Can We Train Military Surgeons in a Civilian Trauma Center?

INTRODUCTION: The objective of this study was to review the trauma workload and operative exposure in a major South African trauma center and provide a comparison with contemporary experience from major military conflict. MATERIALS AND METHODS: All patients admitted to the PMTS following trauma were identified from the HEMR. Basic demographic data including mechanism of injury and body region injured were reviewed. All operative procedures were categorized. The total operative volume was compared with those available from contemporary literature documenting experience from military conflict in Afghanistan. Operative volume was converted to number of cases per year for comparison. RESULTS: During the 4-year study period, 11,548 patients were admitted to our trauma center. Eighty-four percent were male and the mean age was 29 years. There were 4974 cases of penetrating trauma, of which 3820 (77%) were stab wounds (SWs), 1006 (20%) gunshot wounds (GSWs) and the remaining 148 (3%) were animal injuries. There were 6574 cases of blunt trauma. The mechanism of injuries was as follows: assaults 2956, road traffic accidents 2674, falls 664, hangings 67, animal injuries 42, sports injury 29 and other injuries 142. A total of 4207 operations were performed. The volumes per year were equivalent to those reported from the military surgical literature. CONCLUSION: South Africa has sufficient burden of trauma to train combat surgeons. Each index case as identified from the military surgery literature has a sufficient volume in our center. Based on our work load, a 6-month rotation should be sufficient to provide exposure to almost all the major traumatic conditions likely to be encountered on the modern battlefield.

Insulin and the Brain: A Sweet Relationship With Intensive Care.

BACKGROUND: Insulin receptors (IRs) in the brain have unique molecular features and a characteristic pattern of distribution. Their possible functions extend beyond glucose utilization. In this systematic review, we explore the interactions between insulin and the brain and its implications for anesthesiologists, critical care physicians, and other medical disciplines. METHODS: A literature search of published preclinical and clinical studies between 1978 and 2014 was conducted, yielding 5996 articles. After applying inclusion and exclusion criteria, 92 studies were selected for this systematic review. RESULTS: The IRs have unique molecular features, pattern of distribution, and mechanism of action. It has effects on neuronal function, metabolism, and neurotransmission. The IRs are involved in neuronal apoptosis and neurodegenerative processes. CONCLUSION: In this systematic review, we present a close relationship between insulin and the brain, with discernible effects on memory, learning abilities, and motor functions. The potential therapeutic effects extend from acute brain insults such as traumatic brain injury, brain ischemia, and hemorrhage, to chronic neurodegenerative diseases such as Alzheimer and Parkinson disease. An understanding of the wider effects of insulin conveyed in this review will prompt anaesthesiologists and critical care physicians to consider its therapeutic potential and guide future studies.

Coping strategies and risk of cardiovascular disease incidence and mortality: the Japan Public Health Center-based prospective Study.

AIMS: Coping strategies may be significantly associated with health outcomes. This is the first study to investigate the association between baseline coping strategies and cardiovascular disease (CVD) incidence and mortality in a general population cohort. METHODS AND RESULTS: The Japan Public Health Center-based prospective Study asked questions on coping in its third follow-up survey (2000-04). Analyses on CVD incidence and mortality included 57 017 subjects aged 50-79 without a history of CVD and who provided complete answers on approach- and avoidance-oriented coping behaviours and strategies. Cox regression models, adjusted for confounders, were used to determine hazard ratios (HRs) according to coping style. Mean follow-up time was 7.9 years for incidence and 8.0 years for mortality.The premorbid use of an approach-oriented coping strategy was inversely associated with incidence of stroke (HR = 0.85; 95% CI, 0.73-1.00) and CVD mortality (HR = 0.74; 95% CI, 0.55-0.99). Stroke subtype analyses revealed an inverse association between the approach-oriented coping strategy and incidence of ischaemic stroke (HR = 0.79; 95% CI, 0.64-0.98) and a positive association between the combined coping strategy and incidence of intra-parenchymal haemorrhage (HR = 2.03; 95% CI, 1.01-4.10). Utilizing an avoidance coping strategy was associated with increased mortality from ischaemic heart disease (IHD) only in hypertensive individuals (HR = 3.46; 95% CI, 1.07-11.18). The coping behaviours fantasizing and positive reappraisal were associated with increased risk of CVD incidence (HR = 1.24; 95% CI, 1.03-1.50) and reduced risk of IHD mortality (HR = 0.63; 95% CI, 0.40-0.99), respectively. CONCLUSION: An approach-oriented coping strategy, i.e. proactively dealing with sources of stress, may be associated with significantly reduced stroke incidence and CVD mortality in a Japanese population-based cohort.

