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  • Amiloride HCL br ACCEPTED MANUSCRIPT br We further identifie

    2019-09-16


    ACCEPTED MANUSCRIPT
    We further identified the threshold of ABM V40 corresponding to the median post-CRT hematologic toxicity in our data. Relying on linear regression function derived above, the median value of ∆WBC - 2.79 responded to ABM V40 = 24.2%, whereas the median value of ∆ANC (-1.31) indicated ABM V40=20%. Our results suggest that Amiloride HCL the ABM V40Gy ≤ 20-25% correlates to low post-CRT hT. We used multivariable linear regression to identify the correlation between dose ABM V40 and two HT variables (∆WBC, ∆ANC). The results of regression show that the area of under curve of ROC analysis is 0.625 for V40>20% and 0.571 for V40>25%, and 0.569 for V40>18%. For V40 > 20%, the sensitivity of the classification is 0.565, specificity is 0.692, the positive predictive value (PPV) is 0.764, and negative predictive value (NPV) is 0.474 (with TP=13, FN=10, FP=4, and TN=9). The performance of the classification is also interpreted by the Matthews correlation coefficient with 0.248. We examined two variables correlation (∆WBC and ∆ANC) with the Pearson coefficient between is 0.877, and the multi-collinearities index variance inflation factor (VIF) is 4.334, which is less than the ad hoc data range 5 to 10.
    4. Discussion
    These results build on a growing body of literature suggesting PET imaging is an effective approach for evaluating changes in ABM due to CRT and impact on HT in anal cancer patients. Our technique for
    identifying areas of ABM was similar to Noticewala et al.12 such that irradiated pelvic regions were
    ACCEPTED MANUSCRIPT
    normalized to unirradiated extrapelvic bone marrow. We utilized both pre and post treatment PET images and identified significant changes in mean SUV and ABM as a function of CRT While this
    approach was similar to Lee et al16 and Freese et al17, our novelty of utilizing both pre and post PET allowed for identification of change in ABM regions. Specifically, the lumbosacral-∆ABM was the area of strongest correlation. Next, we derived a novel formula for estimating the ∆WBC and ∆ANC by using a V40Gy dose distribution. Lastly, to our knowledge, this is the first study to suggest that patients whose ABM V40Gy ≤ 20-25% had a significant reduction in hematologic toxicity (HT) which correlated with pre and post PET scans.
    Our study suggests that change in pelvic ABM during CRT, as identified using PET/CT, correlates well with HT including neutropenia, lymphopenia and thrombocytopenia. The significance of these findings seems to be higher for lumbro-sacral bone marrow, as compared to lower pelvic bone marrow ABM. In addition, the analysis of bone marrow dosimetric parameters suggests that severity of HT linearly correlates with increasing dose to ABM. The slope of the linear fit can be used to estimate the change in WBC counts. For example, to avoid ∆WBC ≤ 1, our results suggest that V40Gy of ABM should be less than 20%. Meanwhile, to achieve ∆ANC ≤ 1, ABM V40Gy should be less than 25%.
    Several reports suggest that low-dose irradiated pelvic bone marrow is associated with leukopenia and
    other HT. Mell et al18 reported that low dose irradiation of whole pelvic bone marrow PBM-V10 was associated with HT, and patients with PBM-V10 >= 90% were more likely to develop HT. Rose et al also recommended that PBM-V10<95% and V20<80% to reduce G3 leukopenia risk. Additional reports have indicated that high-dose of specific sub-regional pelvic bone marrows is more important in the development of HT. For example, Franco et al showed that LSBM-mean dose is significantly correlated with >=G3 leukopenia and suggested that LSBM-mean dose <32 Gy to minimize G3 HT in anal cancer patients19. Another study of the same group suggested that patients with LSBM-V40>41% were more