Incidence and Severity of Myelosuppression With Palbociclib After Palliative Bone Radiation in Advanced Breast Cancer: A Single Center Experience and Review of Literature.

BACKGROUND: Palbociclib is a cyclin-dependent kinase (CDK) 4/6 inhibitor with a primary toxicity of myelosuppression, especially neutropenia, due to cytostatic CDK6 inhibition on bone marrow. Preclinical studies suggest palbociclib may enhance radiation toxicity, but this was only evaluated in limited case series of palliative radiotherapy and not specific to radiation targeting bony metastases. PATIENTS AND METHODS: This was a single institution retrospective cohort study. We included female patients who initiated palbociclib for advanced breast cancer between 2015 and 2019. The primary exposure was receipt of palliative radiation to bony metastases within 1 year prior to starting palbociclib. The primary outcome was the incidence and severity of myelosuppression during cycle one. Secondary outcomes include treatment interruptions and cycle 2 dose reductions, with subgroup analysis of radiation timing, type, dose, and location. RESULTS: Of the 247 patients, 47 received radiation to bone metastases. Only absolute lymphocyte count (ALC) after cycle one of palbociclib was significantly lower in the group receiving radiation (median ALC 0.84 vs. 1.10 K/mm3, P < .001), with similar rates of neutropenia, anemia, and thrombocytopenia. Patients who received ≥10 fractions radiation were more likely to have cycle one interrupted than those receiving shorter radiation courses (42.9% vs. 11.1%, P = .03). No radiation characteristics were associated with other hematologic toxicities or dose reduction. CONCLUSION: Palliative bone radiation within 1 year prior to palbociclib initiation was associated with greater lymphopenia during the first cycle than patients unexposed to radiation, but not neutropenia, anemia, or thrombocytopenia that would modify treatment.

Decrease in dysbaric osteonecrosis severity as a result of 45-minute oxygen pre-breathe.

Sudden decompression can result in bubble formation as the result of nitrogen gas (N2) dissolved in tissue during disabled submarine escape (DISSUB). This may cause dysbaric osteonecrosis (DON), a condition in long bones where bubbles in fatty marrow result in ischemia and necrosis. Previous research has shown that oxygen (O2) pre-breathe of two hours resulted in a reduction of DON; however, effects of shorter O2 pre-breathe remain uncertain. This study's aim was to understand the effect of shorter lengths of O2 pre-breathe. Eight adult Suffolk ewes (89.5± 11.5 kg) were exposed to 33 feet of seawater (fsw) for 24 hours. They were placed randomly into four groups and exposed to either 45, 30 or 15 minutes of O2 (91-88%) pre-breathe; the controls received none. They were then rapidly decompressed. Alizarin complexone was later injected intravenously to visualize the extent of DON in the right and left long bones (radii, tibiae, femur and humeri). The 30- and 15-minute pre-breathe groups saw the greatest deposition. There was significant decrease of variance in the 45-minute group when compared with all other treatments, suggesting that 45 minutes of O2 pre-breathe is required to effectively increase confidence in the reduction of DON. Similar confidence was not reflected in the 30-minute and 15-minute groups: 45 minutes of pre-breathe was the minimum amount needed to effectively prevent against DON in DISSUB escape at 33 fsw. However, future research is needed to determine how to calculate effective dosages of O2 pre-breathe to prevent DON in any given scenario.

Trilaciclib: First Approval.

Trilaciclib (Cosela™) is a small-molecule, short-acting, inhibitor of cyclin-dependent kinases (CDK) 4 and 6 developed by G1 Therapeutics for its myeloprotection and potential antitumor efficacy and safety benefits in combination with cancer chemotherapy. CDKs govern cell cycle progression, and trilaciclib induces a transient, reversible G1 cell cycle arrest of proliferating haematopoietic stem and progenitor cells in bone marrow, thus protecting them from damage during chemotherapy. In February 2021, trilaciclib received its first approval in the USA to decrease the incidence of chemotherapy-induced myelosuppression in adult patients when administered prior to a platinum/etoposide-containing regimen or topotecan-containing regimen for extensive-stage small cell lung cancer (ES-SCLC). Clinical studies in breast cancer, colorectal cancer and small cell lung cancer are underway in several countries. This article summarizes the milestones in the development of trilaciclib leading to this first approval.

Effect of prophylactic granulocyte-colony stimulating factor (G-CSF) on acute hematological toxicity in medulloblastoma patients during craniospinal irradiation (CSI).

