Chemotherapy-induced Bone Marrow Suppression Research Articles

Megakaryocyte- and erythroblast-specific cell-free DNA patterns in plasma and platelets reflect thrombopoiesis and erythropoiesis levels

Circulating cell-free DNA (cfDNA) fragments are a biological analyte with extensive utility in diagnostic medicine. Understanding the source of cfDNA and mechanisms of release is crucial for designing and interpreting cfDNA-based liquid biopsy assays. Using cell type-specific methylation markers as well as genome-wide methylation analysis, we determine that megakaryocytes, the precursors of anuclear platelets, are major contributors to cfDNA (~26%), while erythroblasts contribute 1–4% of cfDNA in healthy individuals. Surprisingly, we discover that platelets contain genomic DNA fragments originating in megakaryocytes, contrary to the general understanding that platelets lack genomic DNA. Megakaryocyte-derived cfDNA is increased in pathologies involving increased platelet production (Essential Thrombocythemia, Idiopathic Thrombocytopenic Purpura) and decreased upon reduced platelet production due to chemotherapy-induced bone marrow suppression. Similarly, erythroblast cfDNA is reflective of erythrocyte production and is elevated in patients with thalassemia. Megakaryocyte- and erythroblast-specific DNA methylation patterns can thus serve as biomarkers for pathologies involving increased or decreased thrombopoiesis and erythropoiesis, which can aid in determining the etiology of aberrant levels of erythrocytes and platelets.

Analysis of adverse drug reactions/events of cancer chemotherapy and the potential mechanism of Danggui Buxue decoction against bone marrow suppression induced by chemotherapy.

Objective: To analyze the clinical characteristics of adverse reactions/events based on chemotherapy in cancer patients, and then explore the potential mechanism of Danggui Buxue Decoction (DBD) against chemotherapy-induced bone marrow suppression (BMS). Methods: Retrospectively collected and evaluated were the clinical data of patients in a hospital who experienced adverse reactions/events brought on by chemotherapeutic medications between 2015 and 2022. We explored the potential mechanism of DBD against BMS using network pharmacology based on the findings of the adverse reactions/events analysis. Results: 151 instances (72.25%) experienced adverse reactions/events from a single chemotherapy medication. Besides, platinum-based medications produced the most unfavorable effects. The study also found that chemotherapy caused the highest number of cases of BMS, including platinum drugs. Consequently, BMS is the most prevalent adverse reaction disease caused by chemotherapy found in this part. According to network pharmacology findings, DBD can prevent BMS primarily involving 1,510 primary targets and 19 key active ingredients. Based on the enrichment analysis, PI3K-AKT, TNF, MAPK, and IL-17 signaling pathways made up the majority of the DBD-resisting BMS pathways. Molecular docking displayed that kaempferol, the major active ingredient of DBD, had the highest binding energy (-10.08kJmol-1) with PTGS2 (a key target of BMS). Conclusion: Cancer patients who received chemotherapy had a risk to develop BMS. Regular blood tests should be performed while taking medicine; early discovery and treatment can reduce a patient's risk of experiencing adverse reactions/events. Additionally, this study demonstrated that DBD, through a variety of targets and pathways, may be crucial in avoiding BMS.

Effectiveness of Acupuncture for Relieving Chemotherapy-Induced Bone Marrow Suppression: A Systematic Review with a Meta-analysis and Trial Sequential Analysis.