Post-traumatic stress disorder in international surgeons undertaking trauma electives in a South African trauma centre.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a well-documented psychiatric outcome in patients who experience physical trauma. The phenomenon is less studied in the staff involved in caring for such patients. The aim was to investigate the prevalence of PTSD in visiting international surgeons undergoing elective trauma training and to compare to local and international rates. METHODS: A trauma screening questionnaire (TSQ) survey was conducted among surgeons completing their elective trauma service placements in the Pietermaritzburg Metropolitan Trauma Service. RESULTS: Nineteen surveys were completed (32% response rate). Mean age was 38.9 (SD 6.5). Median postgraduate working experience was 5 (2-10) years. Median time of stay in South Africa was 6 (1-72) months. Compared to preelective experience, there was a five-fold increase in the level of trauma resuscitation experience reported during elective placement. 10.5% of surgeons scored > 5 in the TSQ suggesting probable PTSD. No statistical differences in age, years of prior experience, prior trauma rotation, number of major resuscitations, or length of stay in South Africa were observed in those scoring positive versus negative screening in the TSQ questionnaire. CONCLUSION: Despite being exposed to increased levels of trauma related injury, we observed low rates of positive screening for PTSD in our cohort of visiting international surgeons involved in elective trauma service placements. Investigation of potential protective factors against PTSD in this South African tertiary trauma centre is warranted.

Expression of Tac antigen on activated normal human B cells.

Two-color fluorescence analysis revealed that Tac antigen, which was previously reported to be restricted to T cells, was expressed on a proportion of normal B cells activated by Staphylococcus aureus Cowan I (SAC). Immunoaffinity-purified interleukin 2 (IL-2) induced the proliferation of SAC-activated B cells, and the proliferation was completely inhibited by anti-Tac antibody, which blocked the membrane binding and action of IL-2. These results suggest that an IL-2 receptor system is directly involved in the B cell immune response.

The scourge of knife crime: trends in knife-related assault managed at a major centre in South Africa.

BACKGROUND: Knife wounds are common and represent a major burden to the South African healthcare system. This study reviews trends in spectrum, management and outcome of these injuries at a single trauma centre in KwaZulu-Natal(KZN). METHOD: The regional hybrid electronic registry (HEMR) was reviewed for the period January 2013 - December 2018, and all patients who suffered a knife-related assault were identified and reviewed. RESULTS: During the period under review, a total of 2117 patients suffered a knife-related assault. Regions injured were as follows: head 445, neck 572, face 258, chest 939, abdomen 649, pelvic/urogenital 49, upper limb 418, and lower limb 105. The median ISS was 9 (4-10). Imaging comprised 1242 chest X-rays, 315 abdominal X-rays, 162 abdominal ultrasounds/ FAST, and 929 CT scans of which 634 were CT angiograms. A total of 783 (37%) patients required an operation. The rate of laparotomy was 447/649 (69%) and of thoracotomy/sternotomy/thoracoscopy 95/939 (10%). The rate of vascular exploration for upper and lower limb vascular injury was 101/523 (19%). Mortality was 49/2117 (2.3%).. CONCLUSION: Although our clinical outcomes over this period appear to be consistent, suggesting a familiarity with managing knife-related trauma, the persistently high rate of knife-related injury suggests that we have failed to develop a preventative strategy to try and reduce this scourge.

