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Sex and Circadian Timing Modulate Oxaliplatin Hematological and Hematopoietic Toxicities.

ABSTRACT: Oxaliplatin was nearly twice as hematotoxic, with optimal circadian timing differing by 6 h, in women as compared to men with colorectal cancers. Hence, we investigated sex- and timing-related determinants of oxaliplatin hematopoietic toxicities in mice. Body-weight loss (BWL), blood cell counts, bone marrow cellularity (BMC) and seven flow-cytometry-monitored hematopoietic progenitor populations were evaluated 72 h after oxaliplatin chronotherapy administration (5 mg/kg). In control animals, circadian rhythms of circulating white blood cells showed a peak at ZT5 in both sexes, whereas BMC was maximum at ZT20 in males and ZT13h40 in females. All BM progenitor counts presented robust rhythms with phases around ZT3h30 in females, whereas only three of them rhythmically cycled in males with a ≈ -6 h phase shift. In treated females, chronotoxicity rhythms occurred in BWL, WBC, BMC and all BM progenitors with the best timing at ZT15, ZT21, ZT15h15 and ZT14h45, respectively. In males, almost no endpoints showed circadian rhythms, BWL and WBC toxicity being minimal, albeit with a substantial drop in BM progenitors. Increasing dose (10 mg/kg) in males induced circadian rhythms in BWL and WBC but not in BM endpoints. Our results suggest complex and sex-specific clock-controlled regulation of the hematopoietic system and its response to oxaliplatin.

SUBMITTER: Dulong S

PROVIDER: S-EPMC9699532 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Sex and Circadian Timing Modulate Oxaliplatin Hematological and Hematopoietic Toxicities.

Dulong Sandrine S de Souza Lucas Eduardo Botelho LEB Machowiak Jean J Peuteman Benoit B Duvallet Gaelle G Boyenval Déborah D Roth Elise E Asgarova Afag A Chang Yunhua Y Li Xiao-Mei XM Foudi Adlen A Ballesta Annabelle A

Pharmaceutics 20221115 11

Oxaliplatin was nearly twice as hematotoxic, with optimal circadian timing differing by 6 h, in women as compared to men with colorectal cancers. Hence, we investigated sex- and timing-related determinants of oxaliplatin hematopoietic toxicities in mice. Body-weight loss (BWL), blood cell counts, bone marrow cellularity (BMC) and seven flow-cytometry-monitored hematopoietic progenitor populations were evaluated 72 h after oxaliplatin chronotherapy administration (5 mg/kg). In control animals, ci ...[more]

PMID: 36432655

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Project description:Frailty is a state characterized by diminished physiologic reserve and increased vulnerability to stress and adversely affects outcomes in older patients. We aimed to determine the relationship between pre-hematopoietic cell transplant (HCT) frailty and grades 3 to 4 nonhematologic toxicities (Common Terminology Criteria for Adverse Events, version 5.0) and mortality in HCT recipients within 1 year after HCT and also examined whether age at HCT moderated that association. In a prospective longitudinal study of 117 patients aged ≥ 40 years undergoing HCT, we performed formal pre-HCT geriatric assessments. Frailty was assessed using Fried's criteria. Post-HCT toxicities were abstracted through medical record reviews. The prevalence of pre-HCT frailty was 21% and was not different in younger (40 to 59 years) versus older (≥60 years) HCT recipients. Overall, frail recipients (versus nonfrail) had a higher cumulative incidence of any grades 3 to 4 nonhematologic toxicity (86% [95% confidence interval {CI}, 62% to 100%] versus 70% [95% CI, 57% to 83%), P = .03) and more organ-specific grades 3 to 4 toxicities, such as non-neutropenic infections (38% [95% CI, 17% to 59%] versus 13% [95% CI, 6% to 20%], P < .01), nervous system disorders (19% [95% CI, 3% to 35%] versus 4% [95% CI, 0 to 8%], P = .02), and pneumonia (38% [95% CI, 17% to 59%] versus 10% [95% CI, 4% to 17%], P < .01). Frail recipients were 1.9-fold (95% CI, 1.1 to 3.4) more likely to develop any grades 3 to 4 toxicities (P = .03), 4-fold more likely to suffer non-neutropenic infections (95% CI, 1.4 to 11) and pneumonia (95% CI, 1.4 to 12; both P = .01), and 8.6-fold (95% CI, 1.6 to 45.3) more likely to suffer nervous system disorders (P = .01). Frail allogeneic HCT recipients also had a 3.1 times (95% CI, .9 to 9.7; P = .06) higher risk of overall mortality as compared with nonfrail allogeneic HCT recipients. The higher toxicity and mortality observed in frail allogeneic recipients needs to be monitored with high attention. Studies focusing on interventions to reduce frailty and manage morbidities are needed.

Project description:BackgroundCervical cancer ranks third in frequency among female cancers globally and causes high mortality worldwide. Concurrent chemoradiotherapy improves the overall survival in cervical cancer patients by 6% but it can cause significant acute and late toxicities affecting patient quality of life. Whole pelvis radiotherapy doses of 10-20 Gy can lead to myelosuppression and to subsequent hematological toxicities since pelvic bones contain half of bone marrow tissue.MethodsA total of 69 patients with IB-IVB-staged cervical cancer have been included in this retrospective cohort study. We analyzed clinical adverse events and changes in blood cell counts (hemoglobin, neutrophils, leukocytes, and platelets) during radiation or chemoradiotherapy received at the Oncological Institute of Bucharest from 2018 to 2021.ResultsDecreases in hemoglobin levels of over 2.30 g/dL during treatment were associated with BMI > 23.2 kg/m2 (OR = 8.68, 95%CI = [1.01, 75.01]), age over 53 years (OR = 4.60 95%CI = [1.10, 19.22]), with conformational 3D irradiation (OR = 4.78, 95%CI = [1.31, 17.40]) and with total EQD2 of over 66.1 Gy (OR = 3.67, 95%CI = [1.02, 13.14]). The hemoglobin decrease rate of 0.07 g/dL/day was related to 95% isodose volume (OR = 18.00). Neutropenia is associated frequently with gastrointestinal side effects and with the bowel and rectal V45 isodoses (OR = 16.5 and OR = 18.0, respectively). Associations of total external and internal radiation dose with the time durations calculated from the initiation of treatment to the onset of hematological adverse reactions were also obtained. The maximum drop in leukocytes was observed before day 35 from the RT initiation in patients who underwent treatment with 3D conformal radiotherapy (OR = 4.44, 95%CI = [1.25, 15.82]). Neutrophil levels under 2.2 × 103/μL and thrombocyte levels under 131 × 103/μL during the follow-up period were associated with a total planned dose of 54 Gy to the pelvic region volume (OR = 6.82 and OR = 6.67, respectively).ConclusionsThis study shows the existence of clinical and blood predictors of hematological adverse reactions in cervical cancer patients. Thus, patients who are in a precarious clinical situation, with low hematological values (but not yet abnormal), should be monitored during days 29-35 after the initiation of RT, especially if they are obese or over 53 years of age.

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Sex and Circadian Timing Modulate Oxaliplatin Hematological and Hematopoietic Toxicities.

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Sex and Circadian Timing Modulate Oxaliplatin Hematological and Hematopoietic Toxicities.

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