Graft-versus-Host disease Prophylaxis with Everolimus and Tacrolimus Is Associated with a High Incidence of Sinusoidal Obstruction Syndrome and Microangiopathy: Results of the EVTAC Trial

A calcineurin inhibitor combined with methotrexate is the standard prophylaxis for graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Everolimus, a derivative of sirolimus, seems to mediate antileukemia effects. We report on a combination of everolimus and tacrolimus in 24 patients (median age, 62 years) with either myelodysplastic syndrome (MDS; n = 17) or acute myeloid leukemia (AML; n = 7) undergoing intensive conditioning followed by HSCT from related (n = 4) or unrelated (n = 20) donors. All patients engrafted, and only 1 patient experienced grade IV mucositis. Nine patients (37%) developed acute grade II-IV GVHD, and 11 of 17 evaluable patients (64%) developed chronic extensive GVHD. Transplantation-associated microangiopathy (TMA) occurred in 7 patients (29%), with 2 cases of acute renal failure. The study was terminated prematurely because an additional 6 patients (25%) developed sinusoidal obstruction syndrome (SOS), which was fatal in 2 cases. With a median follow-up of 26 months, the 2-year overall survival rate was 47%. Although this new combination appears to be effective as a prophylactic regimen for acute GVHD, the incidence of TMA and SOS is considerably higher than seen with other regimens.     

HLA-identical sibling peripheral blood stem cell transplantation in children and adolescents.

Allogeneic peripheral blood stem cell transplantation (PBSCT) was performed in children and adolescents for the treatment of malignant (n = 49) and nonmalignant hematological disease (n = 8). Granulocyte colony-stimulating factor (G-CSF)-mobilized PBSCs were apheresed from 57 HLA-matched siblings aged 9 months to 24 years (median, 8 years) without any serious adverse, effects. No abnormalities were found in these donors for a median follow-up of 25 months (range, 6-56 months). Patients were conditioned with a TBI-containing regimen (n = 17) or a non-TBI regimen (n = 40). GVHD prophylaxis consisted of methotrexate (MTX) plus cyclosporine A (CSP) for 23 patients, CSP plus methylprednisolone (mPDN) for 22 patients, MTX only for 7 patients, CSP only for 4 patients, and MTX plus CSP plus mPDN for 1 patient. Engraftment was prompt, with a median number of days to reach an absolute neutrophil count (ANC) above 0.5 x 10(9)/L of 13 days (range, 8-23 days), with 1 graft failure. Acute GVHD (grades II-IV) occurred in 8 (16%) of 49 evaluable patients, and chronic GVHD developed in 23 (64%) of 36 evaluable patients. Notably, two thirds of chronic GVHD was extensive. The Kaplan-Meier estimate of 3-year disease-free survival was 0% for refractory disease (n = 6), 37.2% +/- 11.8% for high-risk malignancies (n = 25), 81.4% +/- 9.7% for standard-risk malignancies (n = 18), and 100% for nonmalignant disease (n = 8). The estimated 100-day nonrelapse mortality rate was 9.9% +/- 4.2%. In conclusion, allogeneic PBSCT is feasible in a pediatric population. Although the grade of acute GVHD was set low, as in Japanese BMT studies, the incidence and severity of chronic GVHD appears to be relatively high. For nonmalignant disease, the question arises of whether the higher incidence and severity of chronic GVHD is a drawback of this procedure. For high-risk malignancies, whether or not a graft-versus-leukemia effect prevents relapse needs to be clarified in future comparative studies with BMT.     

