Asciminib Mitigates DNA Damage Stress Signaling Induced by Cyclophosphamide in the Ovary.

Cancer treatments can often adversely affect the quality of life of young women. One of the most relevant negative impacts is the loss of fertility. Cyclophosphamide is one of the most detrimental chemotherapeutic drugs for the ovary. Cyclophosphamide may induce the destruction of dormant follicles while promoting follicle activation and growth. Herein, we demonstrate the in vivo protective effect of the allosteric Bcr-Abl tyrosine kinase inhibitor Asciminib on signaling pathways activated by cyclophosphamide in mouse ovaries. We also provide evidence that Asciminib does not interfere with the cytotoxic effect of cyclophosphamide in Michigan Cancer Foundation (MCF)7 breast cancer cells. Our data indicate that concomitant administration of Asciminib mitigates the cyclophosphamide-induced ovarian reserve loss without affecting the anticancer potential of cyclophosphamide. Taken together, these observations are relevant for the development of effective ferto-protective adjuvants to preserve the ovarian reserve from the damaging effects of cancer therapies.

Evaluation of factors affecting total nucleated cells in umbilical cord blood collected for the Calabria cord blood bank.

BACKGROUND: Total nucleated cell (TNC) count is the most important biological feature to consider in assessing the quality of umbilical cord blood (UCB) for haematopoietic stem cell (HSC) transplantation. Certain obstetric factors have been reported to increase TNC count in UCB units collected for transplantation. The aim of our study was to analyze how various maternal, neonatal and obstetric factors affected TNC count in the UCBs we collected for our cord blood bank in southern Italy. MATERIAL AND METHODS: We performed a retrospective analysis of 634 medical records of UCBs collected by Calabria Cord Blood Bank (CCBB), between January 1, 2010 and December 31, 2016. We analyzed various maternal, neonatal and obstetric variables factors and related this factor with the characteristic of TNC. RESULTS: We found that the average number of TNCs was significantly greater in vaginal delivery than in caesarean delivery. We also found that TNCs were higher in the 40th week of pregnancy and when Apgar 1' scores were ≤ 9. The effect of a newborn's gender was less evident on TNC count. CONCLUSIONS: Knowledge of factors predictive of a higher TNC count would help cord blood banks more efficiently identify donors likely to yield high-quality UCBs for transplantation.

Challenge to Predict Mobilized Peripheral Blood Stem Cells on the Fourth Day of Granulocyte Colony-Stimulating Factor Treatment in Healthy Donors: Predictive Value of Basal CD34+ Cell and Platelet Counts.

A longitudinal, prospective, observational, single-center cohort study on healthy donors was designed to identify predictors of CD34+ cell mobilization on day 4 after granulocyte colony-stimulating factor (G-CSF) administration. As potential predictors of mobilization, age, sex, body weight, height, blood volume, WBC count, peripheral blood (PB) mononuclear cell count, platelet (Plt) count, and hematocrit and hemoglobin levels were considered. Two different evaluations of CD34+ cell counts were determined for each donor: baseline (before G-CSF administration) and in PB on day 4 after G-CSF administration. One hundred twenty-two consecutive healthy donors with a median age of 47.5 years were enrolled. The median value of CD34+ on day 4 was 43 cells/µL (interquartile range, 23 to 68), and 81.1% of donors had ≥20 cells/µL. Basal WBC count, Plt count, and CD34+ were significantly higher for the subjects with CD34+ levels over median values on day 4. A multivariate quartile regression analysis, adjusted by sex, age, basal CD34+, and basal Plt count, showed a progressively stronger relationship between baseline CD34+ and Plt levels and the CD34+ levels on day 4. The basal CD34+ cut-off level to predict the levels of CD34+ on day 4 was either ≤2 cells/µL or ≥3 cells/µL and that of basal Plt count was ≤229 × 109/L or ≥230 × 109/L, respectively, to determine whether mobilization therapy should or should not be attempted. PB stem cell mobilization with G-CSF was highly effective on day 4, and herein we describe a model for predicting the probability of performing PB stem cell collection after a short course of G-CSF.

Prospective study on the impact of BEAM versus FEAM conditioning on occurrence of neutropenic enterocolitis and on transplant outcome in lymphoma patients.

