BACKGROUND:The prescription of antitumor drugs has often been associated with drug-related problems. Pretherapeutic multidisciplinary risk assessment programs including pharmaceutical care have been established to secure the initiation of injectable and oral antitumor therapies. This prospective cross-sectional double-center study evaluated the clinical and economic impact of the pharmacist in detecting drug-related problems in patients initiating antitumor therapies. MATERIALS AND METHODS:Following pharmaceutical consultations, pharmaceutical interventions were validated by a multidisciplinary team. A committee of independent clinical experts assessed the potential clinical impact of drug-drug interactions. The association of clinical variables with pharmaceutical interventions was tested using a multivariate logistic regression model. Pharmacist cost of the program was assessed by valuing pharmacists' time at their salaries and compared with potentially avoided costs. RESULTS:Four hundred thirty-eight patients with solid tumors were included: 62% males, mean age of 65 ± 13 years, and average of 6 medications. Half of the patients required at least one pharmaceutical intervention and independent factors associated with pharmaceutical interventions were the number of medications (5-9 vs <5: OR = 2.91 [95% CI 1.82-4.65], P < .001) and the type of antitumor treatment (immunotherapy vs intravenous chemotherapy: OR = 0.35 [95% CI 0.18-0.68], P = .002). One hundred seventy-four out of 266 pharmaceutical interventions (130 patients) involved clinically significant drug-drug interactions. Pharmacist costs were estimated to range between €4899 and €6125. Average costs were estimated at €11.4-14.3 per patient. Avoided hospitalization costs were estimated to be €180 633. CONCLUSION:Clinical pharmacists contribute to the cost-effective reduction of drug-related problems in pre-therapeutic assessment programs for patients with cancer.

Purpose Pazopanib is approved in advanced renal cell carcinoma (RCC) and soft-tissue sarcoma at a flat-fixed dose despite a large pharmacokinetics interindividual variability and a narrow therapeutic index. To our knowledge, pazopanib exposure in patients with gastrointestinal resections (GIR) has not been described. This report focuses on feasibility of pharmacokinetics-guided dose escalation in these patients and clinical implications for their management. Method A retrospective data collection was performed for three patients with GIR treated with pazopanib, including pazopanib plasma concentrations (high-performance liquid chromatography with UV detection) and treatment adherence (Girerd score). Case presentation First patient (55-year-old man, RCC, gastric bypass surgery) pazopanib C min,ss at day 39 was 4.1 mg/L. Dose escalation to 1800 mg/day fractionated allowed to reach C min,ss of 18.5 mg/L (target threshold in RCC patients: 20.5 mg/L). Patient 2 (50-year-old woman, metastatic myxofibrosarcoma, gastric band) showed C min,ss of 4.0 mg/L at day 13. In patient 3 (49-year-old man, gastric malignant peripheral nerve sheath tumor, gastrectomy), C min,ss at day 13 was 2.7 mg/L. For these two patients, intake with food and dose fractioning only slightly increased pazopanib C min,ss to 12.0 mg/L and 6.5 mg/L, respectively (therapeutic threshold in sarcoma patients: 27 mg/L). Treatment adherence was good in all patients. Conclusion Optimal pazopanib exposure cannot be achieved in patients with GIR, and thus, other therapeutic strategies should be encouraged. Pretherapeutic assessment seems crucial to evaluate factors as bariatric surgery that may impact pazopanib concentrations. Therapeutic drug monitoring could be helpful to optimize pazopanib response in these patients.

Background: Olaparib is an inhibitor of the human poly-(ADP-ribose)-polymerase enzymes (PARP1/2) needed to repair single-strand DNA breaks. It is used in breast, ovarian, prostate and pancreatic cancer. Objectives: This work aimed to describe the pharmacokinetics/pharmacodynamics (PK/PD) relationship between olaparib plasma concentrations and common adverse effects (i.e. anaemia and hypercreatininaemia), in a real-life setting, to propose a target concentration for therapeutic drug monitoring. Methods: Two PK/PD models describing the evolution of haemoglobinaemia and creatininaemia as a function of time were developed, based on data from, respectively, 38 and 37 patients receiving olaparib. The final model estimates were used to calculate the incidence of anaemia and creatinine increase according to plasma trough concentrations for 1000 virtual subjects to define target exposure. Results: The final models correctly described the temporal evolution of haemoglobinaemia and creatininaemia for all patients. The haemoglobinaemia PK/PD model is inspired by Friberg’s model, and the creatininaemia PK/PD model is an indirect response model. Model parameters were in agreement with physiological values and close to literature values for similar models. The mean (population) plasma haemoglobin concentration at treatment initiation, as estimated by the model, was 11.62 g/dL, while creatinine concentration was 71.91 µmol/L. Using simulations, we have identified a target trough concentration of 3500–4000 ng/mL, above which more than 20% of patients would report grade ≥3 anaemia. Conclusion: Based on real-world data, we were able to properly describe the time course of haemoglobinaemia and plasma creatininaemia during olaparib treatment.

