Quantitative ultrasound detects bone impairment after bone marrow transplantation in children and adolescents affected by hematological diseases

PURPOSE: Bone marrow transplantation (BMT) recipients are at risk of bone mass impairment and skeletal morbidity. We investigated bone status with quantitative ultrasound (QUS) technique in children and adolescents with hematological diseases before and after BMT. METHODS: Phalangeal QUS measures for amplitude-dependent speed of sound (AD-SoS) and bone transmission time (BTT) were obtained in 144 hematological patients (81M, 63F; 11.6+/-5.2 years); forty two were evaluated before BMT and 102 after allogeneic or autologous BMT. Bone parameters were expressed as Z-scores based on age-sex-matched normal controls. RESULTS: Mean BTT Z-score was reduced in subjects after BMT compared to patients before BMT (M, -0.35+/-1.04 vs. 0.70+/-1.11, P<0.001; F, -0.60+/-1.23 vs. 0.23+/-1.17, P<0.05). Females and males with hormone deficiencies showed reduced BTT Z-scores when compared with subjects without hormone defects (M, -0.52+/-1.0 vs. 0.05+/-1.17, P<0.05; F, -0.50+/-1.27 vs. -0.19+/-1.26; P=0.06). AD-SoS and BTT Z-scores were reduced in 15 subjects with fractures and/or avascular osteonecrosis compared to patients without bone events (-1.52+/-1.7 vs. -0.41+/-1.32 and -0.85+/-1.19 vs. -0.10+/-1.18; both Ps<0.05). Bone event cumulative incidence was 4 times greater in subjects who suffered from chronic GVHD. CONCLUSIONS: Assessment of phalangeal QUS in young BMT survivors points towards impairment of bone status and endocrine dysfunction and chronic GVHD as risk factors of adverse bone events.     

Similar outcome after unrelated allogeneic peripheral blood stem cell transplantation compared with bone marrow in children and adolescents

This study compares children and adolescents with hematological malignancies undergoing allogeneic stem cell transplantation (ASCT) with unrelated donors receiving either bone marrow (BM, n=39) or peripheral blood stem cells (PBSCs, n=35). Age and other characteristics were comparable in the two groups. All patients were given conventional conditioning and antithymocyte globulin (ATG). Graft-versus-host disease prophylaxis consisted of cyclosporine plus methotrexate or prednisolone. After PBSC, engraftment of neutrophils and platelets were more rapid. The incidences of acute and chronic graft-versus-host disease were similar in the two groups. In the two groups, other outcome variables, such as transplant-related mortality, overall survival, and relapse-free survival, were the same. Patients given BM tended to have more relapses (P=0.1) and patients given PBSC tended to have more incidences of infectious death. Four cases of EBV-lymphomas were found among patients receiving PBSC, whereas no case was seen in patients given BM (P=0.1). We found no differences in transplant-related mortality and survival in children and adolescents receiving BM or PBSC from unrelated donors. More rapid engraftment and a trend for less relapses in patients given PBSC grafts was noted.     

Musculoskeletal manifestations of Hurler syndrome: long-term follow-up after bone marrow transplantation

Bone marrow transplantation (BMT) is effective in ameliorating many of the clinical manifestations of Hurler syndrome. However, long-term data on the natural history of the musculoskeletal disorders of Hurler syndrome after BMT are limited. The authors report the orthopaedic outcomes in seven patients with Hurler syndrome who were successfully engrafted between 1990 and 1999, and have been followed for a mean of 7.6 years since transplantation. Medical records, clinical examinations, and imaging studies were reviewed to assess the development and management of hip dysplasia, genu valgum, spine abnormalities, hand abnormalities, and joint range of motion. BMT does not appear to alter the natural history of the musculoskeletal disorders in Hurler syndrome, although there may be a beneficial effect on upper extremity joint mobility.     