Objective: Bone marrow suppression is the most common side effect of chemotherapy that may lead to discontinuation for treatment pertaining to patients during the therapy course. Acupuncture may relieve bone marrow suppression with regulation hematopoietic function during chemotherapy. The purpose of this study is to evaluate the effectiveness of acupuncture in relieving chemotherapy-induced bone marrow suppression and determine the effects of acupuncture on bone marrow function. Design: PubMed, Embase, Cochrane Library, Medline OVID, CINAHL Plus, Web of Science, and Chinese articles in the Airiti Library and China National Knowledge Infrastructure databases were searched up to February 2023. Publications in both English and Chinese were eligible for inclusion without any limitations on the publication date. Only randomized controlled trials investigating the impact of acupuncture on chemotherapy-induced bone marrow suppression were considered. In addition, a trial sequential analysis was performed to assess the adequacy of the current sample size. Results: A total of 25 studies met the inclusion criteria. Acupuncture was found to increase the levels of hematopoietic cytokine granulocyte colony-stimulating factor (G-CSF) (Hedges' g = 0.79, p < 0.001), as well as stimulate the production of white blood cells (Hedges' g = 0.69, p < 0.001), red blood cells (Hedges' g = 0.37, p = 0.01), neutrophils (Hedges' g = 0.66, p < 0.001), absolute neutrophil count (Hedges' g = 0.89, p = 0.01), hemoglobin (Hb) (Hedges' g = 0.37, p = 0.02), platelets (Hedges' g = 0.50, p < 0.001), and natural killer (NK) cells (Hedges' g = 1.30, p = 0.02). Further, the levels of platelets and NK cells were observed to increase cumulatively over time. Conclusions: Acupuncture may improve chemotherapy-induced bone marrow suppression due to increasing levels of the hematopoietic cytokine, G-CSF and further relieving chemotherapy-induced bone marrow suppression. PROSPERO Registration: This review was registered with PROSPERO (International Prospective Register of Systematic Reviews: CRD42020185813).

Physical function, nutritional status, and quality of life before and after chemotherapy in patients with malignant lymphoma.

This study investigates the efficacy of and gender differences in exercise therapy in patients with malignant lymphoma undergoing chemotherapy. Twenty-six patients (13 men, 13 women) received physical therapy (based on the Borg Scale 13) during hospitalization. Physical function was measured using grip and knee extension strength, 6-minute walking distance, and body composition; nutritional status assessed via Mini Nutritional Assessment (MNA®); and serum albumin levels analyzed. Fatigue was evaluated using the Brief Fatigue Inventory, and health-related quality of life was assessed with the Medical Outcome Study 36-Item Short-Form Health Survey (SF-36v2). The analysis of all patients indicated that the right grip strength, skeletal muscle mass, skeletal muscle index, and leg muscle mass significantly decreased, whereas the serum albumin level, MNA® score, and scores of many items of the SF-36v2 significantly increased after chemotherapy. In a gender-specific analysis, only men showed significant declines in the skeletal muscle mass and skeletal muscle index, and improvement in the MNA® score after chemotherapy. In the SF-36v2, there were significant improvements in general health and physical component summary scores among men, and general health and mental component summary scores among women. Exercise therapy at a Borg Scale intensity of 13 may not prevent muscle mass decline in patients with malignant lymphoma, especially male patients. In addition, this study revealed that there is a gender difference in the effect of exercise therapy on quality of life. Thus, gender should be considered in exercise therapy for patients with malignant lymphoma.

Induction chemotherapy in head and neck cancer – Boon or bane?

Although concurrent chemoradiotherapy is the standard of care for inoperable locally advanced head and neck cancer, induction chemotherapy is considered an alternative approach by head and neck oncologists worldwide. To evaluate the response to induction chemotherapy in terms of loco-regional control and treatment-related toxicity in inoperable locally advanced head and neck cancer patients. This prospective study was conducted on patients who received two to three cycles of induction chemotherapy. Following this, response assessment was performed clinically. Grading of radiation-induced oral mucositis and any interruptions in treatment were noted. At 8 weeks following treatment, magnetic resonance imaging-based radiological response assessment was performed using RECIST criteria version 1.1. Our data revealed 57.7% complete response rate with induction chemotherapy, followed by chemoradiation therapy. We observed that post induction, 67.5% and 47.5% patients had reduction in T-stage (<0.001) and N-stage of disease (<0.001), respectively, with complete response more achieved in younger patients (≤50 years). Chemotherapy-induced bone marrow suppression and febrile neutropenia occurred in 7.5% patients. We demonstrated that a higher grade of radiation-induced mucositis was noticed among those receiving three cycles of induction chemotherapy (ICT) and aged >50 years. We conclude that induction chemotherapy could still be a viable option for down-staging unresectable locally advanced disease, especially for younger patients in terms of better treatment response and tolerability. The number of cycles of ICT seems to influence radiation-induced mucositis. This study underscores the need for further studies to determine the exact role of ICT in locally advanced head and neck cancer.