OBJECTIVES: Haematological toxicity and treatment breaks are common during cranio-spinal irradiation (CSI) due to irradiation of large volume of bone marrow. We conducted this study to see the effect of prophylactic granulocyte colony stimulating factor (GCSF) in reducing treatment breaks. PATIENTS AND METHODS: The study was conducted over a period of 15 months from August 2017 to November 2018. Histopathologically proven Medulloblastoma patients received prophylactic GCSF during CSI. Acute hematological toxicities and treatment breaks were noted and effect of age and pretreatment blood counts were analyzed by SPSS (Statistical Package for Social Sciences) version 23. RESULTS: A total of 28 patients were included in the study. During CSI, hematological toxicity leading to treatment breaks was observed in 11 (39.3 %) patients, of which grade 3 and 2 toxicities were seen in ten and one patients respectively. Younger age (<10 years) at diagnosis was significantly associated with the development of hematological toxicity (p = 0.028, Chi-Square). No correlation was found with pre-treatment blood counts. CONCLUSION: Prophylactic use of GCSF may be effective in preventing radiation induced hematological toxicity and treatment breaks.

Protective effects of Acanthopanax senticosus - Ligustrum lucidum combination on bone marrow suppression induced by chemotherapy in mice.

This study investigated the combination effects of the Acanthopanax senticosus - Ligustrum lucidum (AS-LL) herb pair on bone marrow suppression caused by chemotherapy. A bone marrow suppression model was established by intraperitoneal injection (i.p.) of cyclophosphamide (CTX, 100 mg/kg). The changes in chemical composition between the AS-LL decocted together and single were analyzed, and their effects on the bone marrow nucleated cells, peripheral blood, thymus and spleen indices, in vitro hematopoietic cell culture, ELISA and cell cycle were detected. The results showed that the contents of the main active components, such as salidroside, isofraxidin and specnuezhenide in the sample of AS-LL decocted together, increased significantly compared to singles. Moreover, AS-LL decocted together exhibited a significantly better therapeutic effect on myelosuppression induced by CTX than AS and LL alone. AS-LL decocted together significantly increased the number of bone marrow nucleated cells and displayed a good regulatory effect on peripheral blood (p < 0.01), while significantly increased the thymus index (p < 0.01) and decreased the spleen index (p < 0.01). AS-LL significantly promoted the formation of cell colonies (p < 0.05), the proliferation and differentiation of hematopoietic progenitor cells, and played a positive regulatory role in hematopoietic factors. AS-LL also reduced the proportion of G0/G1 cells, increased the ratio of S and G2/M cells, and increased the cell proliferation index (PI). All these results implied that AS-LL decocted together might be a promising food additives and therapeutic agent for myelosuppression induced by chemotherapy.

Irradiation of anatomically defined pelvic subsites and acute hematologic toxicity in anal cancer patients undergoing chemoradiation.

PURPOSE: Chemoradiation for the treatment of anal cancer is known to cause significant hematologic toxicity (HT). We sought to investigate if radiation dose to specific pelvic subsites is associated with increased HT risk. METHODS AND MATERIALS: Forty-five patients with nonmetastatic anal cancer who received definitive chemoradiation with intensity modulated radiation therapy and concurrent mitomycin-C and 5-fluorouracil were studied. Total pelvic bone marrow (TBM) was divided into 3 subsites: lumbosacral bone marrow (LSBM), including the entire sacrum and L5 vertebral body; iliac bone marrow (IBM) extending from the iliac crests to the superior border of the femoral head; and lower pelvic bone marrow, including the pubic bones, ischia, acetabula, and proximal femurs. The primary endpoint was absolute neutrophil count (ANC) nadir during or within 2 weeks of treatment completion. Generalized linear modeling was used to analyze the correlation between the equivalent uniform dose (with an "a" value of 0.5) to the individual pelvic subsites and the various hematologic endpoints. Age, body mass index, sex, baseline blood counts, and immunosuppression were analyzed as potential covariates. RESULTS: Mean ± standard deviation ANC nadir was 0.77 × 109/L (±0.66 × 109/L). Grades 3+ and 4+ neutropenia occurred in 71.1% and 44.4% of patients, respectively. In addition to radiation dose to pelvic bone marrow, baseline ANC was the only significant predictor of hematologic toxicity on multivariable analysis and was included in all models. The equivalent uniform doses of TBM, LSBM, and IBM were each significantly associated with neutropenia. The model performance of TBM (adjusted R2 = 0.226) was similar to both LSBM (adjusted R2 = 0.206) and IBM (adjusted R2 = 0.249). CONCLUSIONS: Radiation doses to TBM, LSBM, and IBM were individually associated with HT, suggesting that sparing just a portion of pelvic bone marrow is insufficient to decrease rates of clinically significant bone marrow suppression.