Preparing Japanese surgeons for potential mass casualty situations will require innovative and systematic programs.

INTRODUCTION: The ongoing state of global geo-political instability means that it is prudent to prepare civilian surgeons to manage major military-type trauma. Japan has enjoyed a prolonged period of peace and consequently it is unlikely that surgeons will have been exposed to a sufficient volume of cases. This study reviews the state of trauma training and preparedness in Japan and reviews the trauma workload of a major Japanese emergency medical center and compared with a major South African trauma center with the intention of quantifying and comparing the time needed to gain adequate exposure to major trauma at the two centers. MATERIALS AND METHODS: The literature describing the surgical burden from a number of recent military missions was reviewed and the core surgical skills to manage military-type injuries were identified. We then went on to review all patients admitted to both Kurashiki Central Hospital (KCH) and Pietermaritzburg Metropolitan Trauma Service (PMTS) following trauma between the period September 2015 and August 2016. The burden of trauma at each center was quantified and the number of core surgical competencies or procedures performed at each center was then reviewed. These were then compared with the number of the core procedures which were performed on the reported military missions. RESULTS: Three reports on military surgical missions were reviewed. These came from the Dutch, French and British military surgical services. The average number of each core procedures performed on each reported military surgery mission are tabulated in the text. The most common procedures were wound debridement and orthopedic fixation, followed by trauma laparotomy, neck exploration and thoracotomy. During the 12 month study period, 309 trauma patients were admitted to KCH. Of which 206 (67%) were male, and the mean age was 57 years. There were 10 penetrating injuries and 299 blunt injuries. Of the penetrating injuries there were no gunshot wounds. The mechanisms of injury for blunt trauma were as follows: Road traffic accidents (RTAs); 141 (47%), fall; 136 (46%) and other injuries; 22 (7%). In the same period, 2887 trauma patients were admitted by the PMTS. There were 1244 cases (43%) of penetrating trauma and 1644 cases (57%) of blunt trauma in PMTS. The mechanisms of injury for penetrating trauma were as follows: stab wounds (SWs); 955 (77%), gunshot wounds (GSWs); 252 (20%), and other injuries; 37 (3%) and for blunt trauma were as follows: assault; 739 (45%), RTAs; 669 (41%), fall; 166 (10%), and other injuries; 70 (4%). The exposure to all the key competencies required to manage trauma is overwhelmingly greater in South Africa than in Japan. The length of time needed to obtain an equivalent trauma exposure to that achieved in South Africa, working in Japan is prohibitively long. CONCLUSION: Trauma training in Japan is hamstrung by a lack of clinical material as well as by systematic factors. Training a trauma surgeon is difficult. Developing a trauma system in the country may help address some of these deficits. South Africa in contrast has a huge burden of trauma and sufficient infrastructure to ensure that surgeons working there have adequate exposure to major trauma. Developing an academic exchange program between Japan and South Africa may allow for the transfer of trauma experience and skills between the two countries.

Trauma electives in South Africa provide valuable training for international surgeons.

