Acute Bone Marrow Suppression Research Articles

Feasibility and long-term outcomes of post-chemotherapy-based consolidation radiotherapy in extensive stage small-cell lung cancer

BackgroundThe target definition of consolidation radiotherapy (RT) for extensive stage small-cell lung cancer (ES-SCLC) has not been standardized. This study aimed to demonstrate the feasibility of post-chemotherapy based consolidation RT in ES-SCLC. MethodsAll ES-SCLC patients without initial brain metastases who completed ≥ 4 cycles of systemic therapy at Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University from 2012 to 2021 were included in this retrospective study. We correlated the site of first recurrence to the post-chemotherapy-based radiation volume (small-field). Relapse pattern, progression-free survival (PFS) and overall survival (OS) were compared between those received and did not receive consolidation RT. ResultsA total of 152 patients were followed up for a median of 31.7 months (interquartile range [IQR], 23.9–39.6 months). The median PFS and OS of the cohort were 8.3 months (IQR, 6.1–11.2 months) and 16.2 months (IQR, 9.9–24.9 months), respectively. Thoracic consolidation RT served not only as an independent prognostic factor for improved PFS in the entire cohort, but also significantly prolonged OS in the subgroup without synchronous liver metastases. Small-field consolidation RT markedly reduced in-field recurrences (hazard ratio [HR], 0.28 [95% CI, 0.12–0.38]; P < 0.001) without increasing out-of-field recurrences (HR, 0.40 [95% CI, 0.13–1.16]; P = 0.080). No relapse was observed at the margin of the targets. Treatment-related toxicities were moderate, with grade 3 acute radiation pneumonia, radiation esophagitis, and bone marrow suppression rates of 8.3%, 3.1%, and 12.5%, respectively. No grade 5 toxicity occurred. ConclusionSmall-field consolidation RT based on post-chemotherapy volume is safe and can significantly improve local control in ES-SCLC.

Hematological Recovery Persistent for More Than 1 Yearin an Elderly Patient with Acute Monoblastic Leukemiaafter Severe Bone Marrow Suppression Induced by Oral Induction Therapy

Hematological Recovery Persistent for More Than 1 Yearin an Elderly Patient with Acute Monoblastic Leukemiaafter Severe Bone Marrow Suppression Induced by Oral Induction Therapy

Novel 2 Marker Sandwich Immunoassay for the Detection of Precursor- and Mature Granulocyte-Derived Exosomes in Peripheral Blood: A Preliminary Case Study

Introduction: In order to assess hematopoietic precursor cells, bone marrow biopsies are routinely conducted, which is painful for the patient and is not applicable for frequent testing. However, precursor, maturating, and matured cells are known to produce exosomes, which are released into peripheral blood. By analyzing these exosomes in plasma, bone marrow condition may be assessed noninvasively. Myeloid precursor cells express different surface markers than when they have matured. It is reasonable to speculate that these markers would be incorporated into exosomes. In this study, we developed a novel sandwich enzyme-linked immunosorbent assay (ELISA) by using a combination of monoclonal antibodies against 2 different leukocyte antigens, to account for the number of exosomes in plasma. Methods In 6 patients undergoing chemotherapy, venous blood was drawn at regular intervals before, during, and after respective chemotherapies was given. Various clones of monoclonal antibodies against CD11b, CD33, CD34, CD35, CD81, and CD117 were obtained, and antibodies were biotinylated by EZ link Sulfo-NHS-LC-Biotin. Anti-brain antibodies were switched with anti-leukocyte antibodies, and exosome activity was trended. Results CD11b+ and CD 117+ plates showed small changes during chemotherapy (within +/- 50% of the initial value), while plasma WBC count showed a dramatic decrease during chemotherapy. In the recovery phase of WBC after chemotherapy, CD11b+ and CD16+showed a greater than 2-fold increase, with the up-trend taking place earlier than its plasma WBC counterparts. CD 117+ CD33+ also showed an up-trend, but was slower than their CD11b+ and CD16+ counterpart. Finally, each exosome value was divided by other markers to calculate the ratio, and compared between pre and post chemotherapy blood. In half of the cases, there was not a difference, versus an almost double premature/mature ratio in post-chemotherapy blood in the other half of patients. Conclusion From data collected from pre-chemotherapy studies, the lack of correlation between ELISA data compared to plasma WBC data, indicates that plasma exosome analysis might not be suitable for the monitoring of acute bone marrow suppression. Additionally, in the recovery phase, surface markers correlation with WBC was present in only some of the markers, indicating that the assay sensitivity is dependent on the marker combinations. Overall, both myeloid precursor- and mature granulocyte-derived exosomes were increased during the recovery from chemotherapy in 3 out of 5 patients, and exosome profiles were different after chemotherapy in 2 out of 5 patients. Disclosures Mitsuhash: NanoSomiX:Current Employment.

