Lymphocytotoxic antibodies and bone marrow grafts from HLA-identical siblings. I. HLA antibodies.

In a series of 30 bone marrow grafts (in 29 recipients) from HLA-identical siblings for aplastic anemia, no correlation was demonstrated between rejection and pregraft HLA antibodies (P greater than 0.50). However, after grafting, HLA antibodies persisted in nine cases and graft rejection occurred, whereas in all but one of the remaining eight cases the HLA antibodies disappeared and a permanent engraftment was observed (P = 0.0008). These results suggest a relationship between engraftment and persistence or disappearance of HLA antibodies as an indication of the level of immunosuppression obtained with the conditioning regimen.     

Anaesthesia and the lipidoses: a review of patients treated by bone marrow transplantation

There are many potential problems associated with anaesthesia in patients with lipid storage diseases. This review covers an 8-year period (1983–1990) during which time 13 patients presented for procedures associated with bone marrow transplantation. The case notes of 12 patients who underwent a total of 48 general anaesthetics were reviewed. Pre-operative assessment revealed cardiorespiratory disease in six patients. Eighty per cent of the children were anaemic (haemoglobin < 95 g1^-1). Anaesthesia was tolerated well although tracheal intubation in two patients with Gaucher's disease was difficult and became progressively more difficult as they became older. Forty-five per cent of patients with Gaucher's disease were intubated with a tracheal tube smaller than predicted from the age of the child. Few complications were encountered but those which may be anticipated are discussed.     

Anaesthesia and the mucopolysaccharidoses: a review of patients treated by bone marrow transplantation

The mucopolysaccharidoses present many potential difficulties to the anaesthetist. A review was undertaken of the last 10 years' experience at a paediatric hospital which has a special interest in the treatment of these conditions using bone marrow transplantation. Thirty-five patients underwent 150 general anaesthetics. There was a high incidence of airway problems and cardiorespiratory disease. Laryngoscopy and tracheal intubation was difficult in 40% of patients with Hurler's syndrome and 71% of those with Hunter's syndrome. A tracheal tube of smaller than predicted internal diameter was commonly required. Cardiorespiratory problems included both myocardial and valvular disease which could often be identified preoperatively as could kyphoscoliosis. The implications for anaesthesia are discussed.     

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.     

Changing of hepatitis B virus markers in patients with bone marrow transplantation

The hepatitis B virus (HBV) infection and its resulting hepatic abnormalities are very high in prevalence among the Taiwan population. They also seem to compose a major problem to patients subjected to bone marrow transplantation (BMT) due to intensive chemoradiotherapy. In this study, the sera of 42 patients were investigated before and after BMT to detect the presence of HBV markers and to test their liver function (LF). Being followed-up for 3-12 months after BMT, 12 out of 27 were found to have altered HBV markers according to the classification of the following: seroconversion of HBsAg, clearance of HBsAb, appearance of HBeAg, clearance of HBeAb, and acute hepatitis. Thirty-seven out of 42 patients (88.1%) were found in routine LF test to develop one or more abnormality; however, 90% of them turned normal within one year after BMT. Only one patient died of complications associated with fulminant hepatitis. In conclusion, the previous hepatic damage from HBV infection appears unlikely to increase the risk of posttransplant morbidity and mortality.     

Neurologic complications of bone marrow and stem-cell transplantation in patients with cancer

Transplantation of bone marrow or peripheral blood stem cells is increasingly being used to treat a variety of oncologic disorders. These procedures are associated with a large spectrum of neurologic complications that significantly contribute to patient morbidity and mortality. These complications may arise at any time during and after the transplantation process and are particularly common in patients requiring chronic immunosuppression. The most frequent complications are infections and cerebrovascular or metabolic events, and toxicity from radiation or chemotherapy. Because of the unique circumstances and treatments involved in each step of the transplantation process, there is a higher incidence of some neurologic complications during discrete time periods, and an awareness of the temporal relationship of the neurologic disorder to the transplantation process facilitates diagnosis. With the exception of post-transplant lymphoproliferative disorder, in which reduced immunosuppression may be an effective therapeutic strategy, therapies are often the same as in the nontransplant patient. Complications of therapy can arise because of the presence of multiple comorbidities and medication interactions. Anticipation of common opportunistic infections and appropriate use of prophylactic medications can significantly reduce the incidence of infectious complications.     

