Patients Receiving Bone Marrow Transplants Research Articles

Impact of HLA-mismatched unrelated transplantation in patients with adult T-cell leukemia/lymphoma.

This Japanese nationwide retrospective study investigated the impact of HLA-mismatched unrelated transplantation for adult T-cell leukemia-lymphoma (ATL) patients who received transplantation between 2000 and 2018. We compared 6/6 antigen-matched related donor (MRD), 8/8 allele-matched unrelated donor (8/8MUD), and 1 allele-mismatched unrelated donor (7/8MMUD) in the graft-versus-host direction. We included 1191 patients; 449 (37.7%) were in the MRD group, 466 (39.1%) in the 8/8MUD group, and 276 (23.7%) in the 7/8MMUD group. In the 7/8MMUD group, 97.5% of patients received bone marrow transplantation, and no patients received post-transplant cyclophosphamide. The cumulative incidences of non-relapse mortality (NRM) and relapse at 4 years, and the probabilities of overall survival at 4 years in the MRD group were 24.7%, 44.4%, 37.5%, in the 8/8MUD group were 27.2%, 38.2%, and 37.9%, and in the 7/8MMUD group were 34.0%, 34.4%, and 35.3%, respectively. The 7/8MMUD group had a higher risk of NRM (hazard ratio (HR) 1.50 [95% CI, 1.13-1.98; P = 0.005]) and a lower risk of relapse (HR 0.68 [95% CI, 0.53-0.87; P = 0.003]) than the MRD group. The donor type was not a significant risk factor for overall mortality. These data suggest that 7/8MMUD is an acceptable alternative donor when an HLA-matched donor is unavailable.

Effect of the COVID-19 pandemic on allogeneic stem cell transplantation in Japan.

The coronavirus disease 2019 (COVID-19) pandemic affected healthcare quality and access worldwide and may also have negatively affected the frequency and outcomes of allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the effect of the pandemic on allogeneic HSCT in Japan. Our subjects were patients who received allogeneic HSCT during January 2018-December 2020 in Japan. We assessed differences in yearly number of allogeneic HSCTs and 1-year outcomes in 2020 versus both 2019 and 2018. The total number of patients who received allogeneic HSCT increased from 3621 patients in 2018 and 3708 patients in 2019 to 3865 patients in 2020. Some following changes in allogeneic HSCT methods were observed: patients were older, fewer patients received bone marrow transplantation, fewer patients received transplants from unrelated donors, fewer patients received transplants from matched donors, more patients received reduced-intensity conditioning, and fewer patients received anti-thymocyte globulin in 2020 compared with previous years. HSCT outcomes were not affected, as 1-year overall survival was not significantly different (65.8% in 2020, vs. 66.5% in 2019 and 66.4% in 2018). Our results suggest that we can maintain transplant care during the pandemic by controlling the spread of COVID-19 and modifying HSCT methods.

Serum proteomics screening intercellular adhesion molecule-2 improves intermediate-risk stratification in acute myeloid leukemia.

The clinical risk classification of acute myelocytic leukemia (AML) is largely based on cytogenetic and molecular genetic detection. However, the optimal treatment for intermediate-risk AML patients remains uncertain. Further refinement and improvement of prognostic stratification are therefore necessary. The aim of this study was to identify serum protein biomarkers to refine risk stratification in AML patients. This study is a retrospective study. Label-free proteomics was used to identify the differential abundance of serum proteins in AML patients. Transcriptomic data were combined to identify key altered markers that could indicate the risk rank of AML patients. The survival status was assessed by Kaplan-Meier and multivariate Cox regression analyses. We delineated serum protein expression in a population of AML patients. Many biological processes were influenced by the identified differentially expressed proteins. Association analysis of transcriptome data showed that intercellular adhesion molecule-2 (ICAM2) had a higher survival prediction value in the intermediate-risk AML group. ICAM2 was detrimental for intermediate-risk AML, regardless of whether patients received bone marrow transplantation. ICAM2 well distinguishes the intermediate group of patients, whose probability of survival is comparable to that of patients with the ELN-2017 according to the reference classification. In addition, newly established stratified clinical features were associated with leukemia stem cell scores. The inclusion of ICAM2 expression into the AML risk classification according to ELN-2017 was a good way to transfer patients from three to two groups. Thus, providing more information for clinical decision-making to improve intermediate-risk stratification in AML patients.