BACKGROUND: Trauma electives in South Africa (SA) are common and many foreign-based surgeons have undertaken such electives over the past 3 decades. Despite this, little academic attention has been paid to these electives, which remain largely informal and unstructured. This project aims to redress this deficit. OBJECTIVES: To investigate and document the extent of trauma clinical electives and to assess their impact on the careers of foreign surgeons who have undertaken such electives. METHODS: A mixed methods-style questionnaire was compiled, which sought to document the demographics of surgeons undertaking an SA trauma clinical elective, the trauma clinical experience they had prior to the elective, as well as the volume of experience they acquired during the elective. RESULTS: Sixty questionnaires were sent out and 21 were completed. There were 16 male and 5 female respondents. Only 17 had undertaken a formal trauma rotation before their elective in SA. The mean number of major resuscitations managed prior to rotating through surgery departments in SA was 15, and the mean number managed during a 12-month rotation in SA was 204. It would take each respondent 14 years in their country of origin to acquire an equivalent level of exposure to major resuscitation. During the year before their elective, each surgeon had been exposed to a mean number of the following: 0.5 gunshot wounds (GSWs), 2 stab wounds (SWs), 0.1 blast injuries and 19 road traffic accidents (RTAs). The equivalent mean number for their year in SA was 106 GSWs, 153 SWs, 4 blast injuries and 123 RTAs. The time necessary to achieve a similar level of exposure to their SA experience if they had remained in their country of origin was 213 years for GSWs, 73 years for SWs, 41 years for blast injuries and 7 years for RTAs. Compared with their SA elective, it would take each respondent 3 years to insert as many central venous lines, 9 years to perform the same number of tube thoracostomies, 9 years to manage as many surgical airways, 18 years to explore as many SWs of the neck and 93 years to explore as many GSWs of the neck. Furthermore, it would take 33 years to see and perform as many laparotomies for SWs to the abdomen, 374 years to perform an equivalent number of GSWs to the abdomen and 34 years of experience to perform as many damage-control laparotomies in their countries of origin. In terms of vascular trauma, it would take 23 years to see as many vascular injuries secondary to SWs and 77 years to see an equivalent number of vascular injuries secondary to GSWs. CONCLUSIONS: A trauma clinical elective in SA provides an unparalleled exposure to almost all forms of trauma in conjunction with a well-developed academic support programme. Formalising these trauma electives might allow for the development of exchange programmes for SA trainees who wish to acquire international exposure to advanced general surgical training.

Effects of carbon dioxide absorbent cooling and temperature gradient reduction on water condensation in the anaesthesia circuit.

BACKGROUND: Large quantities of water condensation occur in the anaesthesia circuit during low-flow anaesthesia. We hypothesized that cooling of the CO2 absorbent would prevent water condensation. METHODS: To cool CO2 absorbent efficiently, we constructed a novel temperature gradient reduction (TGR) canister, which was cooled by a blower. Experiments were divided into three groups: the conventional canister group (control group, n=6), the TGR canister without cooling group (TGR group, n=6), and the TGR canister with cooling group (TGR cooling group, n=6). One kilogramme of CO2 absorbent was placed into the canister. The anaesthetic ventilator was connected to a 3 litre bag and 300 ml min(-1) of CO2 was introduced. About 500 ml min(-1) of oxygen was used as fresh gas. The anaesthetic ventilator was set at a ventilatory frequency of 12 bpm, and tidal volume was adjusted to 700 ml. RESULTS: The longevity of the CO2 absorbent was 437 (sd 7.8) min in the control group, 564 (13.8) min in the TGR group (P<0.001 vs control), and 501 (5.8) min in the TGR cooling group (P<0.001 vs control, TGR). Total water condensation in the anaesthesia circuit was 215 (9.4) mg min(-1) in the control group, 223 (9.7) mg min(-1) in the TGR group, and 47.7 (5.7) mg min(-1) in the TGR cooling group (P<0.001 vs control, TGR). CONCLUSIONS: TGR of CO2 absorbent with cooling is a useful and simple method to reduce water condensation in the anaesthesia circuit in low-flow anaesthesia, with a little increase in the longevity of the CO2 absorbent.

[Pulmonary schwannoma with hypervascularity; report of a case].

A 54-year-old female was admitted to our hospital with a mass shadow in the right pulmonary hilum. The chest computed tomography (CT) scan revealed a well-circumscribed mass in the lower lobe of the right lung. Bronchoscopic examination showed a submucosal tumor in the right basal bronchus which bled easily, and the angiogram showed a tumor with hypervascularity. The tumor was suspected to be a sclerosing hemangioma or malignant tumor. A right basal segmentectomy was performed, and the pathological diagnosis was that of schwannoma. During the 8 year follow-up period, she exhibited no evidence of recurrence.