Heart transplantation. A retrospective analysis of the long-term results

Long-term results of orthotopic heart transplantation vary among different institutions. The purpose of the present study was to assess the factors, which might affect long-term survival and complications. Between November 1992 and July 2003, 112 heart transplantations (M/F=89:23) were performed. The standard technique was used in the first 57 patients and the bicaval technique in the latter 55 patients. Indications for transplantation in decreasing order of frequency were dilated cardiomyopathy (75%), ischemic cardiomyopathy (7%), and others (18%). The mean follow up duration was 51.8 +/- 31.3 months with 98 patients remaining alive. Preoperatively, all patients were either in NYHA functional class III or IV. Postoperatively, all patients showed improvement to functional class II or I, except 3 patients that remained in NYHA class III. The mean number of rejection cases within the first year was 0.6 +/- 0.8, with humoral rejection noted in 3 cases. The graft vascular disease (GVD)-free survival at 3 and 5 years was 96% and 83%, respectively. The 7-year survival after heart transplantation was 84%. There were 16 deaths, of which infection (n=4) was the most common followed by rejection (n=3), and malignancy (n=2). The present long-term results, were relatively superior to those seen in western countries. The relatively low GVD-free survival rate is thought to have contributed. The complications encountered after transplantation were mostly immunosuppressive drug related, suggesting further potentials for improvement in long-term survival.     

Can Only Partial T-Cell Depletion of the Graft before Hematopoietic Stem Cell Transplantation Mitigate Graft-versus-Host Disease While Preserving a Graft-versus-Leukemia Reaction? A Prospective Phase II Study

The study comprised 37 consecutive patients who underwent transplantation with a Campath-1H in vitro T cell-depleted granulocyte colony-stimulating factor-mobilized peripheral blood stem cell graft from an HLA-identical sibling, followed 24 hours later by an unmanipulated graft. Acute graft-versus-host disease (GVHD) was limited to grade I to II, whereas chronic graft-versus-host disease occurred in 9 patients, mostly (n = 7) with limited disease. Molecular relapses (8 chronic myeloid leukemia [CML] and 1 non-Hodgkin lymphoma) that occurred not earlier than the sixth month after transplantation were treated with donor lymphocyte infusion (DLI), which induced complete remission in all but 1 CML patient with persistent very low BCR-ABL molecular levels. With a median follow-up of 54 months (range, 29-84 months), the actuarial 5-year overall survival, disease-free survival, and transplant-related mortality are 78% (95% confidence interval [CI], 52%-88%), 78% (95% CI, 52%-86%), and 6% (95% CI, 1.5%-32%), respectively. All CML patients are alive and free of disease. The results of this prospective, nonrandomized study show that incomplete T-cell depletion in vitro with Campath-1H (in combination with DLI for molecular relapses in CML) may decrease the incidence of GVHD and transplant-related mortality with no adverse effect on disease-free survival. The described method decreases the number of T cells to an extent that severe GVHD is prevented while relapse is postponed to a time when the patient can be treated with DLI without severe side effects.     

Heart transplantation in children after mechanical circulatory support: comparison of heart transplantation with ventricular assist devices and elective heart transplantation

Heart transplantation (HTx) is an ultimate treatment for children with end-stage heart failure or inoperable congenital heart disease. The supply of hearts is inadequate; therefore, different mechanical support systems must be used as bridge to HTx in pediatric patients with postoperative low output. The use of ventricular assist devices (VADs) as bridge to HTx in children is limited because of size differences. The purpose of this study was to evaluate the overall long-term outcome of pediatric circulatory support before pediatric HTx. From 1989 through 2004, 91 pediatric patients underwent isolated HTx. Seven of them required mechanical support before transplantation. We reviewed retrospectively the course of 91 children (mean age 14.7 years) who underwent HTx. Group A consisted of elective HTx patients who were treated as outpatients before HTx, whereas group B was the VAD-HTx bridging group (n=7; mean age 12.31 +/- 2.8 years). Mean duration of VAD support was 108 +/- 98 days (minimum 1 day, maximum 258 days). Overall survival rate after HTx was 80% at 1 year without significant differences between groups. Five of seven patients survived and could be discharged after successful HTx, for a survival rate of 77%. The mean follow-up period was 16.76 +/- 10.6 months. No differences in posttransplantation long-term survival and rejection episodes occurred between patients transplanted with or without VAD. VAD therapy can keep pediatric patients with end-stage heart failure alive until successful HTx, and bridge to HTx is a safe procedure in pediatric patients. After HTx, survival rates of these children are similar to those of patients awaiting elective HTx.     