Frequency of Infectious Agents After Bone Marrow Transplantation in Various Regions of Iran (2001 - 2017): A Systematic Review

Context: Infections are a major cause of disease and mortality in transplant recipients. Despite the studies conducted in Iran, no comprehensive and general research is available in this area. The present study aimed to determine the frequency of infectious agents in patients after bone marrow transplantation in Iran. Method: In this systematic review, relevant studies were selected based on type and objective, and data were collected from the articles published in Iran regarding the frequency of infectious agents after bone marrow transplantation in different regions of Iran. The studies were collected using systematic search methods. Results: In total, 11 studies were identified regarding infectious agents after bone marrow transplantation. Six studies were conducted in Tehran, three studies were performed in Shiraz, and Mashhad and Semnan provinces were the locations of two separate studies. Most of the case studies identified viral agents (54.5%; n = 6), followed by fungal infectious agents (27.3%; n = 3) and bacterial agents (18.2%; n = 2). Gram-positive bacteria (bacterial agents), cytomegalovirus (viral agents), and Candida and Aspergillus (fungi) had the highest frequency after bone marrow transplantation. Conclusions: According to the results, viral, fungal, and bacterial infectious agents were respectively most frequent in patients receiving bone marrow transplants. Gram-positive bacteria (bacterial agents), cytomegalovirus (viral agents), and Candida and Aspergillus (fungi) had the highest frequency after bone marrow transplantation.

Prognostic factors of pediatric hematopoietic stem cell transplantation recipients admitted to the pediatric intensive care unit.

BackgroundPediatric patients who received hematopoietic stem cell transplantation (HSCT) tend to have high morbidity and mortality. While, the prognostic factors of adult patients received bone marrow transplantation were already known, there is little known in pediatric pateints. This study aimed to identify the prognostic factor for pediatric intensive care unit (PICU) mortality of critically ill pediatric patients with HSCT.MethodsRetrospectively reviewed that the medical records of patients who received HSCT and admitted to PICU between January 2010 and December 2019. Mortality was defined a patient who expired within 28 days.ResultsA total of 131 patients were included. There were 63 boys (48.1%) and median age was 11 years (interquartile range, 4–15 years). The most common HSCT type was haploidentical (38.9%) and respiratory failure (44.3%) was the most common reason for PICU admission. Twenty-eight–day mortality was 22.1% (29/131). In comparison between survivors and non-survivors, the number of HSCTs received, sepsis, oncological pediatric risk of mortality-III (OPRISM-III), pediatric risk of mortality-III (PRISM-III), pediatric Sequential Organ Failure Assessment (pSOFA), serum lactate, B-type natriuretic peptide (BNP) and use of mechanical ventilator (MV) and vasoactive inotropics were significant predictors (P<0.05 for all variables). In multivariate logistic regression, the number of HSCTs received, use of MV, OPRISM-III, PRISM-III and pSOFA were independent risk factors of PICU mortality. Moreover, three scoring systems were significant prognostic factors of 28-day mortality.ConclusionsThe number of HSCTs received and use of MV were more accurate predictors in pediatric patients received HSCT.

Regionalization of Acute Myeloid Leukemia Treatment in a Community-Based Population: Implementation and Early Results.

Regionalization of care for acute myeloid leukemia (AML) has not been described for community-based settings. In 2015, we shifted AML induction from 21 local centers to 3 regional centers. Using time-specific inception cohorts, we assessed whether regionalization was associated with the frequency of use of induction therapy, receipt of bone marrow transplantation, 60-day mortality (treatment toxicity), and 180-day mortality (treatment effectiveness). Information for all adult patients diagnosed with AML from 2013 to 2017 was obtained from the electronic health record. Multivariable methods were used to estimate the adjusted associations of induction, bone marrow transplantation, and death in relation to year of diagnosis before and after regionalization. Of 661 patients diagnosed during 2013 to 2017, 53% were ≥ 70 years, 22% were ≥ 80 years, and 10% died within the week following diagnosis. Comparing 2017 with 2013, the proportion of patients who received induction therapy increased 2.88 times (95% confidence interval [CI] = 1.55-5.35), and the proportion of non-acute promyelocytic leukemia patients receiving bone marrow transplantation increased 2.00 times (95% CI = 0.89-4.50). Regionalization was associated with lower 180-day mortality (hazard ratio [HR] = 0.64; 95% CI = 0.44-0.92), whereas change in 60-day mortality was not statistically significant (HR = 0.67; 95%CI = 0.43-1.04). In this community-based population, many patients were of advanced age yet benefitted from AML induction therapy delivered at a regionally specialized center. These early results suggest the benefit of regionalizing subspecialty leukemia care.