Close association between interleukin 2 receptor mRNA expression and human T cell leukemia/lymphoma virus type I viral RNA expression in short-term cultured leukemic cells from adult T cell leukemia patients.

Human T cell leukemia/lymphoma (T-lymphotropic) virus type I (HTLV-I) infection has been considered to be closely associated with the leukemogenesis of adult T cell leukemia (ATL), in which interleukin 2 (IL-2) receptors are abnormally expressed. In this study, however, Southern blot analysis revealed no gross rearrangement or obvious amplification of the IL-2 receptor gene in ATL leukemic cells, indicating that abnormal IL-2 receptor expression in ATL is not due to the structural change of its gene. Hence, we studied the expression of the IL-2 receptor and HTLV-I at the RNA level during short-term cultures of leukemic cells from 9 ATL patients. Cytoplasmic dot hybridization and Northern hybridization revealed that fresh leukemic cells from seven of nine patients expressed a small amount of IL-2 receptor mRNA but HTLV-I RNA was undetectable in all cases. After cultures for up to 7 d, both IL-2 receptor mRNA and HTLV-I RNA (including pX message) expression concomitantly increased, whereas the amounts of other cellular genes, except for beta-actin, did not. The increases in their RNA expression were inhibited by early addition (within 12 h after the beginning of the culture) of cycloheximide, indicating that these increases are mediated by newly synthesized protein(s). These results strongly suggested that IL-2 receptor expression is closely associated with HTLV-I expression in leukemic cells from ATL patients.

Interleukin-2 receptor (Tac antigen) expressed on adult T cell leukemia cells.

We studied the expression of the interleukin-2 (IL-2) receptor and the proliferative response to exogenous IL-2 of peripheral blood leukemic cells from patients with adult T cell leukemia (ATL) in order to see whether IL-2 receptor expressed on ATL cells is different from normal IL-2 receptor and whether it plays a role in the neoplastic growth in ATL. Peripheral blood leukemic cells from 42 patients with ATL examined expressed IL-2 receptors that were detected by anti-Tac monoclonal antibody when examined immediately after the separation of cells or after the culture for 24 or 48 h. The number of anti-Tac binding sites ranged from 3,100 to 11,400 in fresh cells and from 3,600 to 96,000/cell in short-term cultured leukemic cells, whereas phytohemagglutinin-P (PHA-P)-stimulated normal T cells exhibited 6,900-35,000 anti-Tac binding sites per cell. ATL-derived and human T cell leukemia/lymphoma virus, type I (HTLV-I)-infected cell lines such as MT-1 and Hut102 expressed a much higher number of anti-Tac binding sites. Leukemic cells from 15 patients with ATL examined showed no or very poor proliferative response to various concentrations of immunoaffinity-purified IL-2, although they expressed Tac antigen (Ag). Radiolabeled IL-2 binding experiments demonstrated that ATL leukemic cells could bind IL-2, and they expressed both high and low affinity IL-2 receptors, although the number of high affinity IL-2 receptor was much less than that of low affinity IL-2 receptor and that of anti-Tac binding sites. In contrast, leukemic T cells from a patient with T cell chronic lymphocytic leukemia (CLL), in whom HTLV-I infection was not demonstrated, responded as well as PHA-P-stimulated normal T cells, and their IL-2 receptors, unlike ATL cells, were modulated (down regulated) by anti-Tac antibody. No differences were noted between ATL cells and normal activated T cells in one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis of the IL-2 receptor. Thus, leukemic cells in ATL spontaneously and continuously express IL-2 receptor, which appears to be abnormally regulated and unresponsive to IL-2. These results, taken together with those on normal IL-2 receptors on HTLV-I-negative T-CLL cells, suggest that abnormal expression of the IL-2 receptor in ATL is closely associated with HTLV-I infection and may play a role in the neoplastic growth of ATL cells.