Long-term mortality in adult orthotopic heart transplant recipients

Heart transplantation is now regarded as the treatment of choice for end-stage heart failure. To improve long-term results of the heart transplantation, we analyzed causes of death relative to time after transplantation. A total of 201 consecutive patients, 154 (76.6%) males, aged ≥ 17 yr underwent heart transplantation between November 1992 and December 2008. Mean ages of recipients and donors were 42.8 ± 12.4 and 29.8 ± 9.6 yr, respectively. The bicaval anastomosis technique was used since 1999. Mean follow up duration was 6.5 ± 4.4 yr. Two patients (1%) died in-hospital due to sepsis caused by infection. Late death occurred in 39 patients (19.4%) with the most common cause being sepsis due to infection. The 1-, 5-, and 10-yr survival rates in these patients were 95.5% ± 1.5%, 86.9% ± 2.6%, and 73.5% ± 4.1%, respectively. The surgical results of heart transplantation in adults were excellent, with late mortality due primarily to infection, malignancy, and rejection. Cardiac deaths related to cardiac allograft vasculopathy were very rare.     

Survival after second hematopoietic stem cell transplantation for recurrent pediatric acute myeloid leukemia.

Recurrent acute myeloid leukemia (AML) after hematopoietic stem cell transplantation (HSCT) predicts a dismal prognosis. We sought to determine whether a second HSCT would result in long-term disease-free survival with acceptable toxicity. We evaluated the outcome of a second HSCT with a preparative regimen of cyclophosphamide and total body irradiation in pediatric patients with AML who relapsed after an initial HSCT with a busulfan and cyclophosphamide preparative regimen. Twenty-five patients aged 1.1 to 17.2 years (median, 4.1 years) with AML received a second HSCT for recurrent disease. All patients were conditioned with busulfan and cyclophosphamide for the first HSCT and with cyclophosphamide and total body irradiation for the second HSCT. Donor sources for the first HSCT were autologous (n = 11) or allogeneic (n = 14), whereas all donors for the second HSCT were allogeneic (12 matched related, 9 mismatched related, and 4 unrelated). Engraftment after the second HSCT occurred in all patients at median of 19.0 days (range, 11-32 days). The cumulative incidence of grade II to IV graft-versus-host disease was 76% after the second HSCT. Three patients died from regimen-related toxicity before day 100, 9 relapsed at a median of 5.4 months (range, 1.8-34.0 months), and 12 survived a median of 9.1 years (range, 7.0-14.4 years) after the second HSCT. The Kaplan-Meier estimates of survival at 100 days, 1 year, and 10 years were 88%, 56%, and 48%, respectively. The disease-free survival rate at 10 years was 44%. Multivariate Cox regression analysis suggested that patients who received a second HSCT in relapse had a relative risk of relapse of 7.8 (P =.02) compared with patients who underwent transplantation in remission. In addition, patients who received their second HSCT 相似文献   

Thiotepa,Busulfan, and Fludarabine Conditioning Regimen in T Cell-Replete HLA-Haploidentical Hematopoietic Stem Cell Transplantation

We report the outcomes of 51 patients who underwent unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplantation cyclophosphamide (PT-Cy) and antithymocyte globulin (ATG), from peripheral blood stem cells (PBSCs) or bone marrow, after receipt of a TBF (thiotepa, busulfan, and fludarabine) conditioning regimen. Their median age was 55 years (range, 16 to 72 years). Hematologic diagnoses included acute leukemias (n = 31), lymphoid neoplasm (n = 12), myeloproliferative neoplasm (n = 5), and myelodysplastic syndromes (n = 3). Thirty-seven patients (73%) were in complete remission. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate for all patients, associated with ATG in 39 patients (76.5%). The median time to neutrophil engraftment was 17 days (range, 12 to 34 days). The cumulative incidences of grade II-IV and grade III-IV acute GVHD were 27.5% and 14%, respectively. In patients receiving a PBSC graft and ATG prophylaxis, grade II-IV aGVHD occurred in 16% of patients. The use of ATG and a lower thiotepa dose (5 mg/kg versus 10 mg/kg) were associated with a reduced cumulative incidence of grade II-IV acute GVHD (P = .03 and .005, respectively). The 2-year cumulative incidence of chronic GVHD was 29% and was significantly reduced to 13% with the lower thiotepa dose (P = .002). After a median follow-up of 25 months (range, 12 to 62 months), the cumulative incidences of nonrelapse mortality, relapse, overall survival (OS), disease-free survival (DFS), and GVHD-free, relapse-free survival (GFRFS) were 20%, 22.5%, 67%, 58%, and 51%, respectively. Pretransplantation disease status (complete remission versus others) was the main factor associated with OS, DFS, and GFRFS. In conclusion, the TBF conditioning regimen is an appealing platform in the haplo-HSCT setting with PT-Cy in terms of engraftment rate, toxicity, and disease control. We found no benefit of a thiotepa dose of 10 mg/kg compared with a dose of 5 mg/kg. ATG reduced the risk of acute GVHD without comprising outcomes.     