131I-MIBG negative progressive symptomatic metastatic paraganglioma: response and outcome with 177Lu-DOTATATE peptide receptor radionuclide therapy.

The primary aim of this study was to evaluate the long-term outcome of 177Lu-DOTATATE PRRT in terms of clinical, biochemical and imaging response rates, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in 131I-metaiodobenzylguanidine (MIBG) negative progressive/symptomatic locally advanced or metastatic paragangliomas (PGL). The secondary aims of this study were to determine clinical toxicity of 177Lu-DOTATATE and association of PFS with various variables. 131I-MIBG negative PGL with progressive/symptomatic locally advanced or metastatic disease that underwent 177Lu-DOTATATE PRRT from 2012 to 2019 in our institute were evaluated. Standard dose activity of 5.55-7.4GBq per cycle of 177Lu-DOTATATE was administered in somatostatin receptor (SSTR) positive PGL. Post-PRRT response was evaluated under three broad categories: (a) symptomatic, (b) biochemical, and (c) imaging (molecular and anatomic imaging). The PFS and OS since first 177Lu-DOTATATE cycle were determined. Associations of PFS with various variables were also investigated. The clinical toxicities of 177Lu-DOTATATE in PGL were determined. Amongst a total of 9 PGL patients, response to 177Lu-DOTATATE was seen in six patients, two patients, four patients and three patients on symptomatic, biochemical, molecular and anatomical based imaging response evaluation categories respectively with DCR of 67%. The median PFS and OS were not reached at a median follow-up of 40months. Estimated PFS rate of 63% (95% CI 30-96%) and OS rate of 65% (95% CI 32-97%) were noticed at 40months. Significant association of PFS was found for site of PGL (non-HNPGL), total cumulative dose of PRRT (> 22.2GBq), and number of PRRT cycles patient received (≥ 4cycles). 177Lu-DOTATATE was well tolerated without acute catecholamine crisis, nephrotoxicity or bone marrow suppression of any grade or high-grade (grade ≥ 2) hematological toxicities. Our study showed favorable results with minimal low-grade and easily manageable side effects of 177Lu-DOTATATE in patients of PGL. Thus, 177Lu-DOTATATE may be considered as promising therapeutic option in 131I-MIBG negative and SSTR positive subset of PGL cases. However, further prospective study in a large number of patients is required for validation of our study results.

T cell-mediated bone marrow and splenic hypoplasia in a mouse model of acute graft vs. host disease