Adverse Effects of Busulfan Plus Cyclophosphamide versus Busulfan Plus Fludarabine as Conditioning Regimens for Allogeneic Bone Marrow Transplantation

Background:The side effects of conditioning regimens on the success rate of allogeneic transplantation around the world have been challenging. In this study, we aimed to investigate the side effect of Bu/Cy and Bu/Flu regimens on our patients who underwent allogeneic bone marrow transplantation. Methods:We analyzed 180 patients receiving bone marrow transplantation in Taleghani Hospital, in Tehran, Iran between April 2016 and December 2019. Patients in group A received a combination of intravenous busulfan 0.8 mg/kg QID over two hours for 4 consecutive days (12.8 mg/kg in total)(Savani et al., 2006) and cyclophosphamide 60 mg/kg per day for two consecutive days. Patients in group B received busulfan the same as the first group in combination with fludarabine equal to 40 mg/m² per day. Patients were followed up at regular intervals up to two years after transplantation. Result:Various items were evaluated for patients, including cardiopulmonary function, psychological disorders, GVHD, and endocrine disorders such as hypothyroidism, fertility, or gonad dysfunction. Primary hypothyroidism developed in 13.3% and 11.1% of the Bu/Cy and Bu/Flu groups, respectively (p=0.230). None of the patients in either group experienced infertility or gonad dysfunction. In group A versus group B, pulmonary diseases were detected in 4.4% versus 6.6% of BMT recipients, respectively (p = 0.223). In both groups, mitral and tricuspid regurgitation were observed in patients (8.9% vs. 11.1%; p = 0.189). Incidence of Psychological disorders was no significant difference between the two groups. 32.2% of group A versus 34.45% of group B had skin and liver GVHD, respectively (p = 0.235). Conclusion:The therapeutic-related adverse effects of the two conditioning regimens in patients who underwent allogeneic bone marrow transplant were almost similar. To improve quality of life and overall survival among BMT patients, careful evaluation of treatment-related complications should be part of the regular follow-up of them.

Nicotinamide (vitamin B3) treatment improves response to G‐CSF in severe congenital neutropenia patients

Nicotinamide (vitamin B3) treatment improves response to G‐CSF in severe congenital neutropenia patients

Central Line Associated Blood Stream Infection Incidence and Outcomes in a Large Autologous and Allogeneic Bone Marrow Transplant Cohort

<h3>Background</h3> Patients undergoing bone marrow transplant (BMT) requiring central venous access are at high risk of central line associated blood stream infections (CLABSI) due to prolonged immunosuppression. Currently, there is limited literature directly comparing outcomes and incidences of CLABSIs in the autologous and allogeneic BMT populations. Here, we describe the incidence and outcome of CLABSIs in a large prospective cohort of allogeneic and autologous BMT patients at a quaternary adult oncology center. <h3>Methods</h3> A descriptive analysis was performed on a prospectively assembled cohort of BMT patients collected over a 30-month period between 2017 and 2019. CLABSI determination was made by infection control practitioners and physicians using standardized definitions. Outcomes, including 30-day hospitalization, ICU admission, and all-cause mortality were determined through chart reviews. Chi-square tests were used to assess statistical significance to compare simple proportions. <h3>Results</h3> Of 1278 patients in the cohort, 136 (11%) developed CLABSIs. A significantly higher proportion of allogeneic BMT patients developed CLABSI compared to the autologous BMT patients (21% and 5% of their respective populations, p<0.001). Of 136 patients, 43.4% required admission, 7.4% required ICU admission and 7.7% died within 30-days of the CLABSI onset. Although there were no significant differences between allogeneic and autologous cases in these outcomes, allogeneic cases had a significantly longer time to developing a CLABSI from transplant than autologous cases (median 53 days vs 10 days). <h3>Conclusions</h3> In this large prospective study of patients receiving bone marrow transplants, we found that allogeneic BMT patients are at higher risk for developing a CLABSI compared with autologous BMT patients. Furthermore, these infections are associated with a high degree of morbidity and mortality in both populations. Review of clinical and infection control protocols regarding central line access and maintenance are needed in order to reduce the incidence of this highly morbid complication.