Prognostic indices of survival in patients supported with temporary devices (TAH, VAD)

In an attempt to identify current indications and patient selection criteria for the use of mechanical circulatory support, we reviewed our experience in 83 patients who received a total artificial heart (TAH; n = 43), ventricular assist device (VAD) (n = 13), centrifugal pump (n = 17) or extracorporeal membrane oxigenation (ECMO) (n = 8) as a bridge to transplantation (Group I, n = 50) or for recovery from heart failure (Group II, n = 33). Comparing patients successfully transplanted (n = 20) or weaned (n = 9) who survived initial hospitalization, and those who died on mechanical support, there were no differences in preoperative renal, hepatic or pulmonary functions. Postoperative urinary output and bilirubin levels were the earliest variables affecting survival, and urinary output 24 hours after implant was discriminative in patients who survived (p less than 0.01). Age (above or below 40 years) and modality of terminal heart failure (acute versus chronic) were the most important factors affecting survival in the bridge to transplant group: 82% of young patients with acute decompensation were transplanted and 63% are long-term survivors while all patients over 40 years with chronic heart failure died on mechanical support (MS). In postcardiotomy patients, duration of cardiopulmonary by-pass (CPB) was significantly different comparing survivors with those who died in either bridge or recovery groups and all patients who had a CPB greater than 4 hours died on MS or after transplantation or weaning. In conclusion, preoperative indices indicating reversibility of multiple organ dysfunction remain to be identified.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phase II study of a moderate-intensity preparative regimen with allogeneic peripheral blood stem cell transplantation for hematologic diseases: the Texas Transplant Consortium experience.

Conventional preparative regimens for allogeneic stem cell transplantation are associated with excessive regimen-related toxicity (RRT) in some patients because of underlying comorbidities, advanced age, or prior treatment. We studied a preparative regimen designed to reduce RRT, yet allow for adequate engraftment and development of a graft-versus-malignancy effect. Thirty patients (median age, 57 years) were entered on study. Twenty-nine patientsreceived stem cells from HLA-identical siblings and 1 from a sibling mismatched for 1 antigen at the A locus. Sixteen patients had received previous stem cell transplants (6 allogeneic and 10 autologous). The preparative regimen consisted of fludarabine 30 mg/M2 per day IV on day -10 to day -5, busulfan 1 mg/kg per dose PO (n = 6) or 0.8 mg/kg per dose IV (n = 24) for 8 doses every 6 hours on day -6 to day -5, and horse-derived antithymocyte globulin 5 mg/kg per day IV (n = 12) or 15 mg/kg per day IV (n = 18) on day -4 to day -1. GVHD prophylaxis consisted of cyclosporine (CYA) 3 mg/kg BID PO starting on day -3 (n = 13) or CYA and methotrexate 15 mg/m2 IV on day +1 and 10 mg/m2 IV on day +3 and day +6 (n = 17). The median number of CD34 cells transplanted was 3.19 x 10(6)/kg. All patients demonstrated recovery of hematopoietic function. Twenty-six (89%) of 29 evaluable patients achieved greater than 90% donor cell chimerism before day 100. Three patients never achieved greater than 90% donor chimerism, and another 3 patients subsequently lost donor chimerism. All 6 of these patients had autologous reconstitution with progressive disease. RRT was minimal; 7 patients had greater than grade II nonhematologic toxicity and there were no toxic deaths attributable to the conditioning regimen. Transplantation-related mortality was 7% (95% confidence interval [CI], 6%-8%) at 3 months and 28% (95% CI, 23%-34%) at 12 months after transplantation. Non-relapse-related mortality was most often due to infection. Grade II or greater GVHD developed in 56% of evaluable patients, and all patients with disease response developed GVHD. Actuarial estimates of overall and disease-free survival at 12 months were 52% (95% CI, 43%-63%) and 30% (95% CI, 24%-37%), respectively. Although this preparative regimen allowed adequate engraftment with minimal RRT, GVHD and infectious complications caused significant morbidity and mortality. Further study to define appropriate patient populations for this regimen, while limiting GVHD and infection risks, is needed.     