Progress and perspectives of platinum nanozyme in cancer therapy.

Malignant tumors, one of the worst-case scenarios within human health problems, are now posing an increasing threat to the well-being of the global population. At present, the treatment of malignant tumors mainly includes surgery, radiotherapy, chemotherapy, immunotherapy, etc. Radiotherapy and chemotherapy are often applied to inoperable tumors, and some other tumors after surgery as important adjuvant therapies. Nonetheless, both radiotherapy and chemotherapy have a series of side effects, such as radiation-induced lung injury, and chemotherapy-induced bone marrow suppression. In addition, the positioning accuracy of radiotherapy and chemotherapy is not assured and satisfactory, and the possibility of tumor cells not being sensitive to radiation and chemotherapy drugs is also problematic. Nanozymes are nanomaterials that display natural enzyme activities, and their applications to tumor therapy have made great progress recently. The most studied one, platinum nanozyme, has been shown to possess a significant correlation with radiotherapy sensitization of tumors as well as photodynamic therapy. However, there are still several issues that limited the usage of platinum-based nanozymes in vivo. In this review, we briefly summarize the representative studies regarding platinum nanozymes, and especially emphasize on the current challenges and the directions of future development for platinum nanozymes therapy.

Non-Transferrin-Bound Iron Serves As Iron Source for Aspergillus Fumigatus Growth

The appearance of non-transferrin-bound iron (NTBI) as a consequence of saturated transferrin (Tf) levels in patients undergoing bone marrow transplantation is multifactorial. Chemotherapy-induced tissue damage on the one hand side, causing iron release from apoptotic cells, and chemotherapy-induced bone marrow suppression leading to diminished iron consumption for erythropoiesis on the other hand side as well as chronic transfusion therapy for anemia are among the major contributing factors for iron overload. The existence of NTBI is known to be associated with therapy-related complications, including infections. Nowadays invasive aspergillosis is, in spite of antifungal prophylaxis, still a serious problem with mortality rates ranging up to 70%-90%. The possible interaction of invasive aspergillosis and iron metabolism has been reported.In this study we specifically assessed the role of NTBI on the in vitro growth of Aspergillus fumigatus (A. fumigatus ; ATCC46645) in the presence of plasma. Therefore the growth of A. fumigatus in cultures containing 10% human plasma and various NTBI levels was explored. This assay revealed that the presence of NTBI, but not high Tf-saturation without NTBI, led to a considerable growth advantage. These findings suppose that A. fumigatus growth depends on the presence of NTBI rather than total iron availability. Correspondingly, addition of sufficient amounts of human apo-Tf to eliminate NTBI prevented A. fumigatus growth. These results clearly show that NTBI only exists and promotes A. fumigatus growth if Tf is saturated and disproves the widely believed notion that that Aspergillus utilizes iron from Tf. In contrast to apo-Tf, iron chelators (e.g. deferiprone or deferoxamine) tested in our in vitro system stimulated, rather than inhibited A. fumigatus growth, despite elimination of NTBI.To better understand the underlying molecular mechanisms, different A. fumigatus mutant strains with defects in iron acquisition systems are under investigation. Preliminary data indicate that the uptake of NTBI is not solely dependent on siderophore-mediated iron uptake.In conclusion our findings clearly indicate that NTBI is relevant for fungal growth, at least in vitro in the presence of plasma. Further ongoing experiments aim to clarify whether different clinical A. fumigatus isolates differ in their ability to utilize Tf- bound iron and NTBI. In addition, plasma samples from patients, who had undergone bone marrow transplantation, with already known levels of NTBI, should help to further corroborate the relevance of NTBI for fungal growth in vivo . DisclosuresPlatzbecker:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding.