A novel neuroprotective compound FR901459 with dual inhibition of calcineurin and cyclophilins.

Brain ischemia leads to severe damage in the form of delayed neuronal cell death. In our study, we show that the marked neuroprotection of the new immunosuppressant FR901495 in forebrain ischemia is due not only to inhibition of calcineurin, but also to protection against mitochondrial damage caused by mitochondrial permeability transition pore formation through cyclophilin D, one of the prolyl cis/trans isomerase family members. These findings shed light on the clinical application and development of new drugs for the treatment of ischemic damage in the brain as well as in the heart and liver.

Search for novel gene markers of traumatic brain injury by time differential microarray analysis.

Neuronal and glial cell death caused by axonal injury sometimes contributes to whole brain pathology after traumatic brain injury (TBI). We show that neuroprotection by 2 types of immunosuppressants, cyclosporin A (CsA) and tacrolimus (FK506), in a cryogenic brain injury model results from inhibition of calcineurin and protection from mitochondrial damage caused by formation of a mitochondrial permeability transition pore induced by cyclophilin D (CyPD), one of the prolyl cis/trans isomerase family members. We evaluated why CsA is neuroprotective by microarray analysis of gene expression in the cryogenic brain injury rat model. Analyses of expression patterns demonstrated that expression of over 14,000 genes changed between the groups with and without CsA treatment, and about 350 genes among them were extracted showing a significant difference. We learned that the differential expression of several gene targets showed specific patterns in a time-dependent manner. These results may help elucidate the mechanisms of neuronal cell death after TBI and the neuroprotective effects of CsA after TBI.

Effect of age on antipyrine metabolism in patients with gastric cancer.

The metabolism of antipyrine was studied in 19 male patients with gastric cancer. Three groups of subjects were chosen for the study: 4 patients 46--51 years of age (group 1), 8 patients 52--61 years old (group 2), and 7 patients 62--75 years old (group 3) matched for sex, smoking, alcohol intake, renal function, and liver function. The mean half-life (t 1/2) of antipyrine in group 3 (15.6 +/- 4.8 hr) was significantly longer than that in group 1 (8.1 +/- 0.9 hr, P < 0.01). Similarly, the mean metabolic clearance rate (MCR) in group 3 (246 +/- 78 ml/hr/kg) was significantly lower than that in group 1 (498 +/- 175 ml/hr/kg, P < 0.02). Significant correlations were observed between age and the t 1/2 of antipyrine (r = 0.592, P < 0.01) and between age and MCR (r = -0.499, P < 0.05). The plasma of 8 patients was tested for testosterone levels. Significant correlations were observed between plasma testosterone levels and both the t 1/2 of antipyrine (4 = -0.783, P < 0.05) and MCR (r = 0.912, P < 0.001). These observations indicate that drug-metabolizing ability might decline with age in cancer patients.

Effects of phenobarbital and endotoxin on the lethality and metabolism of 6-mercaptopurine in male BALB/c mice.

In male BALB/c mice, a combination of individually non-lethal doses of 6-mercaptopurine and endotoxin was significantly lethal. In contrast, mice treated with phenobarbital were resistant to this lethal effect. The high levels of thioinosinic acid in mice that were treated with endotoxin contrasted significantly with the levels in phenobarbital-treated mice. On the other hand, the concentration of hypoxanthine was increased by the administration of phenobarbital and decreased by the administration of endotoxin. The sleeping time and levels of pentobarbital hydroxylase found in endotoxin-treated mice were consistent with the lethality and levels of thioinosinic acid. After mice were treated with endotoxin, their sleeping time was prolonged, which agrees with the course of the stimulatory effects of 6-mercaptopurine anabolism. However, there were no significant differences in hypoxanthine-guanine phosphoribosyltransferase. Furthermore, contrary to expectation, there were significant increases in xanthine oxidase after treatment with endotoxin. Thus, the metabolism of 6-mercaptopurine might be modified by hepatic microsomal enzyme activity.