BackgroundA high density of resident memory T cells (TRM) in tumors correlates with improved clinical outcomes in immunotherapy-treated patients. In most clinical studies, TRMare defined by the CD103 marker. However, it is clearly established that not all TRMexpress CD103, but can be defined by other markers (CD49a, CD69, etc). The frequency of these subpopulations of TRMexpressing or not CD103 varies according to the location of the cancer. Little is known about their functionality and their predictive impact on response to immunotherapy. In preclinical models, only some subpopulations of TRMare associated with cancer vaccine efficacy.MethodsMultiparametric cytometry analyses were used to demonstrate the presence of TRMsubpopulations in the lung in mice after vaccination and in fresh ex vivo human non-small cell lung cancer (NSCLC). An analysis of the T-cell repertoire of these TRMwas conducted to search for their relationships. Multiplex immunofluorescence techniques were used to quantify intratumor infiltration of TRMsubpopulations in two cohorts of patients with NSCLC. The impact on the clinical outcome of the TRMtumor infiltration was also investigated.ResultsWe identified two main TRMsubpopulations in tumor-infiltrating lymphocytes derived from patients with NSCLC: one co-expressing CD103 and CD49a (double positive (DP)), and the other expressing only CD49a (simple positive (SP)); both exhibiting additional TRMsurface markers like CD69. Despite higher expression of inhibitory receptors, DP TRMexhibited greater functionality compared with SP TRM. Analysis of T-cell receptor (TCR) repertoire and expression of the stemness marker TCF1 revealed shared TCRs between populations, with the SP subset appearing more progenitor-like phenotype. In the training cohort, PD-L1 (Programmed Death-Ligand 1) and TCF1+CD8+T cells predict response to anti-PD-1. In patient with NSCLC validation cohorts, only DP TRMpredicted PD-1 blockade response. Multivariate analysis, including various biomarkers associated with responses to anti-PD-(L)1, such as total CD8, TCF1+CD8+T cells, and PD-L1, showed that only intratumoral infiltration by DP TRMremained significant.ConclusionsThis study highlights the non-equivalence of TRMsubpopulations. The population of TRMco-expressing CD103 and CD49a appears to be the most functional and has the most significant capacity for predicting response to immunotherapy in multivariate analysis in patients with NSCLC.

Introduction The low incidence and heterogeneity of sarcomas limit understanding of their progression in metastatic cases. The use of metastasectomy is debated due to lack of consensus and evidence-based data. This study aimed to identify simple prognostic factors that could contribute to the therapeutic strategy. Methods We retrospectively reviewed all patients undergoing pulmonary metastasectomy from sarcoma in our referral center between 2011 and 2022. Demographic, radiologic, pathologic, and operative data were collected. Oncological follow-up, survival, and risk factor analyses were performed. Results 192 patients were identified (mean age 49.3 years). Primary sarcoma arose from the trunk (24.6 %) or limbs (75.4 %), and metastases were metachronous in 85.4 % of cases. The median number of operated lesions was 2, and anatomic resection were performed in 24.1 %. The postoperative course was uneventful in 91.3 % of cases. Post-operative chemotherapy followed lung resection in 68.7 %. 1-, 3-, and 5-year Overall Survival (OS) were 89.6 %, 69.8 %, 57.6 %, respectively, with a plateau phase beyond 5 years. Higher grade or trunk location of the primary sarcoma, incomplete or anatomic pulmonary resection, and post-operative systemic treatment were significantly associated with shorter OS. No histological subtype significantly impacted OS. Location of the primary, resection type, and post-operative systemic treatment independently influenced OS. Non-anatomic and repeated pulmonary resections, were independently associated with “long surviving”. Conclusion In metastatic sarcoma, pulmonary resections offer prolonged survival in selected patients, supporting its essential role in the whole therapeutic strategy. Anatomic and sequential metastasectomy should be cautiously discussed.