Prophylaxis of bacterial infections with ciprofloxacin in patients undergoing bone marrow transplantation

Twenty-six oncology patients, 25 of whom received bone marrow transplants, were enrolled in a prospective, randomized, double-blinded, placebo-controlled trial assessing the efficacy of ciprofloxacin, 750 mg p.o. b.i.d., for preventing bacterial infections during prolonged neutropenia. Treatment was begun within 48 hr of initiation of chemotherapy and continued until the absolute granulocyte count recovered to greater than or equal to 500/microliters, or until the onset of fever (greater than or equal to 38.3 degrees C). Seven evaluable subjects received ciprofloxacin, and 11 received placebo. Risk factors for infection were comparable in both groups. Fever occurred in all study subjects, but onset was delayed in ciprofloxacin recipients (median = 6 days after the fall of the absolute granulocyte count to less than or equal to 500/microliters vs. 3 days for placebo recipients, P = 0.01). No clinically or microbiologically documented infections occurred in ciprofloxacin recipients vs. 10 infections in placebo recipients (5 bacteremias, 4 skin/soft tissue infections, 1 urinary tract infection, P = 0.0003). Ciprofloxacin recipients required fewer days of therapeutic antimicrobials (median: 28 antibiotic-days vs. 49, P0.02). The bioavailability of ciprofloxacin appeared comparable to that found in previously published studies of normal volunteers and patients not receiving chemotherapy. Adverse effects and colonization by ciprofloxacin-resistant microorganisms were monitored, but the sample sizes were too small to permit meaningful conclusions about these safety parameters. Ciprofloxacin appears to be effective for preventing bacterial infections in neutropenic patients. Additional trials are needed to establish the optimal dose of ciprofloxacin and to compare its safety and efficacy with those of currently used prophylactic regimens.     

Importance of bone marrow cell dose in bone marrow transplantation

The importance of the size of the infused marrow cell dose (MCD) was investigated in 274 patients undergoing allogeneic BMT between 1975 and 1990. Among those, 65 had acute myelogenous leukemia (AML), 79 acute lymphoblastic leukemia (ALL), 58 chronic myelogenous leukemia (CML) and 25 severe aplastic anemia (SAA). MCD was analyzed in bivariate and multivariate analysis together with 6 other clinical factors. In multivariate analysis a low MCD was significantly associated with increased incidence of acute graft-versus-host disease (GvHD) in all patients (p = 0.005) and in ALL patients (p = 0.02) whereas in CML a high dose was instead correlated to acute GvHD. A low MCD was also correlated to an increased incidence of symptomatic cytomegalovirus (CMV) infection (p = 0.001). A low MCD was also correlated to death in acute GvHD in all patients (p = 0.01) and to a poor survival in all patients (p = 0.04) (AML, p = 0.07).     

Bronchiectasis in bone marrow transplantation

Two patients are described with clinical and radiographic bronchiectasis which occurred after allogeneic bone marrow transplantation for haematological malignancy. Both had evidence of chronic graft versus host disease in other organs. Increased immunosuppression with corticosteroids resulted in clinical response, although both patients persisted with chronic mucopurulent sputum production and one had progressive airflow obstruction. Bronchiectasis may be an under-recognised manifestation of chronic graft versus host disease of the lung.


     

Hematologic recovery in patients who are treated with autologous stem cells transplantation taken from bone marrow after granulocyte-colony-stimulating factor stimulation

Background

We sought to compare hematologic recovery between patients who did or did not receive granulocyte-colony-stimulating factor (G-CSF)-stimulated bone marrow (rich bone marrow [RBM]).

Materials and Methods

The study subjects were 20 patients whose bone marrow was taken without prior stimulation with G-CSF and 15 patients in whom bone marrow was taken after previous G-CSF mobilization. The bone marrow harvest took place on the fifth day after G-CSF initiation. The bone marrow aliquot was 20 mL/kg.

Results

The median value of nucleated cells obtained from patients without G-CSF preparation was 3.65 × 10⁸/kg. The median value of nucleated cells from RBM patients was 4.83 × 10⁸/kg. The median value of stem cells obtained from patients without G-CSF preparation was 0.96 × 10⁶/kg versus 1.9 × 10⁶/kg from RBM patients. The median time to recovery of the hematopoietic system based on an increase in PLT value >20 g/L was 12.6 days for RBM versus 18.8 days without G-CSF preparation. The median time to recovery of the hematopoietic system based on assessment of growth ANC>0.5 g/L was 13.0 days for RBM versus 17.8 days without G-CSF stimulation. Significantly higher values of nucleated cells and increased stem cells were observed among RBM patients compared with those whose bone marrow was harvested without any stimulation (P = .01). There was faster recovery of the hematopoietic system in cases where bone marrow was collected after G-CSF: PLT >20 g/L (P = .015) and ANC >0.5 g/L (P = .01). We also observed that the use of stimulated bone marrow shortened hospital stay after the administration of hematopoietic cells to 17.3 days compared with 23.1 days among patients receiving hematopoietic cells from nonstimulated bone marrow. The number of complications during transplantation was comparable in both cases, the most frequent ones being febrile neutropenia and grade III and IV mucositis.

Conclusion

RBM is a better method to obtain stem cells from bone marrow. Stimulated bone marrow shows faster engraftment compared with nonstimulated bone marrow helping patients who fail to generate are adequate number of stem cells from peripheral blood.     

