were either followed over time or newly identified on each scan with PERCIST-based criteria. Response evaluation methods were compared with Cox regression analyses and Log Rank tests for association with OS. RESULTS: A total of 44 patients were included, with median follow-up of 31 months (IQR 26-36 months) and median OS of 39 months (IQR 32mo-not reached)d. Progressive disease after 9 months (according to RECIST 1.1) was significantly associated with worse OS compared to stable disease [HR 9.04 (95% CI 2.10-38.85)], however not compared to patients with partial response. According to Choi criteria, progressive disease was also significantly associated with worse OS compared to stable disease [HR 6.10 (95% CI 1.38-27.05)] and compared to patients with partial response [HR 22.66 (95% CI 2.33-219.99)]. In some patients, new lesions were detected earlier with [68Ga]Ga-DOTA-TATE PET/CT than with anatomical imaging. After 3 months, new lesions on [68Ga]Ga-DOTA-TATE PET/CT which were not visible on anatomical imaging, were detected in 4/41 (10%) patients and in another 3/27 (11%) patients after 9 months. However, no associations between change in uptake on 68Ga-DOTA-TATE PET/CT or serum CgA measurements and OS was observed. CONCLUSIONS: Progression on anatomical imaging performed 9 months after PRRT is associated with worse OS compared to stable disease or partial response. Although new lesions were detected earlier with [68Ga]Ga-DOTA-TATE PET/CT than with anatomical imaging, [68Ga]Ga-DOTA-TATE uptake, and serum CgA after PRRT were not predictive for OS in this cohort with limited number of patients and follow-up time.

Knowledge-Based Assessment of Focal Dose Escalation Treatment Plans in Prostate Cancer.

PURPOSE: In a randomized focal dose escalation radiation therapy trial for prostate cancer (FLAME), up to 95 Gy was prescribed to the tumor in the dose-escalated arm, with 77 Gy to the entire prostate in both arms. As dose constraints to organs at risk had priority over dose escalation and suboptimal planning could occur, we investigated how well the dose to the tumor was boosted. We developed an anatomy-based prediction model to identify plans with suboptimal tumor dose and performed replanning to validate our model. METHODS AND MATERIALS: We derived dose-volume parameters from planned dose distributions of 539 FLAME trial patients in 4 institutions and compared them between both arms. In the dose-escalated arm, we determined overlap volume histograms and derived features representing patient anatomy. We predicted tumor D98% with a linear regression on anatomic features and performed replanning on 21 plans. RESULTS: In the dose-escalated arm, the median tumor D50% and D98% were 93.0 and 84.7 Gy, and 99% of the tumors had a dose escalation greater than 82.4 Gy (107% of 77 Gy). In both arms organs at risk constraints were met. Five out of 73 anatomic features were found to be predictive for tumor D98%. Median predicted tumor D98% was 4.4 Gy higher than planned D98%. Upon replanning, median tumor D98% increased by 3.0 Gy. A strong correlation between predicted increase in D98% and realized increase upon replanning was found (ρ = 0.86). CONCLUSIONS: Focal dose escalation in prostate cancer was feasible with a dose escalation to 99% of the tumors. Replanning resulted in an increased tumor dose that correlated well with the prediction model. The model was able to identify tumors on which a higher boost dose could be planned. The model has potential as a quality assessment tool in focal dose escalated treatment plans.