Abstract A major limitation with use of hematopoietic stem cell transplantation to treat relapsing hematological malignancies is the development of a potentially lethal, multi-organ inflammatory disorder called acute graft versus host disease (aGVHD). Acute GVHD-associated bone marrow (BM) suppression and lymphoid tissue (LT) hypoplasia creates protracted immunodeficiency that greatly increases the risk of infections, bleeding and death. Objective We wished to define the role that allogeneic CD4+ T cells play in a mouse model of aGVHD-associated BM and LT aplasia that does not require lethal myeloablative conditioning. Methods Allogeneic CD4+CD25−T cells (0.5×106 cells) obtained from Bl6-H2-Ab1bm12 (Bl6-BM12) donor mice were adoptively transferred into sub-lethally irradiated C57Bl6 (Bl6) recipients. Mice were monitored daily for clinical signs of aGVHD. Results Adoptive transfer of allogeneic but not syngeneic T cells induced a time-dependent loss of survival and remarkable reductions of cellularity in the BM and spleen. Virtually all allogeneic mice developed severe anemia at 15 days post transfer. Flow cytometric analyses revealed dramatic and significant losses of CD4+ T cells, myeloid cells and NK cells in the BM and spleen indicating BM suppression and spleen hypoplasia. Interestingly, we observed little immune cell infiltration in the lungs, liver and skin of allogeneic recipients and no evidence of disease in any tissue of syngeneic mice. These data suggest that the major target tissues in this model of aGVHD are BM and spleen. Conclusions When taken together, these data demonstrate that adoptive transfer of allogeneic CD4+ T cells into sub-lethally irradiated recipients induces aGVHD-associated immunodeficiency.

New pharmacological means of radiation protection (literature review)

The review systematized the current data on new classes of pharmacological compounds and biologically active substances in the field of radiation protection in Ukraine, as well as abroad. Methodological approaches and the importance of using appropriate animal models in the development of new pharmacological drugs for radiation protection are described, specifically in the cases when it is impossible to conduct full clinical trials on patients. Current views on the division of pharmacological agents into radioprotectors, radiomitigators, and therapeutic radiation protection agents are examined. The changes in the hematopoietic tissue, gastrointestinal tract and neurovascular system that occur after acute radiation exposure are also described. Particular attention is paid to pharmacological agents that can protect against acute exposure to ionizing radiation by limiting the risk of radiation mortality from the hematological and gastrointestinal forms of radiation syndrome. Results of the effectiveness of tolerant antioxidants with a wide spectrum of biological activity as promising agents for the prevention of acute and delayed radiation-induced pathology, in particular, in lung tissue, are presented. Possible molecular mechanisms of the radioprotective effect of pharmacological compounds on experimental models of total and local radiation exposure are discussed. The effectiveness of the therapeutic use of growth factors and recombinant cytokines in acute bone marrow suppression аfter accidental radiation exposure is shown. The possibilities of cell therapy with myeloid progenitor cells mobilized by tocopherol succinate hematopoietic/progenitor cells and bone marrow mesenchymal stromal cells in acute radiation injuries are shown. Special attention is paid to the importance of improving such methodological approaches and regulatory requirements when introducing into practice new radiation protection facilities in Ukraine. Key words: radiation protection, ionizing radiation, pharmacological agents, acute radiation syndrome. For citation: Uzlenkova NE. New pharmacological means of radiation protection (literature review). Journal of the National Academy of Medical Sciences of Ukraine. 2019;25(3) :268–77

High fat diet-induced obesity exacerbates hematopoiesis deficiency and cytopenia caused by 5-fluorouracil via peroxisome proliferator-activated receptor γ

The aim of the present study was to investigate the influence of a high-fat diet (HFD) on hematopoietic system recovery under stress condition caused by 5-fluorouracil (5-Fu) and to evaluate the alleviating benefit of proliferator-activated receptor γ (PPAR-γ) inhibition on aggravation of 5-Fu-induced toxicity under HFD. Survival rates of HFD or normal diet (ND) mice were monitored after 5-Fu injection. Hematopoietic stem cells (HSCs) and the progenitor cells in bone marrow were detected at various time points after 5-Fu administration by flow cytometry. Genes expressed in stem cell and platelet proliferation was tested by reverse transcription polymerase chain reaction. The blood cell profile and coagulation function were determined with an ADVIA 120 hematology system and rotational thromboelastometry, respectively. None of HFD mice remained alive after 5-Fu injection, whereas 87.4% of ND mice survived. HFD accelerated 5-Fu-induced myelosuppression and cytopenia in the circulation, reflected by the worse recovery of HSCs and myeloid progenitor cells. In HFD mice, the number of platelets significantly decreased, and the Vcam-1/Vla-4 signal pathway was downregulated in bone marrow. Meanwhile, mice receiving HFD exhibited dysfunction of blood coagulation with increased clotting formation time. However, pretreatment of HFD mice with bisphenol A diglycidyl ether (BADGE), the PPAR-γ antagonist, reversed the acute lethal toxicity and bone marrow suppression of 5-Fu and accelerated the recovery of HSCs and platelets. In the light of these results, HFD could exacerbate 5-Fu-induced bone marrow toxicity and cytopenia. BADGE treatment offers a potential strategy to alleviate the aggravated hematopoiesis under an HFD.