Introduction: Carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) are a widely used high-dose chemotherapy regimen for autologous stem cell transplantation transplant (ASCT) in lymphoid malignancies. During BCNU shortages, some centers switched to fotemustine-substituted BEAM (FEAM). Neutropenic enterocolitis (NEC) is a life-threatening complication occurring after intestinal mucosa damage related to intensive chemotherapy. NEC mortality may be up to 30%-50%. In our study, we compared NEC incidence, symptoms, mortality, and transplant outcome in terms of overall survival (OS) and progression-free survival (PFS) in the BEAM vs. FEAM groups. Furthermore, we compared the cost of hospitalization of patients who did vs. patients who did not experience a NEC episode (NECe). Methods: A total of 191 patients were enrolled in this study (N = 129 and N = 62 were conditioned with BEAM and FEAM, respectively). All patients received bed-side high-resolution ultrasound (US) for NEC diagnosis. Results and discussion: NEC incidence and NEC-related mortality were similar in the BEAM and FEAM groups (31% and 40.3%, p = 0.653, and 5% and 8%, p = 0.627, respectively). At a median follow-up of 116 months, no difference was noted between BEAM vs. FEAM groups in terms of OS and PFS (p = 0.181 and p = 0.978, respectively). BEAM appeared equivalent to FEAM in terms of NEC incidence and efficacy. The high incidence of NEC and the low mortality is related to a timely US diagnosis and prompt treatment. US knowledge in NEC diagnosis allows to have comparable days of hospitalization of patients NECpos vs. patients NECneg. The cost analysis of NECpos vs. NECneg has been also performed.

Impact of different chemotherapy regimens on intestinal mucosal injury assessed with bedside ultrasound: a study in 213 AML patients.

Introduction: Neutropenic enterocolitis (NEC) is a life-threatening complication reported in patients with acute myeloid leukemia (AML) following chemotherapy (CHT). Intensive induction and consolidation CHT may damage intestinal mucosa leading to a NEC episode (NECe). NEC reported mortality may be up to 30-60%. Early US-guided bed-side diagnosis and prompt treatment may substantially improve the survival. An emerging worldwide concern is the intestinal colonization by multi-drug-resistant bacteria especially when patients are exposed to chemotherapy regimens potentially correlated to mucosal damage. Methods: In our study we prospectively enrolled all AML patients admitted in our leukemia unit to receive intensive induction and consolidation chemotherapy and experiencing chemotherapy-induced-neutropenia (CHTN). Results and discussion: Overall, we enrolled N=213 patients from 2007 to March 2023. We recorded N=465 CHTN, and N=42 NECe (9.0% incidence). The aim of our study was to assess which chemotherapy regimens are more associated with NEC. We found that ALM1310, followed by 7 + 3 (daunorubicin), 7 + 3 (idarubicin), 5 + 3 + 3 (cytarabine, etoposide, idarubicin), and AML1310 (consolidation) were associated with a statistically higher incidence of NEC. We did not detect NEC episodes in patients treated with CPX-351, 5 + 2 (cytarabine, idarubicine), and high-dose cytarabine. Thus, we found that cytarabine could determine mucosal damage when associated with an anthracycline but not if delivered either alone or as dual-drug liposomal encapsulation of daunorubicin/cytarabine. We also describe NEC mortality, symptoms at diagnosis, intestinal sites involvement, and prognostic significance of bowel wall thickening.

BORN study: a multicenter randomized trial investigating cord blood red blood cell transfusions to reduce the severity of retinopathy of prematurity in extremely low gestational age neonates.

BACKGROUND: Extremely low gestational age neonates (ELGANs, i.e., neonates born before 28 weeks of gestation) are at high risk of developing retinopathy of prematurity (ROP), with potential long-life visual impairment. Due to concomitant anemia, ELGANs need repeated red blood cell (RBC) transfusions. These produce a progressive replacement of fetal hemoglobin (HbF) by adult hemoglobin (HbA). Furthermore, a close association exists between low levels of HbF and severe ROP, suggesting that a perturbation of the HbF-mediated oxygen release may derange retinal angiogenesis and promote ROP. METHODS/DESIGN: BORN (umBilical blOod to tRansfuse preterm Neonates) is a multicenter double-blinded randomized controlled trial in ELGANs, to assess the effect of allogeneic cord blood RBC transfusions (CB-RBCs) on severe ROP development. Recruitment, consent, and randomization take place at 10 neonatology intensive care units (NICUs) of 8 Italian tertiary hospitals. ELGANs with gestational age at birth comprised between 24+0 and 27+6 weeks are randomly allocated into two groups: (1) standard RBC transfusions (adult-RBCs) (control arm) and (2) CB-RBCs (intervention arm). In case of transfusion need, enrolled patients receive transfusions according to the allocation arm, unless an ABO/RhD CB-RBC is unavailable. Nine Italian public CB banks cooperate to make available a suitable amount of CB-RBC units for all participating NICUs. The primary outcome is the incidence of severe ROP (stage 3 or higher) at discharge or 40 weeks of postmenstrual age, which occurs first. DISCUSSION: BORN is a groundbreaking trial, pioneering a new transfusion approach dedicated to ELGANs at high risk for severe ROP. In previous non-randomized trials, this transfusion approach was proven feasible and able to prevent the HbF decrease in patients requiring multiple transfusions. Should the BORN trial confirm the efficacy of CB-RBCs in reducing ROP severity, this transfusion strategy would become the preferential blood product to be used in severely preterm neonates. TRIAL REGISTRATION: ClinicalTrials.gov NCT05100212. Registered on October 29, 2021.