Gastric contents in pediatric patients following bone marrow transplantation

Background: Graft versus host disease (GVHD) of the gut is thought to delay gastric emptying and so may increase the risk of aspirating retained contents while under anesthesia. Knowing that gastric emptying is delayed in patients with GVHD might lead one to choose to intubate the trachea for all patients with suspected GVHD, who present for diagnostic esophagogastricduodenoscopy (EGD). We are not aware of published data that gives specific guidance as to the need for intubation in the pediatric bone marrow or stem cell transplantation (BMT) population. This review was intended to evaluate the gastric contents (pH and volume) in this group of patients, to provide anesthesiologists with data that would inform their decisions about airway management for these patients. Methods: Retrospective chart review of patients ≤19 years of age undergoing EGD between 2004 and 2006. Gastric content volume and pH were measured in addition to underlying disease state and treatment. We compared BMT patients with suspected GVHD to nontransplant patients with other underlying gastrointestinal conditions. Results: Data were obtained for 77 patients post‐BMT undergoing EGD, including 40 patients whose biopsies and endoscopic findings were positive for GVHD, and 37 patients with no demonstrable GVHD. Records of 144 non‐BMT patients undergoing EGD within the same study period were also reviewed. Conclusion: Patients in the BMT group overall did not have higher volumes when compared to non‐BMT patients. A secondary comparison of BMT patients who were found to have GVHD vs BMT patients without GVHD suggests that gastric content volume may be elevated with GVHD. Patients in the BMT group had statistically significantly higher gastric pH than patients in the non‐BMT group. It is possible that the higher gastric volume in the GVHD‐positive group could put them at slightly higher risk for aspiration, but the severity of any pneumonitis, should aspiration occur, might be mitigated, by the tendency toward a higher gastric pH in the BMT patients.     

腹部器官联合移植患者长期存活的临床观察

目的总结腹部器官联合移植患者长期存活的临床经验。方法我院从2001年10月至2005年1月共施行19例腹部器官联合移植术,其中胰肾联合移植6例,肝肾联合移植12例,肝胰十二指肠联合移植1例,术后随访10个月～3年8个月,分析总结腹部器官联合移植患者的原发疾病种类,长期存活的影响因素和器官联合移植的免疫学特点。结果19例患者手术均获成功,18例获随访,16例至今存活,2例肝肾联合移植患者死亡,其中1例术后1年6个月死于心肌梗死,1例术后1年1个月死于肺部巨细胞病毒感染。1例肝肾联合移植和2例胰肾联合移植患者各发生1次急性排斥反应,2例肝肾联合移植患者发生他克莫司中毒。18例患者中存活3年以上者4例,2年以上者7例,1年以上者6例,10个月以上者1例。结论腹部器官联合移植是治疗腹部两个器官衰竭的有效办法,影响患者术后长期存活的因素包括选择合适的受者,优质的供体器官,避免外科并发症,术前心肌梗死病史,免疫抑制方案和术后远期病毒感染等。腹部器官联合移植有不同于单器官移植的免疫学特点。     

Osteoporosis after solid organ and bone marrow transplantation

Organ transplantation has become increasingly common as a therapy for end-stage renal, liver, cardiac and pulmonary disease. The population of patients who have survived organ transplantation has grown dramatically over the last 2 decades. Although organ transplant recipients now benefit from greatly improved survival, long-term complications of organ transplantation, such as osteoporosis, adversely affect quality of life and must be addressed. In the early post-transplantation period, the effects of high dose glucocorticoids, combined with other immunosuppressive drugs such as cycosporine A and tacrolimus, cause rapid bone loss particularly at the spine and proximal femur. In this setting, fracture incidence rates as high as 25-65% have been reported. Treatment and prevention strategies must target this early post-transplant period, as well as the patient awaiting transplantation and the long-term transplant recipient. This review will discuss the clinical features of transplantation osteoporosis, the pathophysiology of post-transplantation bone loss and prevention and therapy of this unique bone disease.     