Association between dose-volume parameters and acute bone marrow suppression in rectal cancer patients treated with concurrent chemoradiotherapy.

Concurrent chemoradiotherapy is one of the main treatments for rectal cancer. Bone marrow suppression is one of the critical factors that affect the progress of radiotherapy. We aimed to explore the association of incidence of acute bone marrow suppression with dose-volume parameters of pelvic bone marrow among rectal cancer patients with concurrent chemoradiotherapy. We retrospectively analyzed 50 rectal cancer patients for multivariate logistic regression analyses. Three subdomains of pelvic bone marrow (PBM), bilateral ilium (IBM), lower pelvis (LPBM), and lumbosacral spine (LSBM) were assigned. The radiation dose-volume parameters from the three subdomains and the whole pelvis were evaluated. Compared to Grade 0-1 leukopenia patients, ≥Grade 2 leukopenia patients exhibited significantly higher levels of IBM V20, V25, V35, mean dose (Dmean), LPBM V20, V25, V30, LSBM V15, PBM V15, V20, and PTV. The PBM V20 of ≥Grade 2 neutropenia patients was significantly higher than that of Grade 0-1 neutropenia patients. Multivariate analysis have demonstrated that IBM V20 and LSBM V15 were the independent factors affecting ≥ Grade 2 leukopenia. There is a correlation between low dose-volume parameters with acute bone marrow suppression. IBM V20, LSBM V15 and PBM V20 can be employed as the predictors of acute bone marrow suppression.

A Rare and Fatal Case of Dobhoff Tube Placement-Associated Small Bowel Perforation Presenting With Acute Leukopenia

Enteral feeding with Dobhoff tubes is a common mode of nutrition in acute or chronically ill patients. Common adverse events associated with Dobhoff placement include epistaxis and sore throat. More serious complications such as esophageal perforation and pneumothorax have been reported. We report a case of small bowel perforation after Dobhoff placement with acute leukopenia as an initial laboratory manifestation. A 75-year-old female presented to the hospital with a 3-year history of worsening hoarseness and shortness of breath. Bedside laryngoscopy demonstrated a large laryngeal mass. Biopsy results were positive for squamous cell carcinoma. Bronchoscopy and esophagoscopy (to pre-pyloric region) were unremarkable. Due to severe protein malnutrition, a Dobhoff was placed for pre-operative optimization for laryngectomy. Post-placement KUB showed tube overlying the body of stomach. 12 hours post Dobhoff insertion, vital signs were notable for hypotension to 72/48 mmHg. Physical exam was notable for diminished bowel sounds. Laboratory results showed an acute leukopenia of 1100 mcL, and lactate of 3.6 mmol/L. KUB showed advancement of the Dobhoff tube, with visualization of bowel wall lumen suggesting pneumoperitoneum. The patient remained hypotensive despite fluid resuscitation and was transferred to the ICU for pressor support. A CT scan of the abdomen revealed intraperitoneal and retroperitoneal air, with the enteric tube noted to be extraluminal with suspected perforation of the second part of the duodenum. Surgery was consulted, however due to the patient progressing to multi-system organ failure, and high surgical mortality risk, the patient was made DNR/Comfort Care and expired 6 hours later. Dobhoff placement is a common procedure performed across the country. Although a relatively safe procedure, it can have complications such as bowel perforation. One of the initial presenting clues may be acute leukopenia. Acute leukopenia has also been reported in laparoscopic bowel perforations during urological surgery. The mechanism of acute leukopenia in bowel perforation could be due to peritonitis leading to sepsis. Sepsis has been shown to cause acute bone marrow suppression leading to leukopenia. Another explanation is the marginalization of leukocytes in conditions of decreased blood flow such as hypotension. Leukocytes are shifted outward by RBCs in laminar flow, and in slow flow the leukocytes will adhere to the endothelial surface in larger number.Figure: Enteric tip overlying the gastric pylorus. Arrow showing “Rigler's Sign”, suggesting air on both sides of bowel concerning for extraluminal air.Figure: Large arrow showing intraperitoneal air in the anterior extraluminal space. Small arrow shows enteric tube possibly in extraluminal space.