De novo germline pathogenic variants (gPV) of the BReast CAncer 1 (BRCA1) gene are very rare. Only a few have been described up to date, usually in patients with a history of ovarian or breast cancer. Here, we report the first case of an incidental de novo BRCA1 germline pathogenic variant which was identified within the framework of the Plan France Médecine Génomique (PFMG) 2025 French national tumor sequencing program. The proband was a 29-year-old man diagnosed with metastatic osteosarcoma. Tumor whole exome sequencing identified a BRCA1 c.3756_3759del p.(Ser1253Argfs*10) pathogenic variant without loss-of-heterozygosity. A low genomic instability score and the absence of single base substitution signatures of homologous recombination deficiency suggested that the BRCA1 variant was not driver in the osteosarcoma tumorigenesis. Germline whole genome sequencing asserted the germline nature of this variant, with a 36

This review provides an overview of histopathology, clinical presentation, molecular pathways, and potential new systemic treatments of high-grade chondrosarcomas (CS), including grade 2–3 conventional, dedifferentiated, and mesenchymal CS. The diagnosis of CS combines radiological and histological data in conjunction with patient clinical presentations. Conventional CS is the most frequent subtype of CS (85%) and represents about 25% of primary bone tumors in adults; they can be categorized according to their bone location into central, peripheral, and periosteal chondrosarcomas. Central and peripheral CS differ at the molecular level with either IDH1/2 mutations or EXT1/2 mutations, respectively. CDKN2A/B deletions are also frequent in conventional CS, as well as COL2A1 mutations. Dedifferentiated CS develops when low-grade conventional CS transforms into a high-grade sarcoma and most frequently exhibits features of osteosarcoma, fibrosarcoma, or undifferentiated pleomorphic sarcoma. Their molecular characteristics are similar to conventional CS. Mesenchymal CS is a totally different pathological entity exhibiting recurrent translocations. Their clinical presentation and management are different too. The standard treatment of CSs is wide en-bloc resection. CS are relatively radiotherapy resistant; therefore, doses >60 Gy are needed in an attempt to achieve local control in unresectable tumors. Chemotherapy is possibly effective in mesenchymal chondrosarcoma and is of uncertain value in dedifferentiated chondrosarcoma. Due to resistance to standard anticancer agents, the prognosis is poor in patients with metastatic or unresectable chondrosarcomas. Recently, the refined characterization of the molecular profile, as well as the development of new treatments, allow new therapeutic options for these rare tumors. The efficiency of IDH1 inhibitors in other malignancies suggests that these inhibitors will be part of IDH1/2 mutated conventional CS management soon. Other treatment approaches, such as PIK3-AKT-mTOR inhibitors, cell cycle inhibitors, and epigenetic or immune modulators based on improving our understanding of CS molecular biology, are emerging.

Background. Around 15% of metastatic endometrial carcinoma (EC) are MMRd/MSI-H improving response to immune checkpoint inhibitors (ICI). So far, few data existed considering the chemotherapy (CT) sensitivity MMRd/MSI-H EC, especially response to first-line platinum-based treatment.Patients and methods. We performed a multicentric retrospective analysis reporting the response to first line platinum CT in MMRd/MSI-H EC patients. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS) with first line platinum-based CT.Results. A total of 112 patients MMRd/MSI-H EC from 8 centers were identified. Median overall survival was 58.0 months (95% CI: 45.3-95.1). Among them, 78 patients received first line platinum CT in recurrent/metastatic setting. With a median follow up of 32.6 months (min: 0.03; max: 135.0), ORR and DCR (disease control rate) were 50% (95% CI: 38.5-61.5) and 68% (95% CI: 56.4-78.1), respectively. Median PFS and OS from first line platinum-based CT was 7.8 months (95% CI: 6.0-9.0) and 51.9 months (95% CI: 28.0-NE), respectively. Median PFS with ICI in second line (n = 48) was 10.7 months (95% CI: 3.4-NE) from ICI initiation.Conclusion. ORR in first line metastatic MMRd/MSI-H EC is consistent with efficacy in an all comer metastatic EC population.(c) 2022 Published by Elsevier Inc.