Bone Marrow Graft-Versus-Host Disease in Major Histocompatibility Complex-Matched Murine Reduced-Intensity Allogeneic Hemopoietic Cell Transplantation.

BACKGROUND: Most clinical allogeneic hemopoietic cell transplants (alloHCT) are now performed using reduced-intensity conditioning (RIC) instead of myeloablative conditioning (MAC); however, the biology underlying this treatment remains incompletely understood. METHODS: We investigated a murine model of major histocompatibility complex-matched multiple minor histocompatibility antigen-mismatched alloHCT using bone marrow (BM) cells and splenocytes from B6 (H-2) donor mice transplanted into BALB.B (H-2) recipients after RIC with fludarabine of 100 mg/kg per day for 5 days, cyclophosphamide of 60 mg/kg per day for 2 days, and total body irradiation (TBI). RESULTS: The lowest TBI dose capable of achieving complete donor chimerism in this mouse strain combination was 325 cGy given as a single fraction. Mice that underwent RIC had a reduced incidence and delayed onset of graft-versus-host disease (GVHD) and significantly prolonged survival compared with MAC-transplanted recipients (TBI of 850 cGy plus cyclophosphamide of 60 mg/kg per day for 2 days). Compared with syngeneic controls, RIC mice with GVHD showed evidence of BM suppression, have anemia, reduced BM cellularity, and showed profound reduction in BM B cell lymphopoiesis associated with damage to the endosteal BM niche. This was associated with an increase in BM CD8 effector T cells in RIC mice and elevated blood and BM plasma levels of T helper1 cytokines. Increasing doses of splenocytes resulted in increased incidence of GVHD in RIC mice. CONCLUSIONS: We demonstrate that the BM is a major target organ of GVHD in an informative clinically relevant RIC mouse major histocompatibility complex-matched alloHCT model by a process that seems to be driven by CD8 effector T cells.

Acromegalic arthropathy in various stages of the disease: an MRI study.

BACKGROUND: Arthropathy is a prevalent and invalidating complication of acromegaly with a characteristic radiographic phenotype. We aimed to further characterize cartilage and bone abnormalities associated with acromegalic arthropathy using magnetic resonance imaging (MRI). METHODS: Twenty-six patients (23% women, mean age 56.8 ± 13.4 years), with active (n = 10) and controlled acromegaly (n = 16) underwent a 3.0 T MRI of the right knee. Osteophytes, cartilage defects, bone marrow lesions and subchondral cysts were assessed by the Knee Osteoarthritis Scoring System (KOSS) method. Cartilage thickness and cartilage T2 relaxation times, in which higher values reflect increased water content and/or structural changes, were measured. Twenty-five controls (52% women, mean age: 59.6 ± 8.0 years) with primary knee OA were included for comparison. RESULTS: Both in active and controlled acromegaly, structural OA defects were highly prevalent, with thickest cartilage and highest cartilage T2 relaxation times in the active patients. When compared to primary OA subjects, patients with acromegaly seem to have less cysts (12% vs 48%, P = 0.001) and bone marrow lesions (15% vs 80%, P = 0.006), but comparable prevalence of osteophytosis and cartilage defects. Patients with acromegaly had 31% thicker total joint cartilage (P < 0.001) with higher cartilage T2 relaxation times at all measured sites than primary OA subjects (P < 0.01). CONCLUSIONS: Patients with active acromegaly have a high prevalence of structural OA abnormalities in combination with thick joint cartilage. In addition, T2 relaxation times of cartilage are high in active patients, indicating unhealthy cartilage with increased water content, which is (partially) reversible by adequate treatment. Patients with acromegaly have a different distribution of structural OA abnormalities visualized by MRI than primary OA subjects, especially of cartilage defects.

Tomotherapy as an adjuvant treatment for gastroesophageal junction and stomach cancer may reduce bowel and bone marrow toxicity compared to intensity-modulated radiotherapy and volumetric-modulated arc therapy.