Efficacy analysis of IMRT on 22 cases with recurrent nasopharyngeal carcinoma

Objective To analyze the efficacy of IMRT in the treatment of recurrentnasopharyngeal carcinoma. Methods Clinical data of 22 patients with recurrent nasopharyngeal carcinoma （NPC）were retrospectively analyzed,We have recurrent NPC tune the amount of synchronization push radiation therapy in patients with clinical data,treatment efficacy and acute toxicity were analyzed.Results All patients were hospitalized on average 50 days, between median follow-up period of 12 months.At the end of 22 patients with no treatment deaths,three deaths （both metastasis） during follow-up,overall survival 86.3%（19/22）,local recurrence in 2 cases,2 cases of bone metasta-sis,1 case of throat and neck lymph node metastasis.The local control rate was 63.6%（14/22）.Acute toxicity main-ly acute skin,oropharyngeal mucosa （12 cases） and bone marrow suppression （4 cases）.1 patient had symptoms of hearing loss and auditory nerve damage,1 case of necrosis of the mandible,all symptoms of dry mouth in patients with radiotherapy were heavier than that of the first drive.Conclusion With the growing popularity of IMRT,NPC patients had significantly improved overall survival, but distant metastasis and recurrence of the tumor, radiotherapy again cause adverse reactions in clinical practice still needs further development and improvement,IMRT treatoffing with re-current nasopharyngeal has broad prospects. Key words: Nasopharyngeal neoplasms/recurrence; Intensity modulated radiation therapy

Analysis of risk factors of multi-drug resistant acinetobacter baumannii infection in patients with sepsis

Objective To investigate the clinical characteristics and risk factors of multi-drug resistant (MDR) acinetobacter baumannii (Ab) infection in patients with sepsis in ICU.Methods Retrospectively analyzed clinical data of 856 cases of sepsis admitted in ICU of our hospital from July 2009 to March 2013,who were divided into MDR Ab related sepsis group (179 cases) and non-MDR Ab related sepsis group (control group,677 cases).Mortality rate,hospitalization expenses,organ function injury level and risk factors of death were compared between two groups.Results Mortality rate,48 hours mortality rate and hospitalization cost of MDR Ab related sepsis group were higher than those of control group (P ＜ 0.05).Septic shock,acute kidney injury and bone marrow suppression more likely occurred in MDR Ab related sepsis group (P ＜ 0.05).APACHE Ⅱ score ＞ 25,septic shock and multiple organ dysfunction syndrome (MODS) within 24 h were risk factors of death in MDR Ab related sepsis group (P ＜ 0.05).Conclusions Patients with MDR Ab related sepsis have worse prognosis and spend more in related treatment.It is important to detect risk factors of death and implement targeting treatment early. Key words: Acinetobacter baumannii; Sepsis; Intensive care unit; Risk factors

Administration of the resveratrol analogues isorhapontigenin and heyneanol-A protects mice hematopoietic cells against irradiation injuries.