Attenuation of immune‐mediated bone marrow damage in conventionally housed mice

In humans, bone marrow (BM) failure syndromes, both constitutional and acquired, predispose to myeloid malignancies. We have modeled acquired immune aplastic anemia, the paradigmatic disease of these syndromes, in the mouse by infusing lymph node cells from specific pathogen-free (SPF) CD45.1 congenic C57BL/6 (B6) donors into hybrid CByB6F1 recipients housed either in conventional (CVB) or SPF facilities. The severity of BM damage was reduced in CVB recipients; they also had reduced levels of CD44+ CD62L- effector memory T cells, reduced numbers of donor-type CD44+ T cells, and reduced expansion of donor-type CD8 T cells carrying T-cell receptor β-variable regions 07, 11, and 17. Analyses of fecal samples through 16S ribosomal RNA amplicon sequencing revealed greater gut microbial alpha diversity in CVB mice relative to that of SPF mice. Thus, the presence of a broader spectrum of gut microorganisms in CVB-housed CByB6F1 could have primed recipient animal's immune system leading to suppression of allogeneic donor T-cell activation and expansion and attenuation of host BM destruction. These results suggest the potential benefit of diverse gut microbiota in patients receiving BM transplants.

Plasma Biomarker Predicts Lethal Acute Graft Versus Host Disease and Non-Relapse Mortality in Japanese Patients

Introduction Allogeneic hematopoietic stem cell transplantation (aHSCT) is a curative treatment option for hematopoietic malignancies. In addition to relapse mortality, non-relapse mortality (NRM) such as severe graft-versus-host disease(GVHD) is a major cause of aHSCT. Pre-transplant clinical risk factors for acute GVHD include the degree of human leukocyte antigen (HLA) match between donor and recipient, recipient age, donor type, and conditioning regimen intensity. Although GVHD prophylaxis is usually decided by these risk factors, excessive immunosuppression induces opportunistic infection. Laboratory test cannot predict the risk of NRM or severe GVHD after aHSCT prior to the onset of GVHD symptoms; however, 2-biomarker (ST2 and REG3α) algorithm, namely MAGIC algorithm, may predict severe GVHD as has been shown recently (Hartwell et al. JCI Insight 2017). We retrospectively analyzed these 2 biomarkers in our patients to try whether the 2-biomarker algorithm is available to identify high risk of lethal GVHD and non-relapse mortality in Japanese patients. Patients and Methods We retrospectively analyzed consecutive 47 patients who received aHSCT for hematologic malignancies at Kansai Medical University Hospital from January 1, 2010 until April 30, 2016.Overall survival (OS), non-relapse mortality, cause of death, and GVHD clinical staging were investigated. Non-relapse deaths were considered related to GVHD if the patient died from either GVHD itself or from an infection that developed while receiving systemic steroids (at least 10 mg prednisone daily or equivalent) for the treatment of GVHD. Bloodsamples were obtained 7 days after transplantation. ST2 and REG3α concentrations were analyzed by ELISA, and were used for the 2-biomarker algorithm (Hartwell et al. JCI Insight 2017). Results Of the 47 patients (male 24, female 23), median age was 52 years (range, 22-69 years). Eleven patients received PBSCT, 27 patients received bone marrow transplantation, and 9 patients received cord blood transplantation. Of 27 patients who received bone marrow transplantation, 3 patients were transplanted allografts from HLA mismatched donor. Twenty-seven patients underwent reduced intensity conditioning regimen. The median survival time and 1-year OS rate were 375 days (range, 7-3236 days) and 53.2 %, respectively.The overall cumulative incidences of 6-month NRM was 23.4%. The incidence of grade II-IV and III-IV acute GVHD were 17.0%, and 13.2%, respectively. Twelve patients were identified as high risk (HR), and 35 patients were identified as low risk (LR) by the MAGIC algorithm. OS was 33.3% in HR and 71.4% in LR (p&lt;0.05). Six-month cumulative incidence of NRM in HR patients was significantly higher than that of LR (58.3% vs. 11.4%, p&lt;0.001) (Figure), whereas the relapse rate did not differ between risk groups. Four and three patients died from GVHD in HR and LR patients, respectively (33.3% vs. 8.6%, p&lt;0.05). Severe gastrointestinal GVHD was greater in HR patients (18.7 % vs. 8.6%). Conclusion The biomarker algorithm based on blood sample taken 7 day after aHSCT can identify HR patients of lethal GVHD and NRM in Japanese patients as well. Figure Disclosures Ito: Celgene: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding.