PURPOSE: To compare dosimetric parameters of intensity-modulated radiotherapy (IMRT), volumetric-modulated arc therapy (VMAT) and tomotherapy (TOMO) in the adjuvant treatment of gastroesophageal junction (GEJ)/stomach cancer. The planning goal was to maintain high target coverage while keeping the dose to the bowel and bone marrow (BM) as low as possible. MATERIALS AND METHODS: After curative surgery, 16 patients with GEJ/stomach cancer were re-planned by coplanar IMRT (five fixed beam), VMAT (double-arc), and TOMO. The dose to the planning target volume (PTV) was 45 Gy in 25 fractions. The target parameters, including the homogeneity index (HI) and conformity index (CI), and doses to the organs at risk (OARs) were analyzed. RESULTS: Dosimetric parameters for PTV and OARs were comparable among the three techniques. However, TOMO provided improved conformity (CI = 0.92±0.03) and homogeneity (HI = 1.07±0.02) than IMRT (CI = 0.87±0.03; HI = 1.09±0.02; p < 0.05) and VMAT (CI = 0.86±0.03; HI = 1.09±0.02; p < 0.01). TOMO also improved dose sparing of the bowel (percentage of the volume receiving a dose of ≥ 30 Gy [V30] = 23.24±9.85) and BM (V30 = 71.66±6.15) compared with IMRT (bowel V30 = 30.02±11.74; BM V30 = 83.74±8.42; p < 0.01) and VMAT (bowel V30 = 31.88±11.59; BM V30 = 79.51±9.07; p < 0.01). CONCLUSIONS: TOMO is a good option for adjuvant treatment of GEJ/stomach cancer in patients undergoing radical surgery due to its superior bowel and BM dose sparing, dose conformity and dose homogeneity; however, future studies are required to validate its clinical efficacy.

Effect of YH0618 soup on chemotherapy-induced toxicity in patients with cancer who have completed chemotherapy: study protocol for a randomized controlled trial.

BACKGROUND: The incidence of cancer has been staying at a high level worldwide in recent years. With advances in cancer diagnosis and therapy strategy, the survival rate of patients with cancer has been increasing, but the side effects of these treatments, especially chemotherapy, are obvious even when the chemotherapy ceases. YH0618, a prescription, has showed efficacy in reducing chemotherapy-induced toxicity through long clinical practice. However, there is no scientific research exploring the effects of YH0618 in patients with cancer. Therefore, using a randomized controlled trial, this study will explore the efficacy of YH0618 on ameliorating chemotherapy-induced toxicity including dermatologic toxicity, myelosuppression, hepatotoxicity and nephrotoxicity and improving fatigue in cancer patients who have completed chemotherapy. METHODS/DESIGN: This is a prospective assessor-blinded, parallel, randomized controlled trial. Patients with cancer at any stage who have completed chemotherapy within two weeks will be randomly divided into group A (YH0618) and group B (wait-list) using a 1:1 allocation ratio. The chemotherapeutic agents include taxanes or anthracyclines. Subjects assigned to group A will receive YH0618 soup 6 days a week for 6 weeks and uncontrolled follow-up for 6 weeks, while group B are required to wait for 6 weeks before receiving YH0618 intervention. The primary outcome of this study is the incidence of protocol-specified grade ≥2 dermatologic toxicities graded by NCI CTCAE Chinese version 4.0 and changes of fingernail color, face skin color and tongue color evaluated by the L*a*b system within 6 weeks. There are some secondary outcomes associated with dermatologic toxicity including fatigue and clinical objective examination. DISCUSSION: There are few scientific and safe methods in ameliorating chemotherapy-induced toxicity. The proposed study may provide direct and convincing evidence to support YH0618 as an adjuvant treatment for reducing chemotherapy-induced toxicity, which could be introduced into clinical settings. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR-IOR-15006486 . Registered on 21 May 2015.

Soluble Vascular Endothelial Cadherin as a New Biomarker of Irradiation in Highly Irradiated Baboons with Bone Marrow Protection.