Identifying and managing CAR T-cell-mediated toxicities: on behalf of an Italian CAR-T multidisciplinary team.

INTRODUCTION: Chimeric antigen receptor (CAR)-T-cell therapy is a new treatment for patients with hematologic malignancies in which other therapies have failed. AREAS COVERED: The review provides an overview for recognizing and managing the most acute toxicities related to CAR-T cells. EXPERT OPINION: The development of immune-mediated toxicities is a common challenge of CAR-T therapy. The mechanism that determines this toxicity is still unclear, although an unfavorable tumor microenvironment and a pro-inflammatory state put patients at risk. The monitoring, diagnosis, and treatment of post-CAR-T toxicities must be determined and based on international guidelines and internal clinical practice. It is urgent to identify biomarkers that can identify patients at greater risk of developing complications. The adoption of consistent grading criteria is necessary to improve toxicity management strategies continually. The first-line therapy consists of supportive care and treatment with tocilizumab or corticosteroids. An early start of cytokine blockade therapies could mitigate toxicity. The plan will include cytokine release prophylaxis, a risk-adapted treatment, prevention of on-target/off-tumor effect, and a switch on/off CAR-T approach.

The role of cord blood platelet gel in the management of a diabetic foot with tendon exposure.

Diabetic foot infection is frequent in diabetic patients and is due to neuropathy, trauma or peripheral arterial disease. The presence of an abscess requires urgent drainage and specific antibiotic therapy. Patients with critical limb ischemia need revascularization and, subsequently the intervention of a plastic surgeon is often required in cases of exposure of tendons and ligaments. During the COVID-19 pandemic, a patient was refered to our department with an abscess on the dorsum of the left foot. After urgent drainage with tendon exposure, he started specific antibiotic therapy and underwent tibial vessels angioplasty. After infection healing cord blood platelet gel was applied, accelerating the healing process, with injection of its liquid part into the exposed tendons, thus retaining the vital functions of the tendons.

Use of cord blood platelet gel to enhance healing of deep surgical site dehiscences after peripheral bypass.

Surgical site dehiscence after lower limb revascularization through bypass represents a serious postoperative complication, especially in diabetic and obese patients, with subsequent risk of early graft failure, infection, sepsis, hemorrhage, major amputation and sometimes death. To prevent bypass exposure and subsequent complications, physicians recur to reoperation, antibiotic therapy, advanced dressing and vacuum-assisted closure therapy. To improve the process of wound healing, cord blood platelet gel can be used to fill deep and large wounds. Growth factors released from platelets in the cord blood platelet gel stimulate the process of healing and allow patients to be followed up in Outpatient Surgery, thus reducing hospital stay and costs, while providing excellent results.

Wernicke's encephalopathy after allogeneic stem cell transplantation.

Wernicke's encephalopathy is an acute neuropsychiatric condition due to thiamine deficiency frequently associated with chronic alcohol abuse. We describe 2 cases of patients who experienced acute Wernicke's encephalopathy after allogeneic stem cell transplantation associated with the use of commercial total parental nutrition. Early diagnosis with magnetic resonance imaging and timely treatment with thiamine resulted in rapid resolution of clinical and radiological signs. In conclusion, the prolonged use of commercial total parental nutrition formulas must be supplemented with thiamine in the form of intramuscularly administered multivitamins.

Efficacy of cord blood platelet gel application for enhancing diabetic foot ulcer healing after lower limb revascularization.