Systematic review and Meta-analysis on chemotherapy-induced bone marrow suppression treated with acupuncture

To review systematically the effectiveness of acupuncture in treatment of chemotherapy-induced bone marrow suppression. From the date of database establishment to April 1, 2020, the articles on randomized controlled trials of chemotherapy-induced bone marrow suppression were retrieved by computer from the following databases, i.e. PubMed, Cochrane central register of controlled trials (CENTRAL), EMbase, cumulative index to nursing & allied health literature (CINAHL), JBI database of systematic reviews and implementation reports, CNKI, Wanfang, VIP and SinoMed. Using RevMan5.3, Meta-analysis was conducted. With GRADEpro GDT, the evidence quality was evaluated. A total of 12 articles were included, 10 articles of which were analyzed by quantitative Meta-analysis. Compared with the control group, the improvements in the decrease of post-chemotherapy leukocyte (P<0.01, MD=0.88, 95%CI=[0.71, 1.05]) and platelet (P<0.01, MD=25.91, 95%CI=[16.86, 34.97]) were better in the observation group. The difference in reducing hemoglobin was not significant between the two groups (P>0.05, MD=2.19, 95%CI=[-1.22, 5.61]). Regarding the improvement in the decrease of post-chemotherapy neutrophile granulocyte (P=0.03, MD=0.40, 95%CI=[0.04, 0.77]) and erythrocyte (P=0.03，MD=0.15，95%CI=[0.01, 0.28]), Karnofsky score (P<0.01, MD=4.19, 95%CI=[3.40, 4.98]) and quality of life (QOL) score (P<0.01, MD=5.01，95%CI=[1.61, 8.42]), the effects in the observation group were better than those in the control group. Acupuncture alleviates the decrease of leukocyte, platelet, neutrophile granulocyte and erythrocyte counts and improves the survival quality of patients with chemotherapy-induced bone marrow suppression.

Review of clinical research on the supplementing Qi and activating blood circulation method in treatment of chemotherapy-induced bone marrow suppression of lung cancer

Lung cancer, as the highest incidence and mortality in the world, has become a major killer of human health. Most patients received chemotherapy to alleviate symptoms and prolong life when they are in the middle and advanced stage of lung cancer. The supplementing Qi and activating blood circulation method of traditional Chinese medicine maybe the breakthrough point for lung cancer. Thus, this paper reviewed the clincial research on the single agent, compound and Chinese patent medicine, which relected the meaning of upplementing Qi and activating blood circulation, for bone marrow suppression caused by lung cancer chemotherapy. Key words: Supplementing Qi and activating blood circulation method; Arrest of bone marrow; Lung cancer; Chemotherapy; Review

Transcutaneous electrical acupoint stimulation (TEAS) ameliorates chemotherapy-induced bone marrow suppression in lung cancer patients.

To investigate the effect of percutaneous electrical stimulation on chemotherapy-induced bone marrow suppression in patients with lung cancer. From December 2014 to August 2015, one hundred ninety-one non-small cell lung cancer patients with chemotherapy naive were randomly divided into control group, medication group, and transcutaneous electrical acupoint stimulation (TEAS) group. Patients with the control group received routine nursing care, the medication group was treated by oral administration of prophylactic agents, and TEAS group received electrical stimulation of acupoints including Dazhui (DU14), Geshu (BL17), Zusanli (ST36), Sanyinjiao (SP6), and Hegu (LI4). The primary end point was the blood routine indexes and secondary end point was the degree of comfort. The white blood cell in the TEAS group was significantly higher than the control group on day 8 and day 14 (P<0.05). The platelet count in the TEAS group was significantly higher than control group on day 5, day 8 and day 11 (P<0.05). The comfort score in the TEAS group was significantly higher than control group on day 8 (P<0.05). Percutaneous electrical stimulation of acupoints could prevent chemotherapy-induced bone marrow suppression in lung cancer patients and ensure a smooth continuation of chemotherapy.

Optimized Animal Model of Cyclophosphamide-induced Bone Marrow Suppression.