Vascular endothelial cadherin is the main component of adherens junctions enabling cohesion of the endothelial monolayer in vessels. The extracellular part of vascular endothelial cadherin (VE-cadherin) can be cleaved, releasing soluble fragments in blood (sVE-cadherin). In some diseases with endothelial dysfunction, a correlation between increased blood sVE-cadherin levels and disease state has been proposed. Irradiation is known to induce endothelial damage, but new serum biomarkers are needed to evaluate endothelial damage after irradiation. Here, the authors investigated whether sVE-cadherin may be an interesting biomarker of irradiation in highly irradiated baboons with bone marrow protection. sVE-cadherin was detected in the plasma of young as well as old baboons. Plasma sVE-cadherin levels significantly decrease a few days after irradiation but recover in the late time after irradiation. Kinetic analysis of plasma sVE-cadherin levels suggests a correlation with white blood cell counts in both the acute phase of irradiation and during hematopoietic recovery, suggesting that plasma sVE-cadherin levels may be partly linked to the disappearance and recovery of white blood cells. Interestingly, after hematopoietic recovery was completed, sVE-cadherin levels were found to exceed control values, suggesting that plasma sVE-cadherin may represent a new biomarker of endothelial damage or neovascularization in the late time after irradiation.

Effect of Shenfu injection on immune function of mice bearing Lewis lung sarcoma with chemotherapy.

Chemotherapy damages immune system and has a lot of side effects. In this study, we investigate the function of Shenfu injection to reduce these unfavorable effects induced by chemotherapy on mice bearing Lewis lung sarcoma. Mice inoculated with Lewis lung sarcoma cells were divided into five groups: Lewis lung sarcoma control group, cyclophosphamide (CTX) group, and Shenfu injection (high, moderate, and low dose) + CTX group. After a 14-day treatment, the counting of peripheral blood cells, CD3+, CD4+, and CD8+ T lymphocytes were done, immunoglobulin (Ig) was measured, coefficients of spleen and thymus were calculated, and spleen T cell proliferation was evaluated in vitro. The CD4+/CD8+ and CD3+ T cells in high- and moderate-dose Shenfu groups were more than the CTX group (p < 0.05); spleen T cell proliferation of mice in high-dose Shenfu + CTX group is more prominent than the CTX group (p < 0.05); coefficients of spleen and thymus, WBC, and platelet (PLT) counting of mice in the CTX group were lower than control and high and moderate dose Shenfu + CTX groups. The level of serous IgG and IgM of all test groups shows no significant difference. Shenfu injection can improve cellular immune function and reduce myolosuppression of mice delivered with chemotherapy.

Haematopoietic toxicity of radium-223 in patients with high skeletal tumour burden.

UNLABELLED: In patients with metastasized, castration resistant prostate cancer (mCRPC) treatment with radium-223 (Xofigo) is an attractive therapeutic option. In particular, patients with high tumour load seem to profit from this treatment in regard of survival and quality of live. Aim of this study was to stratify mCRPC patients according to a quantitative imaging marker derived from routine bone scans (EXINI bone) and analyze haematopoietic toxicity of Xofigo in these patients. PATIENTS, METHODS: Toxicity and oncologic outcome were investigated in a cohort of 14 patients with high tumour load. Additionally, based on a web survey, experience of toxicity in 41 high tumour load patients in Germany in 2014 was collected. RESULTS: In patients with a bone scan index (BSI) greater than 5, significant toxicity occurred in more patients than expected from the ALSYMPCA trial. This was associated with application of fewer cycles. Similar experiences have been made in other centers in Germany. Approximately 7% of these patients will need very long time or will not recover from grade ≥ 3 toxicity. CONCLUSION: Close follow-up of haematopoietic indices and, in case of toxicity, early termination of therapy is in particular necessary in late stage disease where limited bone marrow reserve is likely.

Prevention of myelosuppression and genotoxicity induced by cisplatin in murine bone marrow cells: effect of an organovanadium compound vanadium(III)-l-cysteine.

Cisplatin (CDDP) is one of the first-line anticancer drugs indicated for use against various form of human malignancies; but, the therapeutic outcome of CDDP chemotherapy is limited due to the development of myelosuppression and genotoxicity which may lead to secondary cancer. Induction of oxidative stress in normal host cells is thought to be responsible for these adverse effects. Therefore, in search of a potential chemoprotectant, an oraganovanadium compound, viz., vanadium(III)-l-cysteine (VC-III) was evaluated against CDDP-induced clastogenicity and cytotoxicity in bone marrow cells of Swiss albino mice. CDDP was administered intraperitoneally (5mg/kg body weight [b.w.]) and VC-III was given by oral gavage (1mg/kg b.w.) in concomitant and pretreatment schedule. The results showed that VC-III administration significantly (P < 0.001) enhanced cell proliferation and inhibited apoptosis in the bone marrow niche indicating recovery of CDDP-induced myelosuppression. VC-III also significantly (P < 0.001) decreased the percentage of chromosomal aberrations, the frequency of micronuclei formation and the extent of DNA damage. The observed antigenotoxic and cytoprotective effect of VC-III was attributed to its attenuation of free radicals status and restoration of oxidised and reduced glutathione levels. These results suggest that VC-III is a potential candidate for future development as a chemoprotective agent against chemotherapy-associated primary and secondary complications.