Second allogeneic transplantation after failure of first autologous transplantation.

We evaluated the outcome of second allogeneic bone marrow transplantations (BMTs) in 59 patients aged 1-57 years who relapsed after initial autologous transplantation. Patients received a second transplantation for recurrent acute myeloid leukemia (AML) (n = 24), acute lymphoblastic leukemia (ALL) (n = 13), lymphoma (n = 18), multiple myeloma (n = 3), or chronic myelogenous leukemia (n = 1) from an HLA-matched related (n = 14), mismatched related (n = 25), or matched unrelated (n = 20) donor. The probabilities of nonrelapse mortality, relapse, and disease-free survival (DFS) 2 years after the second BMT were 51%, 26%, and 23%, respectively. The 2-year DFS estimates for AML, ALL, and lymphoma were 46%, 23%, and 0%. Univariate analysis demonstrated that superior DFS was associated with age < or =17 years at the time of the second transplantation, remission before the second transplantation, total-body irradiation-based preparative regimen for the second transplantation, and the diagnosis of AML. These data demonstrate that an allogeneic transplantation after a failed autologous transplantation can result in disease-free survivors, especially in the young. The outcomes after a second transplantation for patients aged >17 years and for those with lymphoma were especially grim. These data suggest that pediatric patients may be appropriate candidates for a second transplantation. In adults, however, the use of an allogeneic transplantation as salvage therapy after failure of the initial autologous transplantation is generally unsuccessful. Alternative experimental strategies, such as low-dose nonmyeloablative allogeneic minitransplantations, should be considered.     

Pediatric and Young Adult Vulvovaginal Graft-versus-Host Disease

Vulvovaginal graft-versus-host disease (GVHD) is an underdiagnosed and poorly recognized complication of hematopoietic stem cell transplantation (HSCT). Previous studies have reported findings restricted to predominantly adult populations. We report a case series of pediatric and young adult vulvovaginal GVHD, which was identified in 19 patients (median age, 11.8 years; range, 2.4 to 21.9 years) out of a total 302 female patients who underwent transplantation over an 8-year period at a pediatric HSCT center. The majority of patients had concomitant nongenital GVHD; only 1 patient had isolated vulvovaginal GVHD. The median time from bone marrow transplantation to diagnosis of vulvovaginal GVHD was 30 months (range, 2.3 to 97.5 months). A high percentage of the patients in our series were without vulvar or vaginal symptoms (n = 8; 42%), even though 17 patients (89%) presented with grade 3 disease based on current adult grading scales. Vulvar examination findings most frequently included interlabial and clitoral hood adhesions (89%), loss of architecture of the labia minora or clitoral hood (42%), and skin erosions or fissures (37%). Only 5 patients underwent a speculum exam, none of whom had vaginal GVHD. Examination findings of primary ovarian insufficiency (POI) can overlap with those of GVHD, and 6 patients (32%) in our cohort were diagnosed with POI. Only 1 patient was on systemic hormone replacement therapy at the time of vulvovaginal GVHD diagnosis. The majority of patients (n = 16) were treated with topical steroid therapy, with a median time to response of 43 days. Five patients (26%) had a complete response to therapy, and 10 patients (53%) had a partial response. This case series provides valuable insight into pediatric and young adult vulvovaginal GVHD and highlights the need for increased screening for vulvar disease in this population.     