Calcineurin-inhibitor-induced pain syndrome after bone marrow transplantation

Calcineurin-inhibitor-induced pain syndrome (CIPS), a rare complication seen in patients with organ transplants, is associated with the use of calcineurin inhibitors (CIs) such as cyclosporine (CSP) and tacrolimus (FK). Patients with this syndrome usually present with severe leg pain. This case report demonstrates the successful pain control of this pain syndrome in a 42-year-old female patient who had been given CIs (FK and CSP) as an immunosuppressive agent after a bone marrow transplant. Twenty-one days after the transplantation, she complained of severe pain in her bilateral lower extremities; this lasted several weeks, and was resistant to ordinary analgesics such as intramuscular pentazocine, intravenous morphine, and even oral nifedipine, which is generally accepted as an effective analgesic agent for the pain in this syndrome. Due to the presence of allodynia, our patient’s pain had neuropathic pain-like characteristics, unlike the pain in previously reported patients with other organ transplants. Her pain was successfully relieved by the administration of oral amytriptyline, clonazepam, oxycodone, and intravenous lidocaine, all of which ordinarily have an analgesic effect on neuropathic pain. CIPS in patients with hematopoietic stem cell transplants treated with FK may have a mechanism by which neuropathic pain may develop that is different from that in patients with other organ transplants.     

Infections after bone marrow transplantation using cyclosporine

The incidence of infection in 86 consecutive patients having bone marrow transplantation for acute or chronic myeloid leukemia, in a protocol in which cyclosporine was the main immunosuppressant, was low. Severe bacterial infections were infrequent and mostly caused by gram-positive cocci but early bacterial infection was often associated with severe graft-versus-host disease. Fungal infections were prevented by nystatin and amphotericin thus avoiding the difficult combination of cyclosporine and ketaconazole. Viral infections were no more common than in other series but, in patients with mismatched grafts, they tended to be associated with neurological complications clinically diagnosed as encephalitis.     

Diagnostic open-lung biopsy after bone marrow transplantation

The development of pulmonary infiltrates is an ominous sign in the immunocompromised host (ICH). Selection of the best diagnostic and therapeutic approach is often difficult, and in part depends on the risk-to-benefit ratio of various diagnostic modalities, such as bronchoscopy, bronchioalveolar lavage, percutaneous needle biopsy, and open-lung biopsy (OLB). We reviewed our experience with OLB and bronchoscopy in a predominantly pediatric bone marrow transplantation population, and attempted to assess the frequency with which OLB results directed a therapeutic change, as well as the clinical results of any such therapeutic alteration. A retrospective chart review was conducted of 87 bone marrow transplantation recipients undergoing diagnostic OLB from 1975 to 1986. Bronchoscopic and OLB cultures, histopathologic studies, serological data, and autopsy results were all carefully examined. An assessment of therapeutic alteration as a result of OLB was made, and clinical changes attributable to an OLB-directed therapeutic alteration were sought. Ninety-four OLBs and 37 bronchoscopic examinations were performed in 87 patients. All patients had undergone bone marrow transplantation, most often for leukemia (58/87) or aplastic anemia (13/87). The mean interval from bone marrow transplantation to OLB was 106 days. There were no intraoperative complications, but minor postoperative surgical complications were frequent (incidence, 21%). Postoperative mortality, defined as a death occurring within 30 days of surgery, was 45% (39/87). Seventy-four percent of the patients (64/87) died during the course of the study, at a mean of 43 days after OLB. Most OLBs (60%) yielded a specific diagnosis, defined as the establishment of a precise cause for the infiltrate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diffuse proliferative glomerulonephritis after bone marrow transplantation

A 15-year-old boy developed nephrotic syndrome and acute renal failure 4 years after allogenic bone marrow transplantation (BMT) for lymphoid crisis of chronic myelocytic leukemia. On admission, he presented with clinical features of chronic GVHD including transient exacerbation of cholestatic liver injury. Renal biopsy showed diffuse proliferative glomerulonephritis with cellular crescents. The patient was treated with methylprednisolone pulse therapy (1 g/day, for 3 days) followed by oral prednisolone. Renal function gradually improved but nephrotic state was persistent. A second renal biopsy showed improvement of acute tubular necrosis and endocapillary proliferation and transformation of crescents into a fibrous form. After tapering of oral prednisolone, cyclophosphamide was started, which resulted in a gradual improvement of proteinuria. Several cases of nephrotic syndrome occurring after BMT have already been reported, but most cases had membranous nephropathy. In our case, renal biopsy revealed diffuse proliferative glomerulonephritis with findings of active cellular immunity, and aggressive treatment resulted in attenuation of these findings. Moreover, chronic GVHD-related liver injury was noted at the time of this episode. Our findings suggest that chronic GVHD may be complicated with diffuse proliferative glomerulonephritis through unknown cellular immune mechanism.     