Plano de almohadas: valoración de su efectividad como sistema preventivo de las úlceras por presión en pacientes con lesión medular / The flat pillow: evaluation of its effectiveness in preventing pressure ulcers in patients with a spinal cord injury

Introducción. Este estudio analiza las diferencias de presión en la interfaz (manta de presiones) en las posiciones de decúbito supino y decúbito lateral sobre 2 planos de apoyo: una cama de hospital estándar y un plano de almohadas. Material y métodos. La presión de la interfaz se registró en 27 pacientes con lesión medular (22 hombres y 5 mujeres). Resultados. Se demuestran disminuciones significativas (p < 0,001) de las presiones máximas, presiones medias y superficies de contacto con riesgo de úlceras por presión (más de 32 mmHg) de las zonas de apoyo con el plano de almohadas para las posturas en decúbito supino. En decúbito lateral, estas diferencias son más pequeñas (p < 0,005). Conclusiones. El plano de almohadas se presenta como un medio alternativo y de bajo costo en la prevención de las úlceras por presión (AU)

Introduction. This study examines differences in interface pressure (rug pressure) in supine and lateral decubitus positions at two levels of support: standard hospital bed and flat pillow. Material and methods. Interface pressure was recorded in 27 patients with a spinal cord injury (22 men and 5 women). Results. Significant decreases (P<.001) were found in peak pressures, average pressures, and contact surfaces with a risk of producing pressure ulcer (more than 32 mmHg) in areas of flat pillow support for supine positions. These differences were smaller (P<.005) in lateral decubitus. Conclusions. The flat pillow is an inexpensive alternative in the prevention of pressure ulcers (AU)

Radioprotector WR-2721 and mitigating peptidoglycan synergistically promote mouse survival through the amelioration of intestinal and bone marrow damage.

The identification of an agent effective for the treatment of intestinal and bone marrow injury following radiation exposure remains a major issue in radiological medicine. In this study, we evaluated the therapeutic impact of single agent or combination treatments with 2-(3-aminopropylamino) ethylsulphanyl phosphonic acid (WR-2721) and peptidoglycan (PGN, a toll-like receptor 2 (TLR-2) agonist) on radiation-induced injury of the intestine and bone marrow in lethally irradiated male C57BL/6 mice. A dose of 3 mg of WR-2721 per mouse (167 mg/kg, intraperitoneally) was given 30 min before irradiation, and 30 µg of PGN per mouse (1.7 mg/kg) was injected intraperitoneally 24 h after 10 Gy irradiation. Bone marrow cluster of differentiation (CD)45(+) and CD34(+) markers of multiple haematopoietic lineages, number of granulocyte-erythroid-macrophage-megakaryocyte (GEMM) progenitor colonies, bone marrow histopathology, leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) expression in the intestines, xylose absorption and intestinal histopathology were all assessed at various time-points after irradiation. Furthermore, nuclear factor kappa B (NF-κB) p65 protein in the ileum was stained by immunofluorescent labelling. PGN-treated irradiated mice showed an increase in CD45(+)CD34(+) cells compared with untreated mice 1.25 days after 10 Gy ionizing radiation (IR) (P < 0.05). Furthermore, combined PGN and WR-2721 treatment had an obviously synergistic radio-protective effect in nucleated cells in the bone marrow, including GEMM progenitors and CD45(+)CD34(+) cells 4 days after 10 Gy IR. Single agent PGN or WR-2721 treatment after 10 Gy IR clearly increased Lgr5-positive pit cells (P < 0.05) and xylose absorption (P < 0.05). However only PGN and WR-2721 combination treatment markedly increased villus height (P < 0.05), number of crypts (P < 0.05) and whole-body weights after 10 Gy whole-body irradiation (WBI). The NF-κB p65 subunit was translocated to the nucleus, and phosphate-IκBα (Ser32/Ser36) was detected after stimulation with either PGN or WR-2721, which indicates that these two agents act synergistically through the activation of the NF-κB pathway. Administration of PGN in combination with WR-2721 was demonstrated to have a synergistic effect on the increase in haematopoietic cells and intestinal reconstitution, as well as improved survival in lethally irradiated mice, but resulted in some degree of an immune disorder.