无关供者异基因造血干细胞移植治疗骨髓增生异常综合征9例患者临床分析

目的探讨无关供者异基因造血干细胞移植(UD-HSCT)治疗骨髓增生异常综合征(MDS)的疗效和可行性。方法MDS患者9例,其中男性6例,女性3例;年龄7～46岁,中位年龄30岁。其中难治性贫血(RA)1例,难治性血细胞减少伴有多系发育异常(RCMD)2例,难治性贫血伴有原始细胞过多-2(RAEB-2)5例,MDS进展为急性髓系白血病(MDS-AML)1例。接受UD-HSCT治疗的MDS患者中外周血造血干细胞移植(PBSCT)8例,骨髓移植(BMT)1例。供受者HLA高分辨配型10/10位点相合4例、9/10位点相合4例、7/10位点相合1例。预处理方案为BU+CY+Flud+Ara-C+ATG 8例、BU+Mel+Flud+Ara-C+ATG 1例,移植物抗宿主病(GVHD)预防方案为FK506+MTX+MMF 8例、CsA+MTX+MMF 1例。结果9例患者均获得造血重建,中性粒细胞≥0.5×109/L和血小板≥20×109/L的中位时间分别为移植后15(11～20)d和23(8～32)d。6例患者发生急性GVHD(aGVHD),其中Ⅰ度4例,Ⅱ度2例,5例患者发生局限型慢性GVHD(cGVHD)。中位随访20.3(6.4～50.0)个月,1例患者移植后14个月复发死亡,其余8例患者中位随访27.9(6.4～50.0)个月,均无病存活,总体生存率(OS)及无病生存率(DFS)均为85.7%±13.2%。结论UD-HSCT治疗MDS安全有效,在无同胞全合供者时,无关供者也可以作为此类患者有效治疗选择。     

Intravenous busulfan and melphalan, tacrolimus, and short-course methotrexate followed by unmodified HLA-matched related or unrelated hematopoietic stem cell transplantation for the treatment of advanced hematologic malignancies.

Results of allogeneic hematopoietic stem cell transplantation (HCT) to treat advanced leukemia or myelodysplastic syndrome (MDS) remain poor due to excessive relapse and transplant-related mortality. To improve transplant outcome in this patient population, 43 patients (median age, 46.1 years) with high-risk or advanced lymphoid (n = 5) or myeloid malignancy (n = 38) were prospectively enrolled on a pilot trial of cytoreduction with intravenous busulfan and melphalan followed by an unmodified HLA-A, -B, and -DRbeta1-matched related (n = 18) or unrelated (n = 25) HCT. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Thirty-four patients had > or = 5% blasts at the time of HCT; 12 of these had > 20% blasts. Seventeen patients had unfavorable cytogenetics, 8 patients underwent transplantation for secondary MDS or acute myelogenous leukemia, and 4 patients had relapsed after a previous allogeneic transplantation. Although mucositis was the most significant regimen-related toxicity, requiring the addition of folinic acid rescue and failure to receive all 4 doses of methotrexate in 23 patients, the nonrelapse mortality at 30 and 100 days was low at 0% and 16%, respectively. The cumulative incidence of grade II-IV acute GVHD was 24%, and that of extensive chronic GVHD was 7%. With a minimum follow-up of 18 months, the estimated 3-year overall survival is 37% and the estimated disease-free survival (DFS) is 33%. For 18 patients with MDS (< or = RAEB-2) or high-risk myeloproliferative disorder, the estimated 3 year DFS is 61%. These data demonstrate the curative potential of this regimen in patients with high-risk myeloid malignancies.     

Survival time, causes of death, and tumor/treatment-related morbidity in 100 women with ovarian cancer

One hundred cases of ovarian cancer were studied at autopsy to determine the effect of morphologic and clinical factors on survival time, the primary cause of death, and tumor/treatment-related morbidity. The mean survival time was 19 months (0 to 174 months). Increasing neoplastic histologic grade and increasing clinical stage at diagnosis were each associated with decreased survival time. In grade I tumors, the mean survival time was 84 months; in grade II tumors, it was 18 months; and in grade III tumors, it was 12 months (P = .0008). Patients who presented in stage I or II had a better survival time (28 months) than those who presented in stage III or IV (15 months) (P = .02). The most common causes of death were disseminated carcinomatosis (48%), infection (17%), pulmonary embolus (8%), and combinations of infection and carcinomatosis (11%). In patients dying of infection, 43% had sepsis, 21% had pneumonia, and 25% had a combination of sepsis and pneumonia. Escherichia coli and Klebsiella were the most common pathogens identified postmortem. Intestinal obstruction (51%) and ureteral obstruction (28%) were the most common forms of tumor-induced morbidity. Bone marrow depression and resultant pancytopenia was the most common form of treatment-induced morbidity.     

Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Dyskeratosis Congenita

We describe outcomes after allogeneic transplantation in 34 patients with dyskeratosis congenita who underwent transplantation between 1981 and 2009. The median age at transplantation was 13 years (range, 2 to 35). Approximately 50% of transplantations were from related donors. Bone marrow was the predominant source of stem cells (24 of 34). The day-28 probability of neutrophil recovery was 73% and the day-100 platelet recovery was 72%. The day-100 probability of grade II to IV acute GVHD and the 3-year probability of chronic graft-versus-host disease were 24% and 37%, respectively. The 10-year probability of survival was 30%; 14 patients were alive at last follow-up. Ten deaths occurred within 4 months from transplantation because of graft failure (n = 6) or other transplantation-related complications; 9 of these patients had undergone transplantation from mismatched related or from unrelated donors. Another 10 deaths occurred after 4 months; 6 of them occurred more than 5 years after transplantation, and 4 of these were attributed to pulmonary failure. Transplantation regimen intensity and transplantations from mismatched related or unrelated donors were associated with early mortality. Transplantation of grafts from HLA-matched siblings with cyclophosphamide-containing nonradiation regimens was associated with early low toxicity. Late mortality was attributed mainly to pulmonary complications and likely related to the underlying disease.     

Epidemiology and Clinical Features of Myocarditis/Pericarditis before the Introduction of mRNA COVID-19 Vaccine in Korean Children: a Multicenter Study

BackgroundKorean health authority plans to vaccinate adolescents against coronavirus disease 2019 (COVID-19) starting high school seniors during the summer vacation of 2021. However, the myocarditis/pericarditis following COVID-19 vaccine has been reported recently in adolescents and young adults. This study was performed to answer the urgent questions about the basic epidemiology and clinical course of myocarditis/pericarditis in hospitalized patients prior to the introduction of COVID-19 vaccines in pediatric population.MethodsA retrospective medical record analysis including frequency, clinical characteristics, etiology and outcome of myocarditis/pericarditis was conducted in 17 years and younger patients who were hospitalized in two referral hospitals in Korea between 2010 and 2019.ResultsTotal 142 patients with myocarditis (n = 119) and/or pericarditis (n = 23) were identified. Median age was 5.4 years (interquartile range, 0.6–12.9 years; range, 11 days–17.8 years), and male was 61%. In adolescents aged 12–17 years, the male to female ratio was 3.2. Myocarditis/pericarditis occurred 0.70 per 1,000 in-patients during the study period: 0.96 (< 1 year), 0.50 (1–5 years), 0.67 (6–11 years) and 1.22 (12–17 years) per 1,000 in-patients, respectively. There was an increasing tendency for the annual frequency from 0.34 in 2010 to 1.25 per 1,000 in-patients in 2019 (P = 0.021). Among the 56 (40%) proven pathogens at admission, Mycoplasma pneumoniae (n = 11, 8%) and enterovirus (n = 10, 7%) were most common. Of the 142 patients, 99 (70%) required pediatric intensive care unit care and 10 (7%) received heart transplantation. In addition, 61 patients (61/131, 47%) without heart medication at admission needed heart medication when they were discharged. Eleven (7.7%) patients died, of which five patients were previously healthy. The median age of deceased patients was lower than the survival group (0.8 vs. 6.3 years, P = 0.014).ConclusionThe frequency of myocarditis/pericarditis was highest among male adolescent in-patients; however, the outcome was favorable in this group without any mortality.     

Results of the cord blood transplantation study (COBLT): outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with lysosomal and peroxisomal storage diseases.