Ionizing radiation (IR) is known not only to cause acute bone marrow (BM) suppression but also to lead to long-term residual hematopoietic injury. These effects have been attributed to IR inducing the generation of reactive oxygen species (ROS) in hematopoietic cells. In this study, we examined if isorhapontigenin and heyneanol-A, two analogues of resveratrol, could mitigate IR-induced BM suppression. The results of cell viability assays, clonogenic assays, and competitive repopulation assays revealed that treatment with these compounds could protect mice BM mononuclear cells (BMMNC), hematopoietic progenitor cells, and hematopoietic stem cells from IR-induced BM suppression. Moreover, the expression of genes related to the endogenous cellular antioxidant system in hematopoietic cells was analyzed. The expression and activity of SOD2 and GPX1 were found to be decreased in irradiated BMMNC, and the application of the resveratrol analogues could ameliorate this damage. Our results suggest that in comparison with resveratrol and isorhapontigenin, treatment with heyneanol-A can protect hematopoietic cells from IR-induced damage to a greater degree; the protective effects of these compounds are probably the result of their antioxidant properties.

Effect of High Dose of Steroid on Plateletcount in Acute Stage of Dengue Fever with Thrombocytopenia

Dengue infection is the most rapidly spreading mosquito-borne viral disease in the world and an estimated 50 million dengue infections reported annually. The pathogenesis of Thrombocytopenia in dengue fever (DF) is not clearly understood. Increased peripheral destruction of antibody coated platelets and acute bone marrow suppression were strongly suspected as the possible mechanism. This often leads to life threatening dengue hemorrhagic fever (DHF) and Dengue shock syndrome (DSS). Steroids are used in the treatment of Idiopathic thrombocytopenic purpura to increase the platelet count which is mediated by auto antibodies .This hypothesis would support the use of steroids in dengue fever. The objective of this study was to test whether an intravenous high dose dexamethasone was efficacious in increasing the platelet count in acute stage of dengue fever with thrombocytopenia. During the study period between June 2010 - 2011 in JSS Hospital Mysore, 127 patients were screened for dengue fever with thrombocytopenia (<50000/cumm) and 61patients were randomly allocated, 30 to the study group and 31 to the control group, in an open labeled study. The study group received intravenous dexamethasone 8mg initially followed by 4 mg every 8 h thereafter for 4 days and IV fluids whenever required. The control Group received only IV fluids and antipyretics whenever it was indicated. The daily measurement of platelet count was carried out in all patients from the day of enrolment to the fourth day of post treatment. The baseline data (age, sex, and the mean duration of the illness, Hb%, haematocrit, and platelets) were similar in both the groups. The analysis of variance (ANOVA) statistics showed a significant linear association of the mean platelet counts with the days in either group. The mean platelet counts increased steadily in both the groups from days 1 to 4: day1 (0.687), day2 (0.34), day3 (0.530) and day4 (0.844). There was no significant difference between the two groups. We conclude that at a high dose dexamethasone regimen was not effective in achieving a higher rise in the platelet count in the acute stage of dengue fever.

Inhibition of p38 MAPK Attenuates Ionizing Radiation-Induced Hematopoietic Cell Senescence and Residual Bone Marrow Injury

Exposure to a moderate or high total-body dose of radiation induces not only acute bone marrow suppression but also residual (or long-term) bone marrow injury. The induction of residual bone marrow injury is primarily attributed to the induction of hematopoietic cell senescence by ionizing radiation. However, the mechanisms underlying radiation-induced hematopoietic cell senescence are not known and thus were investigated in the present study. Using a well-established long-term bone marrow cell culture system, we found that radiation induced hematopoietic cell senescence at least in part via activation of p38 mitogen-activated protein kinase (p38). This suggestion is supported by the finding that exposure to radiation selectively activated p38 in bone marrow hematopoietic cells. The activation was associated with a significant reduction in hematopoietic cell clonogenic function, an increased expression of p16(INK4a) (p16), and an elevated senescence-associated β-galactosidase (SA-β-gal) activity. All these changes were attenuated by p38 inhibition with a specific p38 inhibitor, SB203580 (SB). Selective activation of p38 was also observed in bone marrow hematopoietic stem cells (HSCs) after mice were exposed to a sublethal total-body dose (6.5 Gy) of radiation. Treatment of the irradiated mice with SB after total-body irradiation (TBI) increased the frequencies of HSCs and hematopoietic progenitor cells (HPCs) in their bone marrow and the clonogenic functions of the irradiated HSCs and HPCs. These findings suggest that activation of p38 plays a role in mediating radiation-induced hematopoietic cell senescence and residual bone marrow suppression.