Aplastic anemia associated with Crohn’s disease: a tertiary center retrospective study

Aplastic anemia (AA) has been reported to be associated with inflammatory bowel disease (IBD), but mostly with ulcerative colitis (UC). Little is known about the associations between AA and Crohn's disease (CD). We aim to determine the portraits of patients with AA-CD. Among a total of 657 patients with CD registered in Xijing Hospital of Digestive Diseases IBD center from January 2008 to October 2018, the patients diagnosed with concurrent AA were reviewed. Clinical presentation, medical history, endoscopic features, response to treatment, and prognosis in this set of patients were collected. Six male patients confirmed as CD associated with AA were identified. The incidence rate was 0.91% for CD associated with AA in our series. Average age at diagnosis of CD and AA was 41.5 and 39.2years old, respectively. Abdominal pain and hyperpyrexia were the most common symptoms. Endoscopic findings showed discontinued severe inflammation, and all these patients presented with deformed ileocecal valve. Conventional pharmacotherapy failed to achieve a favorable effect. Four of six patients died from CD progression and its complications. None of these patients received bone marrow transplantation treatment because of poverty. Concurrence of AA and CD is a relatively rare condition. Immunologic impairment may play an important pathogenic role and deserves further attention. Males are more susceptible to this condition. Patients with AA-CD are prone to a severe clinical course and poor prognosis. Conventional therapy achieves no potent effect, and allogeneic stem cell transplantation may be a potentially efficient therapy.

Prediction of FLAG ± Ida Regimen Efficacy in Patients with Relapsed/ Refractory Acute Myeloid Leukemia

Aim. To assess the efficacy of FLAG/FLAG-Ida regimen and to identify factors that influence remission, duration of disease-free survival (DFS) and overall survival (OS) of patients with relapsed/refractory acute myeloid leukemia (AML). Materials &amp; Methods. The trial included 54 patients (28 men and 26 women), median age was 37 years (range 18-70 years). 27 (50 %) out of 54 patients had refractory AML and 27 (50 %) patients had relapsed AML. FLAG and FLAG-Ida regimens were administered as induction therapy. 37 (68.5 %) patients received bone marrow transplantation. Molecular genetic and cytogenetic examinations were performed prior to therapy and on the 28&lt;sup&gt;th&lt;/sup&gt; day after the start of treatment. WT1 gene expression was evaluated on the 14&lt;sup&gt;th&lt;/sup&gt;-16&lt;sup&gt;th&lt;/sup&gt; day of treatment. Results. Complete remission (CR) was achieved in 42 (77.8 %) out of 54 patients. Refractoriness to therapy was observed in 9 (16.7 %) out of 54 patients, mortality was 5.5 % (3/54). Remission rate was higher in patients with relapsed AML compared with refractory AML: 85.2 % (23/27) and 70.4 % (19/27), respectively. On the 14&lt;sup&gt;th&lt;/sup&gt;-16&lt;sup&gt;th&lt;/sup&gt; day of treatment patients with blast cell count ≥ 10 % in bone marrow (BM) showed significantly lower CR rate (60 %) compared with the group of patients with &lt; 10 % blast cells in BM (89.6 %; p = 0.024) and shorter DFS (median 7.6 vs. 17.6 months, respectively; p = 0.03). Median DFS in patients with WT1 expression reduction to &lt; 1 log on the 14&lt;sup&gt;th&lt;/sup&gt;-16&lt;sup&gt;th&lt;/sup&gt; day was 5 vs. 18 months in patients without WT1 expression reduction (p = 0.01). DFS varied in groups of patients with blast cell count &lt; 10 % in BM on the 14&lt;sup&gt;th&lt;/sup&gt;-16&lt;sup&gt;th&lt;/sup&gt; day of treatment based on the level of WT1 expression reduction (p = 0.04). MRD-negative patients (57.1 %) showed significantly longer DFS and OS compared with MRD-positive patients (median DFS was 17.6 vs. 5.2 months, respectively, p = 0.02; median OS was 19 vs. 6.9 months, p = 0.0002). Median DFS and OS were different only in ELN low- and high-risk groups (median not reached vs. 5.2 months, respectively, p = 0.039; median not reached vs. 10.2 months, p = 0.039). Conclusion. FLAG and FLAG-Ida are effective and safe regimens in the treatment of relapsed/refractory AML. Achieving remission depends on neither the risk group nor the time of relapse occurrence. The blast cell count in BM on the 14&lt;sup&gt;th&lt;/sup&gt;-16&lt;sup&gt;th&lt;/sup&gt; day of FLAG/FLAG-Ida treatment is a prognostic factor determining achievement and duration of remission. WT1 expression level in the early post-induction period is a sensitive DFS marker. MRD status and molecular genetic risk (ELN) group affiliation are essential prognostic factors determining DFS and OS.