The efficacy of umbilical cord blood platelet gel (CBPG) application on healing foot ulcers was analyzed in 10 diabetic patients treated for critical lower limb ischemia by surgical or endovascular arterial revascularization. During a 9-month period, 20 diabetic patients affected by critical lower limb ischemia with tissue loss were enrolled in this nonblinded, consecutive series, randomized clinical trial. After clinical evaluation, patients underwent endovascular or surgical revascularization of the affected limb, followed by minor amputations or surgical debridement of ischemic lesions. Patients were then randomly divided into two groups: 10 patients in Group A treated with standard wound care and 10 patients in Group B treated with topic application of CBPG. The CBPG protocol consisted of platelet gel application twice a week for 4 weeks and then once a week for an additional 4 weeks. Healing was assessed by direct ulcer dimension tracing onto clear plastic sheet and subsequent computerized planimetry. The mean pretreatment and post-treatment ulcer areas at 30 days for Group A were 15.1 cm2 and 8.1 cm2, respectively, and for Group B were 15.7 cm2 and 3.25 cm2, respectively; resulting in a mean ulcer area reduction of 46% for Group A and 79% for Group B patients (P < .01). These observations suggest CBPG application can promote more rapid wound healing than standard care, and indicate the need for a randomized, multicenter trial to confirm clinical efficacy.

Application of autologous platelet-rich plasma to enhance wound healing after lower limb revascularization: A case series and literature review.

Dermal tissue loss in patients affected by critical limb ischemia represents a serious wound-healing problem, with high morbidity, prolonged hospital stay, and high patient care costs. Treatment of ischemic foot lesions requires limb revascularization by endovascular or open surgical intervention and individualized patient-specific wound care, including antibiotic therapy; devitalized/infected wound debridement; and advanced wound dressing. In selected patients, spinal cord stimulation, vacuum-assisted closure therapy, and bioengineered tissue or skin substitutes and growth factors have been shown to improve wound healing. In this study, we present our preliminary results on topical application of autologous platelet-rich plasma to enhance the process of wound healing after revascularization of lower limbs in patients affected by critical limb ischemia.

Differences in transplant-related complications between hematologic malignancies and solid tumors receiving high-dose chemotherapy and autologous peripheral blood stem cell transplantation.

Multiple factors contribute to transplant-related complications after high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation, including conditioning regimens, number of infused stem cells and clinical characteristics of patient at transplant. We compared the transplant-related complications of 141 patients affected with hematological malignancies with those of 109 patients with solid tumors. The total number of peripheral blood stem cell transplantations performed was 339. High-dose chemotherapy mainly consisted of melphalan-, busulphan- or thiotepa-based regimens. Despite the equal number of infused CD34+ cells, patients with a hematological malignancy showed a slower absolute neutrophil count (days to neutrophils > 0.5 x 10(9)/L, 10.6 +/- 3.6 for hematological malignancies versus 9.1 +/- 1.2 for solid tumors, P < 0.0001) and platelet recovery (days to platelets > 20 x 10(9)/L, 16.4 +/- 9.8 for hematological malignancies versus 12.3 +/- 4.1 for solid tumors, P < 0.0001) than patients with a solid tumor. A significantly higher requirement of red blood cell (3.3 +/- 4.1 versus 2.0 +/- 1.9, P < 0.0029) and platelet units (7.5 +/- 10.4 versus 4.2 +/- 3.4, P < 0.0001) was observed for hematological malignancies than for solid tumors. Five graft failures were documented exclusively in patients with a hematological malignancy. Moreover, such patients displayed a longer duration of mucositis (P < 0.0028) and hospital stay (P < 0.0001), but no difference was observed in terms of febrile episodes. Transplant-related mortality was similar between the two groups. In conclusion, patients with a hematological malignancy overall have more complications than those with a solid tumor.

High-dose chemotherapy with mitoxantrone + melphalan and autologous stem cell rescue in metastatic breast cancer patients: a study of feasibility and tolerability.

Hematological and extra-hematological toxicity of mitoxantrone-containing regimens with autologous stem cell rescue was evaluated in 32 metastatic breast cancer patients. The schedule was the final part of two high-dose chemotherapy programs, including an induction phase with three courses of conventional chemotherapy with epirubicin (120 mg/m2) and cyclophosphamide (600 mg/m2) plus three courses of docetaxel (100 mg/m2) and a first high-dose chemotherapy consisting of cyclophosphamide (6000 mg/m2), thiotepa (500 mg/m2) and carboplatin (800 mg/m2) or melphalan (160 mg/m2) plus thiotepa (600 mg/m2). The final second autograft phase included mitoxantrone (60 mg/m2) associated with melphalan (160 mg/m2) and autologous stem cell rescue infusion. The median duration of severe neutropenia and thrombocytopenia was 9 (range, 7-13) and 11.5 (range, 9-29) days. The median number of units of erythrocytes and platelets transfused was 1 (0-11) and 4 (1-9), respectively. Fever for a median of 2 (0-8) days developed in 71.8% of the patients. Mucositis was observed in 81.2% (WHO grade 3-4 in 25%). No acute or late cardiac toxicity was observed. One patient died because of a transplant-unrelated cause. The response according to the program phase showed an increased rate of complete response, from 12.5% at the end of conventional chemotherapy to 21.9% after the first high-dose chemotherapy course, to increase to 43.9% after the treatment with mitoxantrone-melphalan. We conclude that a conditioning regimen with high dose mitoxantrone-melphalan fits well within the high-dose chemotherapy program.