The Cord Blood Transplantation Study (COBLT), sponsored by the National Heart, Lung, and Blood Institute, is a phase II multicenter study designed to evaluate the use of cord blood in allogeneic transplantation. In this report, we evaluated the outcomes of cord blood transplantation in 69 patients with lysosomal and peroxisomal storage diseases. Patients with mucopolysaccharidoses I to III, mucolipidoses (ML) II (n = 36), adrenoleukodystrophy (n = 8), metachromatic leukodystrophy (n = 6), Krabbe disease (n = 16), and Tay-Sachs disease (n = 3) were enrolled between August 1999 and June 2004. All patients received the same preparative regimen, graft-versus-host disease (GVHD) prophylaxis, and supportive care. End points included survival, engraftment, GVHD, and toxicity. Sixty-nine patients (64% men; 81% white) with a median age of 1.8 years underwent transplantation with a median cell dose of 8.7 x 10(7)/kg. One-year survival was 72% (95% confidence interval, 61%-83%). The cumulative incidence of neutrophil engraftment by day 42 was 78% (95% confidence interval, 67%-87%) at a median of 25 days. Grade II to IV acute GVHD occurred in 36% of patients. Cord blood donors are readily available for rapid transplantation. Cord blood transplantation should be considered as frontline therapy for young patients with lysosomal and peroxisomal storage diseases.     

Complete spinal cord injury treatment using autologous bone marrow cell transplantation and bone marrow stimulation with granulocyte macrophage-colony stimulating factor: Phase I/II clinical trial

To assess the safety and therapeutic efficacy of autologous human bone marrow cell (BMC) transplantation and the administration of granulocyte macrophage-colony stimulating factor (GM-CSF), a phase I/II open-label and nonrandomized study was conducted on 35 complete spinal cord injury patients. The BMCs were transplanted by injection into the surrounding area of the spinal cord injury site within 14 injury days (n = 17), between 14 days and 8 weeks (n = 6), and at more than 8 weeks (n = 12) after injury. In the control group, all patients (n = 13) were treated only with conventional decompression and fusion surgery without BMC transplantation. The patients underwent preoperative and follow-up neurological assessment using the American Spinal Injury Association Impairment Scale (AIS), electrophysiological monitoring, and magnetic resonance imaging (MRI). The mean follow-up period was 10.4 months after injury. At 4 months, the MRI analysis showed the enlargement of spinal cords and the small enhancement of the cell implantation sites, which were not any adverse lesions such as malignant transformation, hemorrhage, new cysts, or infections. Furthermore, the BMC transplantation and GM-CSF administration were not associated with any serious adverse clinical events increasing morbidities. The AIS grade increased in 30.4% of the acute and subacute treated patients (AIS A to B or C), whereas no significant improvement was observed in the chronic treatment group. Increasing neuropathic pain during the treatment and tumor formation at the site of transplantation are still remaining to be investigated. Long-term and large scale multicenter clinical study is required to determine its precise therapeutic effect. Disclosure of potential conflicts of interest is found at the end of this article.     

Clinical results of high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation in children with advanced stage rhabdomyosarcoma

Regardless of improvement in cure of Rhabdomyosarcoma (RMS), the results in treatment of advanced stage of RMS in children are still dismal. Recently, high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (HDC/APBSCT) has been tried to manage the advanced high-risk RMS patients. We investigated the effectiveness of HDC/APBSCT by reviewing the clinical records of high-risk pediatric RMS patients in single institute database. Over twenty years, 37 patients were diagnosed as RMS with high-risk at the time of first diagnosis. These patients were classified as two groups according to treatment method. The first group was HDC/APBSCT and the other was conventional multi-agent chemotherapy group. Differences of clinical results between the two groups were analyzed. The median age of patients was 5 yr, ranging from 6 months to 15 yr. The 5-yr event free survival rate (EFS) of all patients was 24.8% ± 4.8%. HDC/APBSCT group and conventional multi-agent chemotherapy group were 41.3% ± 17.8% and 16.7% ± 7.6% for 5-yr EFS, respectively (P = 0.023). There was a significant difference in the result of HDC/APBSCT between complete remission or very good partial response group and poor response group (50% ± 20.4% vs 37.5% ± 28.6%, P = 0.018). HDC/APBSCT can be a promising treatment modality in high-risk RMS patients.