Analysis of Clinical Characteristics and Prognosis of Mantle Cell Lymphoma With Gastrointestinal Involvement

Introduction: Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by rapid disease progression. Studies on gastrointestinal (GI) involvement of MCL are lacking. In this study, we investigated the clinical features and prognosis of MCL with GI involvement. Methods: We retrospectively analyzed 64 patients who diagnosed MCL from January 2009 to April 2017 consecutively. At the time of MCL diagnosis, patients who were identified to have GI involvement by endoscopy or radiologic examination were assigned to the GI-MCL group. And those who were confirmed to have no GI involvement were assigned to the non GI-MCL group. The clinical characteristics and the outcomes of both groups were compared. Results: The GI-MCL group included 29 patients (45.3%). There were no significant differences in age and gender between the GI and non GI-MCL group. The stage of GI-MCL group was higher compared to the non GI-MCL group and all of 29 patients were stage IV. The mean of International Prognostic Index (IPI) score was also significantly higher in GI-MCL (2.97 vs. 1.97, p=0.047). Bone marrow involvement in the GI-MCL group was much greater than non GI-MCL group (69.0% vs. 40.0%, p=0.021). R-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone combined with rituximab) was the most abundant in 1st line chemotherapy (44/64, 69.8%). After 1st line chemotherapy, 56 of 64 patients showed complete remission (87.5%). Although there was no difference in complete remission rate between the two groups, recurrence rate was much higher in GI-MCL group (72.% vs. 41.2%, p=0.024). A total of 15 patients received bone marrow transplantation (15/64, 23.4%). The median follow up period was 37 months and 11 out of 64 patients died during this period (17.2%). There was no significant difference in mortality between the two groups. Conclusion: The patients with MCL invading GI tract tended to have advanced stage, higher IPI score, more bone marrow involvement and more recurrence than MCL not involving the GI tract. Endoscopic examination to rule out GI involvement in patients with MCL is warranted.

Patients with TTC7A Deficiency Causing Multiple Intestinal Atresia with Combined Immunodeficiency (MIA-CID) Can Survive Well Beyond Infancy

Introduction: TTC7A gene mutations have recently been identified as a cause of Multiple Intestinal Atresia with Combined Immunodeficiency (MIA-CID), an extremely rare condition with few patients surviving beyond infancy. This case series reports the clinical characteristics of six surviving children. Methods: Records of all children with MIA-CID and TTC7A mutations confirmed on genetic testing at two tertiary intestinal rehabilitation centres were reviewed retrospectively to identify common phenotypic findings and current management strategies. Results: Six patients (three female) were identified. All patients had multiple intestinal atresias requiring early surgical intervention. All patients required additional operations for acquired strictures. Mean length of remaining small bowel in continuity was 8 cm (range 4 to 20 cm). Only one patient was able to tolerate any substantial enteral feed; all patients required lifelong parenteral nutrition, except one, who achieved full enteral autonomy after a multivisceral transplantation at five years of age. Four patients received bone marrow transplants with successful engraftment as treatment of their immunodeficiency, which was characterized primarily by severe T-cell lymphopenia. All patients developed intestinal failure associated liver disease. One child had a multivisceral transplantation, a second is listed and a third is undergoing evaluation for multivisceral transplantation. The other three have stable liver disease on non-soybean-based lipid formulations. There is variable occurrence of pulmonary, dermatological and cardiac disease in our cohort. Conclusions: Patients with TTC7A deficiency leading to MIA-CID can survive beyond infancy with intensive surgical and multidisciplinary medical management. Patients develop intestinal strictures requiring proximal stomas and are unable to establish enteral autonomy leading to parenteral nutrition dependence. Intestinal failure associated liver disease is seen in all patients. The optimal timing of bone marrow transplantation requires consideration, especially for patients considering multivisceral transplantation and for those who do not have a fully matched donor.