Myelosuppression is one of the serious side effects of anticancer chemotherapeutic drugs that deteriorate the bodily functions of patients, thereby affecting the quality of life considerably. Prevention of myelosuppression in anticancer chemotherapy is an important research topic. A stabilized chemotherapy-induced myelosuppression animal model is necessary in experimental research. This study aimed to establish an optimized animal model of chemotherapy-induced bone marrow suppression. After C57BL/6 mice were treated with intermediate- and high-dose (25/50 mg/kg) cyclophosphamide (CTX) for 10 days, the body-weight, changes in thymus and spleen, number of white blood cells (WBCs), red blood cells (RBCs), and platelets (PLTs) and changes in bone marrow in the mice were systematically evaluated at the next 2, 7 and 14 days. Our results demonstrated that CTX treatments could significantly decrease the body-weight of mice, as well as the ratios of the weights of thymus and spleen to body-weight. The physiological structures of thymus and spleen were destroyed by CTX treatments. The number of WBCs and RBCs significantly declined after CTX treatments; however, the number of PLTs increased. Moreover, the expression of Sca1 in bone marrow cells decreased on Day 2 but increased on Day 14. The expression of CD34 decreased in bone marrow cells after CTX treatments. In conclusion, mice models, with high-dose CTX treatments for 10 days, can be an optimized animal model for chemotherapy-induced bone marrow suppression.

54P Correlation of Raman and NIR spectroscopy for diagnosis of peripheral lung cancer

Background: TCM syndrome typing of chemotherapy-induced bone marrow suppression is Qi and blood deficiency and Qi and Yin deficiency [15]. According to the TCM channel and collateral theory, Dazhui (DU14), Geshu (BL17), Zusanli (ST36), Sanyinjiao (SP6), and Hegu (LI4) play a role in enriching blood and treating leucopenia. Although the literature reports no incompatibility between these acupoints, their combined effects have not been studied yet. The objective is to investigate the effect of percutaneous electrical stimulation on chemotherapy-induced bone marrow suppression in patients with lung cancer. Methods: From December 2014 to August 2015, one hundred ninety-one non-small cell lung cancer patients with chemotherapy naive were randomly divided into transcutaneous electrical acupoint stimulation (TEAS) group, medication group, and control group. Patients with TEAS group received electrical stimulation of acupoints including Dazhui (DU14), Geshu (BL17), Zusanli (ST36), Sanyinjiao (SP6), and Hegu (LI4), the medication group was treated by oral administration of prophylactic agents, and the control group received routine nursing care. The primary end point was the blood routine indexes and secondary end point was the degree of comfort. Results: The white blood cell in the TEAS group was significantly higher than the control group on day 8 and day 14 (P < 0.05). The platelet count in the TEAS group was significantly higher than control group on day 5, day 8 and day 11 (P < 0.05). The comfort score in the TEAS group was significantly higher than control group on day 8 (P < 0.05). Conclusions: Percutaneous electrical stimulation of acupoints could prevent chemotherapy-induced bone marrow suppression in lung cancer patients and ensure a smooth continuation of chemotherapy. Legal entity responsible for the study: Lili Hou Funding: Shanghai Health Talent Development Fund Disclosure: All authors have declared no conflicts of interest.

53P Transcutaneous electrical acupoint stimulation ameliorates chemotherapy-induced bone marrow suppression in lung cancer patients

53P Transcutaneous electrical acupoint stimulation ameliorates chemotherapy-induced bone marrow suppression in lung cancer patients

Upregulated heme oxygenase-1 expression of mouse mesenchymal stem cells resists to chemotherapy-induced bone marrow suppression