Yttrium-based therapy for neuroendocrine tumors.

Peptide receptor radionuclide therapy with (90)Y-peptides is generally well tolerated. Acute side effects are usually mild; some are related to the coadministration of amino acids and others to the radiopeptide itself. Chronic and permanent effects on target organs, particularly kidneys and bone marrow, are generally mild if necessary precautions are taken. The potential risk to kidney and red marrow limits the amount of radioactivity that may be administered. However, when tumor masses are irradiated with adequate doses, volume reduction may be observed. (90)Y-octreotide has been the most used radiopeptide in the first 8 to 10 years of experience.

Gamma-tocopherol-N,N-dimethylglycine ester as a potent post-irradiation mitigator against whole body X-irradiation-induced bone marrow death in mice.

We examined the radioprotective and mitigative effects of gamma-tocopherol-N,N-dimethylglycine ester (GTDMG), a novel water-soluble gamma-tocopherol derivative, against X-irradiation-induced bone marrow death in mice. Mice (C3H, 10 weeks, male) were injected intraperitoneally with GTDMG suspended in a 0.5% methyl cellulose solution before or after receiving of 7.5-Gy whole body X-irradiation. GTDMG significantly enhanced the 30-day survival rate when given 30 min before or immediately after the irradiation. Its mitigative activity (administered after exposure) was examined further in detail. The optimal concentration of GTDMG given immediately after irradiation was around 100 mg/kg body weight (bw) and the 30-day survival rate was 97.6 ± 2.4%. When GTDMG was administered 1, 10 and 24 h post-irradiation, the survival rate was 85.7 ± 7.6, 75.0 ± 9.7 and 36.7 ± 8.8%, respectively, showing significant mitigation even at 24 h after irradiation (P < 0.05). The value of the dose reduction factor (100 mg/kg bw, given intraperitoneally (i.p.) immediately after irradiation) was 1.25. GTDMG enhanced the recovery of red blood cell-, white blood cell-, and platelet-counts after irradiation and significantly increased the number of endogenous spleen colonies (P < 0.05). Subcutaneous (s.c.) administration also had mitigative effects. In conclusion, GTDMG is a potent radiation mitigator.

Protection against radiation-induced hematopoietic damage in bone marrow by hepatocyte growth factor gene transfer.

PURPOSE: To investigate whether adenovirus-mediated delivery of the human hepatocyte growth factor (HGF) gene could prevent radiation-induced hematopoietic damage. MATERIALS AND METHODS: Thirty C57BL/6 mice were randomized into three groups, in which phosphate buffer saline (PBS), mock adenovirus vector (Ad-null) or adenovirus vector containing HGF (Ad-HGF) were injected into the tail vein of each group, respectively. After 48 hours, the mice received a single irradiation dose of 6.5 Gy (60)Co gamma rays. Blood samples were extracted via the tail vein at day 0, 4, 7, 10, 14, 21, 24 and 30 after irradiation, for red blood cell (RBC) and white blood cell (WBC) and cluster of differentiation4 (CD4)/cluster of differentiation8 (CD8) ratio assessment. At weekly intervals following irradiation, serum erythropoietin (EPO), Interleukin-6 (IL-6) and Interferon-gamma (IFN-γ) levels were measured using enzyme-linked immunosorbent assay (ELISA). On post-irradiation day 30, the mice were autopsied and erythroid burst-forming units (BFU-E) were evaluated. RESULTS: Adenovirus-mediated HGF gene transfer could increase human HGF level in serum and have a significant elevation in RBC and WBC count. Ad-HGF increased EPO and IL-6 levels and prompted BFU-E formation. Ad-HGF decreased radiation- induced micronucleus frequency in the mouse bone marrow (BM). Most evidence of radiation-induced hematopoietic damage was observed morphologically in bone marrow specimen four weeks after irradiation. Ad-HGF protected against radiation-induced BM failure and increased survival. Finally, Ad-HGF increased the thymic index and enhanced immune function in the irradiated C57BL/6 mice. CONCLUSIONS: This is the first report to date that demonstrates the potential of HGF gene transfer to prevent radiation-induced hematopoietic damage.