Autologous bone marrow transplantation in patients with adult acute leukemia in relapse.

Nine patients with adult acute leukemia were treated in relapse with piperazinedione plus supralethal total body irradiation in conjunction with autologous marrow infusion. Bone marrow cells were collected and stored in first remission. Storage time varied from 3 to 23 months. Before storage, marrow cells were separated using density albumin gradients in order to reduce the number of leukemic cells in the graft. Three patients died before day 14 after transplantation because of complications already present at the time of transplantation. In six patients, hemopoietic recovery started to occur within 14 days after transplantation. In four patients leukemia-free periods were obtained, lasting 60+ days. The three patients with the longest leukemia-free period after transplantation (range 75 to 220+ days) are reported in more detail. One patient is still alive without evidence of leukemia, with full hematological recovery 220+ days after transplantation.     

Bone marrow transplantation using unrelated donors for patients with advanced leukemia or bone marrow failure

Thirty-four patients received bone marrow transplants from unrelated donors. Donors and recipients were phenotypically matched for 6 of 6 HLA-A, B, and DR antigens in 27 cases and at 5 of 6 antigens in 7 cases. Twenty-three patients had leukemia, six had myelodysplasia, and five had aplastic anemia. Twenty-four patients had durable engraftment. Five died of sepsis prior to engraftment. Five patients failed to engraft; 2 of these patients had autologous bone marrow recovery. Seventeen patients developed grade greater than or equal to II acute graft-versus-host disease for an actuarial probability of 67 +/- 20%. The severity of acute graft-versus-host disease and its mortality appeared increased for recipients matched for 5 of 6 HLA-A, B, and DR antigens. Of the 34 patients, 13 (38%) are alive; actuarial survival beyond 6 months is 44 +/- 17%. None of the 25 leukemia and myelodysplasia patients achieving engraftment have relapsed. For leukemia and myelodysplasia recipients of 6 of 6 HLA-matched grafts, actuarial survival at 6 months was 55 +/- 21% compared with 14 +/- 26% for recipients matched for 5 of 6 HLA loci (P = 0.19). Infection and acute graft-versus-host disease were the primary causes of death in the engrafted patients. Survival for aplastic anemia patients was 20%. Late deaths due to pneumonia and bronchiolitis obliterans occurred after one year in 2 patients. Closely matched unrelated donor bone marrow transplants are associated with a higher incidence of graft failure and graft-versus-host disease than typically reported for transplants from HLA-identical siblings, but these preliminary data suggest a lower rate of relapse.     

Pemphigoid-like ocular lesions in patients with graft-versus-host disease following allogeneic bone marrow transplantation

We present two patients who developed keratitis sicca and pemphigoid-like symptoms following allogeneic bone marrow transplantation (BMT). The diagnosis of ocular graft-versus-host disease (GvHD) was considerably delayed in both. They were admitted to the reference ophthalmology and posttransplant care departments years after allogeneic BMT, when skin biopsy revealed changes typical for chronic GvHD. In both cases either systemic or local immunosuppressive treatment led to improvement of the clinical condition but did not significantly change patients' quality of life.     

Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury

Stem cell transplants into spinal cord lesions may help to improve regeneration and spinal cord function. Clinical studies are necessary for transferring preclinical findings from animal experiments to humans. We investigated the transplantation of unmanipulated autologous bone marrow in patients with transversal spinal cord injury (SCI) with respect to safety, therapeutic time window, implantation strategy, method of administration, and functional improvement. We report data from 20 patients with complete SCI who received transplants 10 to 467 days postinjury. The follow-up examinations were done at 3, 6, and 12 months after implantation by two independent neurologists using standard neurological classification of SCI, including the ASIA protocol, the Frankel score, the recording of motor and somatosensory evoked potentials, and MRI evaluation of lesion size. We compared intra-arterial (via catheterization of a. vertebralis) versus intravenous administration of all mononuclear cells in groups of acute (10-30 days post-SCI, n=7) and chronic patients (2-17 months postinjury, n=13). Improvement in motor and/or sensory functions was observed within 3 months in 5 of 6 patients with intra-arterial application, in 5 of 7 acute, and in 1 of 13 chronic patients. Our case study shows that the implantation of autologous bone marrow cells appears to be safe, as there have been no complications following implantation to date (11 patients followed up for more than 2 years), but longer follow-ups are required to determine that implantation is definitively safe. Also, we cannot yet confirm that the observed beneficial effects were due to the cell therapy. However, the outcomes following transplantation in acute patients, and in one chronic patient who was in stable condition for several months prior to cell implantation, are promising. It is evident that transplantation within a therapeutic window of 3-4 weeks following injury will play an important role in any type of stem cell SCI treatment. Trials involving a larger population of patients and different cell types are needed before further conclusions can be drawn.