Background Bone marrow hematopoietic function suppression is one of the most common side effects of chemotherapy. After chemotherapy, the bone marrow structure gets destroyed and the cells died, which might cause the hematopoietic function suppression. Heme oxygenase-1 (HO-1) is a key enzyme of antioxidative metabolism that associates with cell proliferation and resistance to apoptosis. The aim of this study was to restore or resist the bone marrow from the damage of chemotherapy by the HO-1 expression of mouse mesenchymal stem cells (mMSCs) homing to the mice which had the chemotherapy-induced bone marrow suppression. Methods One hundred and sixty female Balb/c mice (6–8-weeks old) were randomly divided into four groups. Each group was performed in 40 mice. The control group was intraperitoneally injected for 5 days and tail intravenously injected on the 6th day with normal saline. The chemotherapy-induced bone marrow suppression was established by intraperitoneally injecting cyclophosphamide (CTX) into the mice which performed as the chemotherapy group. The mMSCs were tail intravenously injected into 40 chemotherapically damaged mice which served as the mMSCs group. The difference between the HO-1 group and the mMSCs group was the injected cells. The HO-1 group was tail intravenously injected into the mMSCs that highly expressed HO-1 which was stimulated by hemin. The expression of HO-1 was analyzed by Western blotting and RT-PCR. Cell proliferation was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Histopathologic examinations were performed 1 week after injection. Results Compared with the control group, the expression levels of HO-1 mRNA and protein were significantly higher in the HO-1 group (all P &lt;0.05), even obviously than the mMSCs group. CTX treatment induced apoptosis and inhibited proliferation. After injected, the white blood cell (WBC), red blood cell (RBC) and platelet (PLT) declined fast and down to the bottom at the 7th day. The bone marrow structure was destroyed incomplete. In vitro, the survival rate of cells in chemotherapy group was less than 50% after 24 hours. In contrast, mMSCs could do a favor to the cellular cleavage and proliferation. They slowed down the cell mortality and more than 50% cells survived after 24 hours. The effects of blocking apoptosis and bone marrow recovery could be more effective in the HO-1 group. In the HO-1 group, it had observed that the bone marrow structure became complete and the hemogram closed to normal at 7th day. Conclusions HO-1 played an important role in promoting the recovery of CTX-induced hematopoietic damage. We suggest that HO-1 is able to restore the functions of chemotherapy-induced hematopoietic damage.

Activated expression of the chemokine Mig after chemotherapy contributes to chemotherapy-induced bone marrow suppression and lethal toxicity

AbstractAlterations in gene expression after chemotherapy may potentially help to identify mediators that induce suppression or regeneration in bone marrow. This paper reports our observation that the expression of the chemokine monokine induced by IFN-γ (Mig) and its receptor CXCR3 was significantly activated in mice after treatment with the chemotherapeutic agent 5-fluorouracil (5-FU). The neutralization of antibodies against the activated Mig increased the survival rate and accelerated BM recovery after chemotherapy. In addition, elevation of Mig plasma levels after 5-FU treatment corresponded with increased mortality. The cell cycle–inhibiting effect of the prophylactic administration of Mig protected hematopoietic progenitor cells (HPCs) from 1-β-d-arabinofuranosylcytosine in spleen colony assays and enhanced the irradiated recipients' survival. In CXCR3−/− mice, Mig did not propagate BM suppression, indicating that the suppressive effect of Mig is dependent on CXCR3. On the one hand, Mig stimulated p70 S6K and Erk1/2 pathways in mesenchymal stroma cells, inhibiting mesenchymal stroma cell–dependent HPC expansion. Moreover, Mig suppressed the STAT5 pathway in HPCs, inhibiting leukocyte differentiation. Our results strongly suggest that Mig contributes to the acute lethal toxicity arising from 5-FU administration. Neutralization of Mig may offer new strategies to alleviate BM toxicity with potentially dramatic implications for chemotherapy.

Chemokine/chemokine receptor nomenclature.

Chemokine/chemokine receptor nomenclature.

Clinical observation on effect of shuanghuang shengbai granule on chemotherapy induced myelpsuppression in tumor patients and on ultrastructure of bone marrow in mice

To observe the leucocyte increasing effect of Shuanghuang Shengbai Granule (SHSBG) in tumor patients treated by chemotherapy and the bone marrow microenvironment protecting effect in mice. Patients of non-small-cell pulmonary, mammary, gastric or intestinal cancer, who were ready for receiving re-treatment of chemotherapy, were enrolled and divided into 4 groups randomly. The 28 cases in SHSBG group A received chemotherapy combined with SHSBG; the 27 in the SHSBG group B received chemotherapy alone at first, and SHSBG was added when their peripheral white blood cell (WBC) count lowered to <4×109/L; the 33 in control group A and 24 in control group B were treated by the method similar to that applied to SHSBG group A and B respectively but with Rubidate instead of SHSBG. Experimental study of electron microscopic observation on bone marrow ultrastructure in mice was also conducted. The total leukocyte increasing effective rate occurred in SHSBG group A and B was 75.00% and 88.89%, while in control group A and B, 54.55% and 58.33% respectively, and the difference between the SHSBG groups and the control groups was significant (P<0. 01). Experimental study showed that SHSBG has good bone marrow hematopoietic microenvironment protecting and improving effect in mice. SHSBG has obvious protecting and treating effect on chemotherapy induced bone marrow suppression in tumor patients.

