Dataset Information

Circulating Lymphocyte Counts Early During Radiation Therapy Are Associated With Recurrence in Pediatric Medulloblastoma.

ABSTRACT:

Purpose

Decreased peripheral lymphocyte counts are associated with survival after radiation therapy (RT) in several solid tumors, although they appear late during or after the radiation course and often correlate with other clinical factors. Here we investigate if absolute lymphocyte counts (ALCs) are independently associated with recurrence in pediatric medulloblastoma early during RT.

Methods and materials

We assessed 202 patients with medulloblastoma treated between 2000 and 2016 and analyzed ALC throughout therapy, focusing on both early markers (ALC during week 1 - ALC_wk1; grade 3+ Lymphopenia during week 2 - Lymphopenia_wk2) and late markers (ALC nadir). Uni- and multivariable regressions were used to assess association of clinical and treatment variables with ALC and of ALC with recurrence.

Results

Thirty-six recurrences were observed, with a median time to recurrence of 1.6 years (range, 0.2-10.3) and 7.1 years median follow-up. ALC during RT was associated with induction chemotherapy (P < .001), concurrent carboplatin (P = .009), age (P = .01), and high-risk status (P = .05). On univariable analysis, high-risk disease (hazard ratio = 2.0 [1.06-3.9]; P = .03) and M stage≥1 (hazard ratio = 2.2 [1.1-4.4]) were associated with recurrence risk, as was lower ALC early during RT (ALC_wk1, hazard ratio = 0.28 [0.12-0.65]; P = .003; Lymphopenia_wk2, hazard ratio = 2.27 [1.1-4.6]; P = .02). Neither baseline ALC nor nadir correlated with outcome. These associations persisted when excluding carboplatin and pre-RT chemotherapy patients, and in the multivariable analysis accounting for confounders lymphocyte counts remained significant (ALC_wk1, hazard-ratio = 0.23 [0.09-0.57]; P = .002; Lymphopenia_wk2, hazard-ratio = 2.3 [1.1-4.8]; P = .03).

Conclusions

ALC during weeks 1 and 2 of RT was associated with recurrence, and low ALC is an independent prognostic factor in medulloblastoma. Strategies to mitigate the risk of radiation-induced lymphopenia should be considered.

SUBMITTER: Grassberger C

PROVIDER: S-EPMC8238781 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:MethodsBetween December 2017 and December 2018, 153 HCC patients (134 males and 19 females; mean age, 56.0 ± 10.2 years; range, 28-78 years) treated with radical therapy were enrolled in our retrospective study and were divided into a training cohort (n = 107) and a validation cohort (n = 46). All patients underwent preoperative CTC tests and CEUS examinations before treatment. The ultrasomics signature was extracted and built from CEUS images. Univariate and multivariate logistic regression analyses were used to identify the significant variables related to ER, which were then combined to build a predictive nomogram. The performance of the nomogram was evaluated by its discrimination, calibration and clinical utility. The predictive model was further evaluated in the internal validation cohort.ResultsHBV DNA, serum AFP level, CTC status, tumour size and ultrasomics score were identified as independent predictors associated with ER (all p < 0.05). Multivariable logistic regression analysis showed that the CTC status (OR = 7.02 [95% CI, 2.07 to 28.38], p = 0.003) and ultrasomics score (OR = 148.65 [95% CI, 25.49 to 1741.72], p < 0.001) were independent risk factors for ER. The nomogram based on ultrasomics score, CTC status, serum AFP level and tumour size exhibited C-indexes of 0.933 (95% CI, 0.878 to 0.988) and 0.910 (95% CI, 0.765 to 1.055) in the training and validation cohorts, respectively, fitting well in calibration curves. Decision curve analysis further confirmed the clinical usefulness of the nomogram.ConclusionThe nomogram incorporating CTC, ultrasomics features and independent clinical risk factors achieved satisfactory preoperative prediction of ER in HCC patients after radical treatment.Advances in knowledge1. CTC status and ultrasomics score were identified as independent predictors associated with ER of HCC after radical treatment. 2. The nomogram constructed by ultrasomics score generated by 17 ultrasomics features, combined with CTCs and independent clinical risk factors such as AFP and tumour size. 3. The nomogram exhibited satisfactory discriminative power, and could be clinically useful in the preoperative prediction of ER after radical treatment in HCC patients.

Project description:BACKGROUND:Resistance to radiation treatment remains a major clinical problem for patients with brain cancer. Medulloblastoma is the most common malignant brain tumor of childhood, and occurs in the cerebellum. Though radiation treatment has been critical in increasing survival rates in recent decades, the presence of resistant cells in a substantial number of medulloblastoma patients leads to relapse and death. METHODS:Using the established medulloblastoma cell lines UW228 and Daoy, we developed a novel model system to enrich for and study radiation tolerant cells early after radiation exposure. Using fluorescence-activated cell sorting, dead cells and cells that had initiated apoptosis were removed, allowing surviving cells to be investigated before extensive proliferation took place. RESULTS:Isolated surviving cells were tumorigenic in vivo and displayed elevated levels of ABCG2, an ABC transporter linked to stem cell behavior and drug resistance. Further investigation showed another family member, ABCA1, was also elevated in surviving cells in these lines, as well as in early passage cultures from pediatric medulloblastoma patients. We discovered that the multi-ABC transporter inhibitors verapamil and reserpine sensitized cells from particular patients to radiation, suggesting that ABC transporters have a functional role in cellular radiation protection. Additionally, verapamil had an intrinsic anti-proliferative effect, with transient exposure in vitro slowing subsequent in vivo tumor formation. When expression of key ABC transporter genes was assessed in medulloblastoma tissue from 34 patients, levels were frequently elevated compared with normal cerebellum. Analysis of microarray data from independent cohorts (n = 428 patients) showed expression of a number of ABC transporters to be strongly correlated with certain medulloblastoma subtypes, which in turn are associated with clinical outcome. CONCLUSIONS:ABC transporter inhibitors are already being trialed clinically, with the aim of decreasing chemotherapy resistance. Our findings suggest that the inhibition of ABC transporters could also increase the efficacy of radiation treatment for medulloblastoma patients. Additionally, the finding that certain family members are associated with particular molecular subtypes (most notably high ABCA8 and ABCB4 expression in Sonic Hedgehog pathway driven tumors), along with cell membrane location, suggests ABC transporters are worthy of consideration for the diagnostic classification of medulloblastoma.