Accidental radioisotope burns - Management of late sequelae

ABSTRACTAccidental radioisotope burns are rare. The major components of radiation injury are burns, interstitial pneumonitis, acute bone marrow suppression, acute renal failure and adult respiratory distress syndrome. Radiation burns, though localized in distribution, have systemic effects, and can be extremely difficult to heal, even after multiple surgeries. In a 25 year old male who sustained such trauma by accidental industrial exposure to Iridium192 the early presentation involved recurrent haematemesis, pancytopenia and bone marrow suppression. After three weeks he developed burns in contact areas in the left hand, left side of the chest, abdomen and right inguinal region. All except the inguinal wound healed spontaneously but the former became a non-healing ulcer. Pancytopenia and bone marrow depression followed. He was treated with morphine and NSAIDs, epidural buprinorphine and bupivicaine for pain relief, steroids, antibiotics followed by wound excision and reconstruction with tensor fascia lata(TFL) flap. Patient had breakdown of abdominal scar later and it was excised with 0.5 cm margins up to the underlying muscle and the wound was covered by a latissimis dorsi flap. Further scar break down and recurrent ulcers occurred at different sites including left wrist, left thumb and right heel in the next two years which needed multiple surgical interventions.

Accidental radioisotope burns - Management of late sequelae

Accidental radioisotope burns are rare. The major components of radiation injury are burns, interstitial pneumonitis, acute bone marrow suppression, acute renal failure and adult respiratory distress syndrome. Radiation burns, though localized in distribution, have systemic effects, and can be extremely difficult to heal, even after multiple surgeries. In a 25 year old male who sustained such trauma by accidental industrial exposure to Iridium192 the early presentation involved recurrent haematemesis, pancytopenia and bone marrow suppression. After three weeks he developed burns in contact areas in the left hand, left side of the chest, abdomen and right inguinal region. All except the inguinal wound healed spontaneously but the former became a non-healing ulcer. Pancytopenia and bone marrow depression followed. He was treated with morphine and NSAIDs, epidural buprinorphine and bupivicaine for pain relief, steroids, antibiotics followed by wound excision and reconstruction with tensor fascia lata(TFL) flap. Patient had breakdown of abdominal scar later and it was excised with 0.5 cm margins up to the underlying muscle and the wound was covered by a latissimis dorsi flap. Further scar break down and recurrent ulcers occurred at different sites including left wrist, left thumb and right heel in the next two years which needed multiple surgical interventions.

Niacin status and treatment-related leukemogenesis

Chemotherapy often causes damage to hematopoietic tissues, leading to acute bone marrow suppression and the long term development of leukemias. Niacin deficiency, which is common in cancer patients, causes dramatic genomic instability in bone marrow cells in an in vivo rat model. From a mechanistic perspective, niacin deficiency delays excision repair and causes double strand break accumulation, which in turn favors chromosome breaks and translocations. Niacin deficiency also impairs cell cycle arrest and apoptosis in response to DNA damage, which combine to encourage the survival of cells with leukemogenic potential. Conversely, pharmacological supplementation of rats with niacin increases bone marrow poly(ADP-ribose) formation and apoptosis. Improvement of niacin status in rats significantly decreased nitrosourea-induced leukemia incidence. The data from our rat model suggest that niacin supplementation of cancer patients may decrease the severity of short- and long-term side effects of chemotherapy, and could improve tumor cell killing through activation of poly(ADP-ribose)-dependent apoptosis pathways.