Predictive factors that affect the mobilization of CD34(+) cells in healthy donors treated with recombinant granulocyte colony-stimulating factor (G-CSF).

No specific characteristics have been identified as predictors of peripheral blood stem cells (PBSC) mobilization in healthy donors. In this study, clinical characteristics and laboratory data for 122 healthy donors who underwent apheresis on day 5 of treatment with recombinant granulocyte colony-stimulating factor (G-CSF) were retrospectively analyzed for correlations with CD34(+) cell mobilization. The variables that were analyzed included age, sex, body weight, basal complete blood count, and maximum white blood count (WBC) before apheresis, G-CSF type, and dosage. Median age and body weight were 42.5 years (range 16-65) and 72.5 kg (range 47-121), respectively. By univariate analysis, male sex (P = 0.007), body weight (< or = 70 vs. >70 kg, P = 0.04), and donor's age (< or = 50 vs. > 50 years; P = 0.015) were correlated with the number of CD34(+) cells mobilized. By multivariate analysis, donor's age and male sex were the only two variables that significantly predicted a high CD34(+) cell level. In conclusion, our data suggest that male sex and younger age are the only factors that significantly affect CD34(+) mobilization in healthy donors.

Harvesting peripheral blood progenitor cells from healthy donors: retrospective comparison of filgrastim and lenograstim.

Mobilization of CD34+ into peripheral blood is attained by either glycosylated (lenograstim) or non-glycosylated recombinant G-CSF (filgrastim). 101 donors, 57 males, median age 42 years (range 16-63) entered this retrospective study. Group I (55 cases) received filgrastim and group II lenograstim subcutaneously for 5-6 days. The peak number of CD34+ cells/microl blood observed on day 4 and 5 was not significantly different in the two groups. No differences were shown in terms of both circulating CFU-GM at the time of harvesting and CD34+ target of collection. The most frequent side effects were bone pain (18.2% grade I; 36.4% grade II, 7.3% grade III), headache (18.2%), nausea (9.1%), fever (5.5%) and a mild splenomegaly (> 2 cm) (5.5%) in filgrastim group, and bone pain (37.0% grade I, 26.1% grade II, 2.2% grade III), headache (17.4%), nausea (15.2%), fever (4.4%) and a mild splenomegaly (4.3%) in lenograstim group, respectively. CD34+ collection was associated with thrombocytopenia, which was not significantly different between the two groups. No donor in either group developed long-term adverse effects. We conclude that both G-CSFs are comparable in terms of CD34+ cell collection, safety and tolerability.

Administration of recombinant human erythropoietin alpha before autologous stem cell transplantation reduces transfusion requirement in multiple myeloma patients.

Recombinant human erythropoietin administered after peripheral blood stem cell transplantation (PBSCT) has been ineffective for the treatment of anemia. We administered recombinant human erythropoietin alpha (rHuEPO) prior to high-dose therapy after peripheral blood stem cell (PBSC) collection to evaluate its efficacy on transfusion requirements and hematological parameters during the post-transplant aplastic phase. Twenty-two multiple myeloma patients (EPO-MM) were included in the trial to receive rHuEPO 10,000 IU subcutaneous daily starting 30 days before PBSCT. Forty hemoglobin (Hb)-matched patients who had not received rHuEPO before transplant were retrospectively selected (Ctr-MM) for comparative data. None of the patients received transfusions at study entry. All but one patient responded to rHuEPO. However, no significant differences in Hb levels were obtained between the two groups at the time of transplantation. At nadir, the EPO-MM cases had a significantly higher Hb level (median 10 g/dl versus 7.6 g/d; p=0.001). Consequently, less than 20% of EPO-MM patients required packed red blood cell (PRBC) transfusions compared to more than half the Ctr-MM patients (p=0.007). Furthermore, the number of PRBC transfusions performed in the EPO-MM group was significantly lower (median 0 versus 1; p=0.008). Independently of Hb levels at PBSCT, rHuEPO therapy was significantly associated with a lower risk of transfusion requirement. In conclusion, rHuEPO is shown to be effective when administered prior to high-dose therapy in MM.