Management of cholelithiasis in pediatric patients who undergo bone marrow transplantation

PURPOSE: The aim of this study was to determine the incidence, risk factors, and proper management for asymptomatic cholelithiasis in children undergoing bone marrow transplantation (BMT). METHODS: The authors reviewed retrospectively the records of 575 children who underwent bone marrow transplantation at a University bone marrow transplantation unit (BMT) unit between February 1991 and October 1999. Of these patients, 235 underwent abdominal ultrasonography for evaluation of jaundice, sepsis, abdominal pain, or metastasis. To identify risk factors for cholelithiasis, the authors stratified the patients based on their disease and treatment regimen. Finally, the authors analyzed the natural history and management of BMT children with cholelithiasis. RESULTS: The authors identified 20 cases of cholelithiasis (8.5%) in the 235 BMT patients who underwent ultrasonography. Children who underwent BMT to treat bone marrow failure showed a significantly increased risk of cholelithiasis compared with children treated for malignancy (27% v 7.4%; P<.01). Most children (85%) with gallstones did not require surgical intervention. Specifically, 9 (45%) died from their primary disease, 5 (25%) showed sonographic resolution of their gallstones, and 3 (15%) underwent follow-up nonoperatively with persistent cholelithiasis. Three of the 20 patients with gallstones (15%) had signs of acute cholecystitis and underwent surgery. There were no surgical complications or deaths in the operative group. CONCLUSIONS: Cholelithiasis occurs at a high incidence in pediatric bone marrow transplant patients. Children undergoing BMT for bone marrow failure are at higher risk of having gallstones than those being treated for malignancy. Finally, these data support a strategy of nonoperative management for asymptomatic cholelithiasis in this highly selected group of patients.     

Bladder dysfunction in children and adolescents after renal transplantation

The underlying mechanisms of urinary-tract infections (UTI) in renal transplant recipients are still not fully understood. In otherwise healthy children, bladder dysfunction increases the susceptibility to UTI. The aim of this study was to evaluate lower-urinary-tract function in children and adolescents after renal transplantation. Sixty-eight recipients of renal transplants, 5–20 years of age and 1–15 years after transplantation, were evaluated for their bladder function with a questionnaire, uroflowmetry and bladder ultrasound, and for renal function (glomerular filtration rate) by measuring clearance of inulin or iohexol. Forty-nine patients (72%) had some type of abnormality of bladder function. Abnormal bladder capacity was found in 26%, abnormal urinary flow in 50% and residual urine in 32% of the patients. There was no significant difference in bladder or renal function in children with urinary-tract malformations compared with those with normal urinary tract. Furthermore, there was no significant difference in renal function in patients with bladder dysfunction compared with those without. The incidence of bladder dysfunction is high in children and adolescents after renal transplantation, but the clinical significance of this finding and whether there is a correlation between bladder dysfunction and UTI in these patients need to be clarified further.     