Background: Nivolumab improved patients’ survival in metastatic renal cell carcinoma (mRCC). We aimed to evaluate resting energy expenditure (REE) (i.e., patients’ basal metabolism) to predict efficacy. Methods: We conducted a monocentric, observational study of mRCC patients receiving nivolumab between October 2015 and May 2020. REE was measured prior to initiating immunotherapy using indirect calorimetry to determine hypo, normo and hypermetabolism. Primary endpoint was 6-month, progression-free survival (PFS), and secondary endpoints were response rate, PFS and overall survival (OS). Results: Of the 51 consecutive patients, 15 (29%) were hypermetabolic, 24 (47%) normometabolic, and 12 (24%) hypometabolic. The 6-month PFS was 15% for hypermetabolic patients and 65% for non-hypermetabolic patients (p < 0.01). In the multivariate analysis, hypermetabolism was the only baseline factor predicting 6-month PFS (OR 9.91, 95%CI [1.62–60.55], p = 0.01). Disease progression was noted as the best response in 73% of hypermetabolic patients and 26% of non-hypermetabolic patients (p = 0.02). Median PFS was 2.8 and 8.7 months (p < 0.01), and median OS was 20.2 and 35.1 months (p = 0.13) in the hypermetabolic and non-hypermetabolic groups, respectively. Conclusions: Our study identifies an association between mRCC patients’ energy expenditure and nivolumab efficacy. The measurement of REE by indirect calorimetry in routine practice could help identify patients at risk of nivolumab failure.

Background: Pazopanib (PAZ) is an oral angiogenesis inhibitor approved to treat soft tissue sarcoma (STS) but associated with a large interpatient pharmacokinetic (PK) variability and narrow therapeutic index. We aimed to define the specific threshold of PAZ trough concentration (Cmin) associated with better progression-free survival (PFS) in STS patients. Methods: In this observational study, PAZ Cmin was monitored over the treatment course. For the primary endpoint, the 3-month PFS in STS was analyzed with logistic regression. Second, we performed exposure–overall survival (OS) (Cox model plus Kaplan–Meier analysis/log-rank test) and exposure–toxicity analyses. Results: Ninety-five STS patients were eligible for pharmacokinetic/pharmacodynamic (PK/PD) assessment. In the multivariable analysis, PAZ Cmin < 27 mg/L was independently associated with a risk of progression at 3 months (odds ratio (OR) 4.21, 95% confidence interval (CI) (1.47–12.12), p = 0.008). A higher average of PAZ Cmin over the first 3 months was associated with a higher risk of grade 3–4 toxicities according to the NCI-CTCAE version 5.0 (OR 1.07 per 1 mg/L increase, CI95 (1.02–1.13), p = 0.007). Conclusion: PAZ Cmin ≥ 27 mg/L was independently associated with improved 3-month PFS in STS patients. Pharmacokinetically-guided dosing could be helpful to optimize the clinical management of STS patients in daily clinical practice.

AbstractBackgroundSpatial inequalities in cancer management have been evidenced by studies reporting lower quality of care or/and lower survival for patients living in remote or socially deprived areas. NETSARC+ is a national reference network implemented to improve the outcome of sarcoma patients in France since 2010, providing remote access to specialized diagnosis and Multidisciplinary Tumour Board (MTB). The IGéAS research program aims to assess the potential of this innovative organization, with remote management of cancers including rare tumours, to go through geographical barriers usually impeding the optimal management of cancer patients.MethodsUsing the nationwide NETSARC+ databases, the individual, clinical and geographical determinants of the access to sarcoma-specialized diagnosis and MTB were analysed. The IGéAS cohort (n = 20,590) includes all patients living in France with first sarcoma diagnosis between 2011 and 2014. Early access was defined as specialised review performed before 30 days of sampling and as first sarcoma MTB discussion performed before the first surgery.ResultsSome clinical populations are at highest risk of initial management without access to sarcoma specialized services, such as patients with non-GIST visceral sarcoma for diagnosis [OR 1.96, 95% CI 1.78 to 2.15] and MTB discussion [OR 3.56, 95% CI 3.16 to 4.01]. Social deprivation of the municipality is not associated with early access on NETSARC+ remote services. The quintile of patients furthest away from reference centres have lower chances of early access to specialized diagnosis [OR 1.18, 95% CI 1.06 to 1.31] and MTB discussion [OR 1.24, 95% CI 1.10 to 1.40] but this influence of the distance is slight in comparison with clinical factors and previous studies on the access to cancer-specialized facilities.ConclusionsIn the context of national organization driven by reference network, distance to reference centres slightly alters the early access to sarcoma specialized services and social deprivation has no impact on it. The reference networks’ organization, designed to improve the access to specialized services and the quality of cancer management, can be considered as an interesting device to reduce social and spatial inequalities in cancer management. The potential of this organization must be confirmed by further studies, including survival analysis.