In Vivo Adenovirus Vector-Mediated Transfer of the Human Thrombopoietin cDNA Maintains Platelet Levels During Radiation- and Chemotherapy-Induced Bone Marrow Suppression

Thrombopoietin (TPO, c-mpl ligand) has emerged as a major hematopoietic cytokine stimulating megakaryocyte proliferation, endomitosis, and platelet production. This study shows that a single administration of an adenovirus (Ad) vector encoding TPO (AdCMV.TPO) abrogates thrombocytopenia induced in mice by carboplatin and irradiation. Normal Balb/c mice receiving the vector had increased platelet counts peaking at 7 days and returning to baseline by day 15. Mice rendered pancytopenic with 500 rads and 1.2 mg of carboplatin had a nadir platelet count of five percent of the baseline. Mice receiving AdCMV.TPO 3 days before receiving irradiation and chemotherapy achieved a platelet nadir fourfold higher, and had significant reduction in duration of thrombocytopenia, than mice receiving the control Ad vector. Introduction of AdCMV.TPO the same day of chemotherapy and irradiation was equally effective in acceleration of platelet recovery, but administration of AdCMV.TPO 3 days after chemotherapy-radiation had little effect on platelet recovery. At 30 days after therapy bone marrow and spleen of mice treated with AdCMV.TPO were populated with a large number of polyploid megakaryocytes, but there was no evidence of circulating megakaryocytes in the liver or lungs and no pathologic bone abnormalities such as osteosclerosis or myelofibrosis. These observations suggest that an Ad vector may be an excellent delivery system to provide adequate TPO production to maintain platelet levels in circumstances associated with life-threatening thrombocytopenia.

Bullous pyoderma gangrenosum after granulocyte colony-stimulating factor treatment

The hematopoietic growth factors are under investigation for the treatment of patients with chemotherapy-induced bone marrow suppression. One such trial at the University of California, Los Angeles involves chemotherapy with or without granulocyte colony-stimulating factor (G-CSF) in patients with small cell lung cancer. The authors report a case of a patient who had bullous pyoderma gangrenosum at the site of previous eczema during treatment with G-CSF. The lesions resolved promptly when the drug was discontinued. Other investigators have recently reported inflammatory complications of G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF) but this is the first case report of biopsy-proven neutrophilic dermatosis associated with administration of a hematopoietic growth factor. Patients should be monitored for development of inflammatory processes during G-CSF therapy and this therapy should be given with caution to those patients with existing inflammatory conditions.

Oral lithium carbonate increases colony stimulating activity production from human mononuclear cells.

Oral lithium carbonate therapy produces a reversible neutrophilic leukocytosis (Murphy et al., 1971; Shopsin et al., 1971). What was initially regarded as a medical curiosity in psychiatric patients has been exploited therapeutically in the treatment of neutropenia (Gupta et al., 1976; Schapria et al., 1977; Jacob and Herbert, 1974; Barrett et al., 1977a) and chemotherapy induced bone marrow suppression (Turner and MacDonald, 1979). A true increase in granulocyte mass occurs with lithium ingestion rather than a shift of neutrophils from the marrow reserve or demargina-tion of granulocytes (Rothstein et al., 1978; Stein et al., 1978). Elevated urinary and serum colony stimulating activity (CSA) has been reported in neutropenic patients on lithium (Gupta et al., 1976) and lithium has been shown to augment CSA production in vitro from mouse lung (Harker et al., 1977) and mononuclear cells (Joyce and Chervenick, 1975). A major source of CSA in man are the peripheral blood mononuclear cells (Chervenick and LoBuglio, 1972). These studies examined the effects of oral lithium carbonate on human mononuclear cell production of CSA as measured by its capacity to stimulate human granulocyte-macrophage colony formation.