Hyperparathyroidism and long-term bone loss after renal transplantation

BACKGROUND: While early bone loss after renal transplantation (RT) is well described, factors affecting the long-term fate of bone have received less attention. METHODS: Whole body (WB), lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD) was measured using dual energy X-ray absorptionometry in 126 stable RT patients and repeated in 114 survivors after 3 yr. Percentage change per year (%/yr) was correlated to clinical and biochemical markers of bone metabolism. RESULTS: Low bone mass was a marker of increased mortality (FN < 80% normal 6.3%/yr; >80% 2.2%/yr). Percent change was WB -0.7 +/- 1.5 (p < 0.01); LS -0.3 +/- 2.6; FN -1.0 +/- 3.0 (p < 0.01) and, corrected for expected loss for age and sex: WB -0.5 (p < 0.01); LS 0.0; FN -0.8 (p < 0.05). Factors associated with increased loss rates were (LS%): short RT duration [<2 yr: -3.1 (p < 0.01)], high prednisone dose [>9 mg/d: -1.9 (p < 0.01)], high cyclosporine trough concentration [>175 ng/L: -1.9 (p < 0.05)], high hyperparathyroidism (PTH) [>150 ng/L: -1.5 (p < 0.05)], high alkaline phosphatase [>275 U/L: -1.6 (p < 0.05)], high osteocalcin [>75 microg/L: -1.6 (p < 0.05)]. Marginal detrimental effects of uremia, hypoalbuminemia and hyperphosphatemia were noted. Thiazide treatment seemed to protect against, and furosemide to exacerbate, bone loss, but this may have been related to associated uremia. Patients treated with vitamin D gained bone, while untreated patients with low initial 1,25-dihydroxyvitamin D lost bone [FN%-2.1 (p < 0.05)]. The prevalence of PTH (52%) and hypercalcemia (22%) remained unchanged. There was no effect of sex hormone levels, calcium and phosphate excretion, or serum calcium. CONCLUSION: While LS BMD stabilizes after RT, there is a continuing loss of WB and FN BMD. The major causes of bone loss are steroid therapy and continuing PTH, with no tendency towards spontaneous resolution. Increased vitamin D and calcium therapy should be considered for this patient group, and more aggressive therapy, e.g. parathyroidectomy given for patients with resistant PTH of >150 ng/L.     

Lung transplantation for bronchiolitis obliterans after allogenic bone marrow transplantation

Introduction

Bronchiolitis obliterans (BO) occurring after allogeneic bone marrow transplant (ABMT) may be an expression of lung damage of multifactorial origins. At present, it is not a usual condition for lung transplant (LT), accounting for <1% of all indications in the international registry. We sought, to describe the clinical features and outcomes of patients undergoing LT for BO after ABMT in our group.

Patients and Methods

We undertook a cross-sectional study of patients with an indication for LT due to BO after ABMT from the beginning of our program. We recorded the type of transplant, patient age, clinical course, functional outcome, and survival.

Results

Among 313 LT, 13 cases (4.2%) were due to BO, including 3 after ABMT (0.96%). ABMT was indicated after bone marrow aplasia in 2 cases and acute myeloid leukemia in the other patient. The patients were 2 men (both 35 years old) and 1 woman, aged 25 years. All subjects received double elective LT at 24, 20, and 9 years post ABMT. At the time of LT, all displayed severe obstructive ventilatory defects with a forced expiratory volume in 1 second (FEV₁) <30% and partial respiratory insufficiency. The initial immunosuppression was cyclosporine, mycophenolate mofetil, and steroids in all cases. Two of the subjects required changes in the immunosuppressive regimen: 1 due to chronic graft rejection with subsequent functional recovery and the other due to hematologic and neurologic toxicity. After 96, 37, and 9 months, all the patients were alive with baseline dyspnea of functional class 0 and a FEV₁ of about 68%.

Conclusion

LT is an effective therapy in terms of lung function and survival for patients with respiratory failure secondary to the development of BO after ABMT.     

Adult bone marrow transplantation after stroke in adult rats

We transplanted adult whole bone marrow prelabeled with bromodeoxyuridine (BrdU) into the ischemic boundary zone of the adult rat brain at 1 day after 2 h of middle cerebral artery occlusion (MCAo). Approximately 3.3% of 10(6) transplanted bone marrow cells were BrdU reactive at 14 days after MCAo. BrdU-reactive cells expressed neuronal and astrocytic proteins, neuronal nuclei protein (NeuN, 1%), and glial fibrillary acidic protein (GFAP, 5%) immunoreactivities, respectively. In addition, bone marrow transplantation promoted proliferation of ependymal and subependymal cells, identified by nestin (a neuroepithelial stem cell marker), within the ventricular zone and subventricular zone (VZ/SVZ). These data suggest that intracerebral transplantation of bone marrow could potentially be used to induce plasticity in ischemic brain.