Factors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients from “real life” data. The clinical endpoint was the onset of SAE (grade III/IV toxicity or dose reduction/discontinuation). Plasma olaparib concentration was assayed using liquid chromatography at any time over the dosing interval. Trough concentrations (CminPred) were estimated using a population pharmacokinetic model. The association between toxicity and clinical characteristics or CminPred was assessed by logistic regression and non-parametric statistical tests. Twenty-seven patients were included, among whom 13 (48%) experienced SAE during the first six months of treatment. Olaparib CminPred was the only covariate significantly associated with increased risk of SAE onset (odds ratio = 1.31, 95%CI = [1.10; 1.57], for each additional 1000 ng/mL). The ROC curve identified a threshold of CminPred = 2500 ng/mL for prediction of SAE onset (sensitivity/specificity 0.62 and 1.00, respectively). This study highlights a significant association between olaparib plasma exposure and SAE onset and identified the threshold of 2500 ng/mL trough concentration as potentially useful to guide dose adjustment in ovarian cancer patients.

Cancer patients are a highly vulnerable group in the COVID-19 pandemic and it has been necessary for oncology units to adapt to this unexpected situation. We present our management of outpatients with cancer during the pandemic. We applied two major adaptations: extending the intervals between injections for maintenance therapy and protocol adaptation for patients with comorbidities. Between 17 March and 30 April 2020, 406 patients were treated in our outpatients department. Protocols were adapted for 94 (23.1%) patients. Among them, 49% had an extended interval between treatment administrations, 22.3% had modified protocols to reduce toxicity, 20.2% had therapeutic interruptions and 5.3% did not receive their treatment because of a COVID-19 infection. Overall, protocol adaptations concerned more than 20% of the patients. This pandemic was an opportunity for oncologists to re-examine the risk versus benefit balance of administering immunosuppressive treatment and highlighted that oncology daily routine should not be applied automatically.

Abstract Background: Neoadjuvant chemotherapy with intercalated surgery is the standard of care for resectable high-grade bone sarcoma (BS) but identification of biomarkers for chemosensitivity prediction is still needed. Insulin-like Growth Factor (IGF) pathway was first linked with sarcoma biology approximately 30 years ago (El-Brady OM, 1990). Methods: We recruited 138 pts with newly diagnosed primary localized or metastatic BS. We measured fasting blood glucose and insulin, body mass index (BMI). The HOMA-IR (Homeostasis Model Assessment) score ((Glucose (mmol/l) x Insulin) / 22.5), which has been proven to reliably detect insulin resistance IR was calculated, and patients with HOMA-IR > 2.6 were considered as IR. We collected characteristics usually associated with insulin resistance: age, obesity, diabetes, dyslipidemia and hypertension. Results: Out of 138 pts, 50 (36%) were insulin resistant: HOMA-IR >2.6. Thirty-two IR patients (64%) had no cardiovascular risk factor. In univariate analysis, IR was associated with obesity (BMI > 30 kg/m2)(22% vs 3%, p=0.0015), but not with age (median 36,8 vs 41 years, p=0.19). IR was more prevalent in Ewing sarcoma (14/29; 48%) and chondrosarcoma (7/16; 44%) followed by osteosarcoma (25/67; 37%) and other rare bone sarcomas (4/26; 15.3%), but not significantly (p=0.097). After neoadjuvant chemotherapy and surgery of Ewing tumor and osteosarcoma, pathologic tumor necrosis was higher in IR pts (88.9 vs 75%, p= 0.028). Conclusion: Our results suggest that metabolic profile may help to discriminate best candidates for neoadjuvant chemotherapy in high-grade bone sarcomas. Further studies are needed to confirm and explain these results. Citation Format: Pascaline Boudou-Rouquette, Ithar Gataa, Sixtine De Percin, Camille Tlemsani, David Biau, Valerie Dumaine, Virginie Audard, Frédérique Larousserie, Philippe Anract, Anne Jouinot, François Goldwasser. Relationship between insulin resistance and chemosensitivity of high grade bone sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3721.