Phenotypic and Functional Changes Induced in Hematopoietic Stem/Progenitor Cells After Gamma-Ray Radiation Exposure

Ionizing radiation (IR) exposure causes rapid and acute bone marrow (BM) suppression that is reversible for nonlethal doses. Evidence is accumulating that IR can also provoke long-lasting residual hematopoietic injury. To better understand these effects, we analyzed phenotypic and functional changes in the stem/progenitor compartment of irradiated mice over a 10-week period. We found that hematopoietic stem cells (HSCs) identified by their repopulating ability continued to segregate within the Hoechst dye excluding "side population (SP)" early after IR exposure. However, transient phenotypic changes were observed within this cell population: Sca-1 (S) and c-Kit (K) expression levels were increased and severely reduced, respectively, with a concurrent increase in the proportion of SP(SK) cells positive for established indicators of the presence of HSCs: CD150 and CD105. Ten weeks after IR exposure, expression of Sca-1 and c-Kit at the SP cell surface returned to control levels, and BM cellularity of irradiated mice was restored. However, the c-Kit(+)Sca-1(+)Lin(-/low) (KSL) stem/progenitor compartment displayed major phenotypic modifications, including an increase and a severe decrease in the frequencies of CD150(+)Flk2(-) and CD150(-)Flk2(+) cells, respectively. CD150(+) KSL cells also showed impaired reconstituting ability, an increased tendency to apoptosis, and accrued DNA damage. Finally, 15 weeks after exposure, irradiated mice, but not age-matched controls, allowed engraftment and significant hematopoietic contribution from transplanted congenic HSCs without additional host conditioning. These results provide novel insight in our understanding of immediate and delayed IR-induced hematopoietic injury and highlight similarities between HSCs of young irradiated and old mice.

Thiopurine S-methyltransferase and inosine triphosphate pyrophosphohydrolase genes in Japanese patients with inflammatory bowel disease in whom adverse drug reactions were induced by azathioprine/6-mercaptopurine treatment

The main cause of azathioprine (AZA)/6-mercaptopurine (6MP)-induced adverse reactions is a reduction in the activities of the metabolizing enzymes thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphohydrolase (ITPA). Adverse reactions develop at a high frequency in Japanese patients at half the dose required for European and American patients; however, the association with TPMT and ITPA gene polymorphisms in Japanese has not been fully investigated. Gene mutations of TPMT and ITPA, the major AZA/6-MP -metabolizing enzymes, were investigated retrospectively in 16 Japanese patients with inflammatory bowel disease (IBD) in whom AZA/6MP treatment induced adverse reactions. The TPMT gene was found to have a wild-type sequence in all patients, but in the ITPA gene a mutation, 94C>A, was detected at a rate of 50% (8/16), with 83.3% (5/6) occurring in patients with acute bone marrow suppression and 75% (3/4) in those with agranulocytosis. The 94C>A allele frequency was 10 of 32 (0.313; 95% CI, 0.180-0.486). Adverse reactions developed earlier in patients with the 94C>A mutation. However, in half the patients, no gene polymorphism was noted. It is suggested that the ITPA gene mutation is closely related to the adverse reactions of AZA/6-MP in Japanese patients, and screening for the mutant allele is useful for predicting the most serious adverse reactions, agranulocytosis and acute bone marrow suppression.

Acute Liver Failure and Myelosuppression due to Parvovirus B19 Infection: A Case Report

Parvovirus B19 has been associated with different diseases, such as erythema infectiosum, arthropathy and transient aplastic crisis. However, parvovirus B19 infection presenting as hepatic dysfunction and myelosuppression is rarely reported in adult patients. Herein, we report an adult case of acute parvovirus B19 infection presented with acute liver failure and myelosuppression. After being treated with gamma globulin, the patient’s liver function and bone marrow test improved. We conclude that the parvovirus B19 infection should be considered as a possible cause of acute liver injury and bone marrow suppression. The antibody for B19 virus should be routinely tested in patients with liver dysfunction and/or myelosuppression of unclear etiology.