Varying probability of the development of acute nonlymphoblastic leukemia in refractory anemia patients with an excess of blasts.

The cumulative leukemia-free survival rate of refractory anemia with excess of blasts was fitted to three parametric failure time models, i.e., the usual exponential and Weibull, and exponential mixture models. Among the three, the best fit model was the exponential mixture model, which was 119 times more likely to assume that samples came from the exponential mixture distribution than to assume that those were from the usual Weibull distribution. This strongly suggests that refractory anemia with excess of blasts consists of subgroups with very high and very low probability to develop acute nonlymphoblastic leukemia. The estimated proportion of the very low probability group was about 30%. Analysis by the exponential mixture model with covariates revealed that the probability of a patient to develop acute nonlymphoblastic leukemia could be estimated by three covariates, i.e., bone marrow blast percentage; abnormal granules of granulocytes; and mononuclear large megakaryocytes. The estimated probabilities ranged from 17 to 99%, according to the model.

Factors influencing nonleukemic death in refractory anemia, refractory anemia with ring sideroblasts, and refractory anemia with excess of blasts.

The association between nonleukemic death and various features recorded at presentation in patients with refractory anemia (RA), RA with ring sideroblasts, and RA with excess of blasts was analyzed in 251 patients using the proportional hazards model. Features associated with higher nonleukemic death rates were: 1% or more metamyelocytes in peripheral blood (PB); lower 59Fe incorporation rate; 1% or more blasts in PB; lower hematocrit or hemoglobin; presence of giant platelets; 1 microgram/liter or higher serum vitamin B12 levels; higher periodic acid-Schiff positive erythroblasts; and 1% or higher promyelocytes in PB. Multivariate analysis was also performed using the following predictor variables: metamyelocytes in PB, micromegakaryocytes, hemoglobin, giant platelets, presence or absence of RA with excess of blasts, and mononuclear large megakaryocytes. Patients were divided arbitrarily into low (hazard ratio, less than 0.55), intermediate (hazard ratio, 0.55-1.5), and high (hazard ratio, greater than 1.5) risk groups. The cumulative nonleukemic death rates in the high and intermediate risk groups reached a median at 602 and 1984 days from presentation, respectively, while the rate reached a plateau level of 49.4% after 2644 days in the low risk group. The risk factors for leukemic transformation and nonleukemic death were found to be different and to need separate consideration.

Factors influencing leukemic transformation in refractory anemias with excess of blasts, with ringed sideroblasts, and without ringed sideroblasts.

The association between leukemic transformation and various features recorded at presentation in patients with refractory anemia with excess of blasts and with or without ringed sideroblasts was analyzed in 255 patients using the proportional hazard model. Features associated with higher transformation rates were: higher values of blasts in peripheral blood or bone marrow; serum haptoglobin; vitamin B12; megakaryocytes in bone marrow; morphological abnormalities in granulo- or megakaryocyte series; male sex; circulating megakaryocytes in peripheral blood; older age; and lower ringed sideroblast proportion. Multivariate analysis was also performed using the following predictor variables: presence or absence of refractory anemia with excess of blasts; sex; abnormal granules in granulocytes; age; and mononuclear large megakaryocytes. Patients were divided arbitrarily into low (hazard ratio, less than 0.45), intermediate (hazard ratio, 0.45-1.85) and high (hazard ratio, greater than 1.85) risk groups. The cumulative leukemia-free rates in the low and intermediate risk groups showed long plateau phases at 95 and 71%, respectively, while in the high risk group, the rate was 10% at 5 years. For clinical purposes, the low risk group should be considered to have nonpreleukemia and the high risk group to have preleukemia.