e22506 Background: Neoadjuvant chemotherapy with intercalated surgery is the standard of care for resectable high-grade bone sarcoma (BS) but identification of biomarkers for chemosensitivity prediction is still needed. Methods: We recruited 121 pts with new primary localized or metastatic BS, measured fasting blood glucose and insulin, body mass index (BMI). The HOMA-IR (Homeostasis Model Assessment) score ((Glucose (mmol/l) x Insulin) / 22.5), which has been proven to reliably detect insulin resistance was calculated, and patients with HOMA-IR > 2.6 were considered as insulin resistant (IR). We collected characteristics usually associated with insulin resistance (IR): age, obesity, diabetes, dyslipidemia and hypertension. Results: Out of 121 pts, 48 (40%) were IR: HOMA-IR > 2.6. Thirty IR patients (62%) had no cardiovascular risk factor. In univariate analysis, IR was associated with obesity (BMI > 30 kg/m2)(23% vs 3%, p = 0.0013), but not with age (median 38.4 vs 43.3 years, p = 0.15). IR was more prevalent in Ewing sarcoma (12/21; 57%) and chondrosarcoma (7/13; 54%) followed by osteosarcoma (25/61; 41%) and other rare bone sarcomas (4/26; 15.3%)(p = 0.037). After preoperative chemotherapy and surgery of Ewing tumor and osteosarcoma, pathologic tumor necrosis was higher in IR pts (85.8 vs 69.3%, p = 0.012). Using multivariate linear regression models, IR was independently associated with pathologic tumor necrosis (p = 0.042) but not with obesity (p = 0.55). Conclusions: Our results suggest that tumor-induced metabolic profile may help to discriminate best candidates for preoperative chemotherapy in high-grade bone sarcomas. Further studies are needed to confirm and explain these results.

Heme oxygenase-1 (HO-1) is stress-inducible, cytoprotective enzyme degrading heme to carbon monoxide (CO), biliverdin and Fe2+. We showed that HO-1 knock-out mice (HO-1−/−) have a twofold higher level of granulocytes than wild type (WT) mice, despite decreased concentration of granulocyte colony-stimulating factor (G-CSF) in the blood and reduced surface expression of G-CSF receptor on the hematopoietic precursors. This suggests the effect of HO-1 on granulopoiesis. Here we aimed to determine the stage of granulopoiesis regulated by HO-1.The earliest stages of hematopoiesis were not biased toward myeloid differentiation in HO-1−/− mice. Within committed granulocytic compartment, in WT mice, HO-1 was up-regulated starting from myelocyte stage. This was concomitant with up-regulation of miR-155, which targets Bach1, the HO-1 repressor. In HO-1−/− mice granulopoiesis was accelerated between myelocyte and metamyelocyte stage. There was a higher fraction of proliferating myelocytes, with increased nuclear expression of pro-proliferative C/EBPβ (CCAAT/enhancer binding protein beta) protein, especially its active LAP (liver-enriched activator proteins) isoform. Also our mathematical model confirmed shortening the myelocyte cyclic-time and prolonged mitotic expansion in absence of HO-1. It seems that changes in C/EBPβ expression and activity in HO-1−/− myelocytes can be associated with reduced level of its direct repressor miR-155 or with decreased concentration of CO, known to reduce nuclear translocation of C/EBPs. Mature HO-1−/− granulocytes were functionally competent as determined by oxidative burst capacity.In conclusion, HO-1 influences granulopoiesis through regulation of myelocyte proliferation. It is accompanied by changes in expression of transcriptionally active C/EBPβ protein. As HO-1 expression vary in human and is up-regulated in response to chemotherapy, it can potentially influence chemotherapy-induced neutropenia.