Vulvar and vaginal graft versus host disease: A healthcare clinic initiative

Objective:In patients receiving bone marrow transplantation (BMT), their mucosa becomes altered and sclerotic changes in the female external genital organs occur. Although a few studies have specifically addressed vulvar and vaginal graft versus host disease (VVGvHD) and its repercussions on the sexual health and quality of life of patients, VVGvHD can be overlooked by health practitioners. The objective of the study is to describe the initiation of a health care clinic specializing in VVGvHD in a general tertiary hospital.Methods:A VVGvHD clinic was founded as a part of BMT daycare in a joint initiative of the nursing staff and the medical director of the department and a gynecologist specializing in vulva and vaginal disease. Patients were assessed for vulvovaginal symptoms, such as dryness, burning, itching, pain to touch, pain during intercourse, and dysuria. These patients might be subsequently referred to the VVGvHD clinic according to their needs assessed by daycare nurses. Treatment guidelines were developed by the specialist gynecologist.Results:A total of 81 women aged 2–66 years (median age = 38 years) visited the clinic from 2009 to 2015. Of these women, 70 received an allogeneic transplant and 11 underwent autologous transplantation before consultation in our clinic. VVGvHD was detected in 54% of the patients.Conclusions:The VVGvHD clinic was developed to fulfill the specific needs of female patients who underwent BMT. The pioneer clinic was founded as a joint effort of the multidisciplinary team. Evidence supporting the optimum treatment for this condition is insufficient. This was the main reason for performing this study to explore the clinic that was newly based in Israel. VVGvHD may be a fluctuating condition with frequent deterioration and improvement. Therefore, regular clinical examinations are necessary.

WITHDRAWN: Nutrition support for bone marrow transplant patients.

This is an update of the original Cochrane review published in Issue 2, 2002. Bone marrow transplantation involves administration of toxic chemotherapy and infusion of marrow cells. After treatment, patients can develop poor appetite, mucositis and gastrointestinal failure, leading to malnutrition. To prevent this, parenteral nutrition (PN) support is often first choice but is associated with increased risk of infection. Enteral nutrition (EN) is an alternative, as is addition of substrates. To determine efficacy of EN or PN support for patients receiving bone marrow transplant. Search of The Cochrane Library, MEDLINE, EMBASE and CINAHL in November 2000 and subsequently June 2006. RCTs that compared one form of nutrition support with another, or control, for bone marrow transplant patients. Twenty nine studies were identified. Data were collected on participants' characteristics; adverse effects; neutropaenia; % change in body weight; graft versus host disease; and survival. In two studies (82 participants) glutamine mouthwash reduced number of days patients were neutropenic (6.82 days, 95%CI (1.67 to 11.98) P = 0.009) compared with placebo. Three studies reported (103 participants) that patients receiving PN with glutamine had reduced hospital stay, 6.62 d (95%CI 3.47 to 9.77, P = 0.00004) compared with patients receiving standard PN. However, in the update a further study was added (147 participants) which altered the pooled results: duration in hospital may be increased for those who receive PN with additional glutamine - 0.22 days (95%CI (1.29 to 1.72). Two other studies reported that (73 participants) patients receiving PN plus glutamine had reduced incidence of positive blood cultures (OR 0.23, 95%CI 0.08 to 0.65, P = 0.006) compared to those receiving standard PN. However, a study from the update (113 participants in total) showed the odds of having a positive blood culture have increased but are still less likely if the patient receives PN with glutamine compared to standard PN (OR 0.46, 95%CI 0.20 to 1.04). When patients were given PN versus IV hydration, (25 participants) patients receiving PN had a higher incidence of line infections (OR 21.23, 95%CI 4.15 to 108.73, P = 0.0002) compared to those receiving standard IV fluids. The update identified one study which recognised that (55 participants) those who received IV were likely to spend less time in hospital, 3.30 days (95%CI -0.38 to 6.98, P = 0.08), although this result was not significant. As reported in the original review there remains no evaluable data to properly compare PN with EN. In this update an additional study that compared PN and Glutamine versus standard PN showed that the certain benefits of parenteral nutrition with added glutamine compared to standard PN for reducing hospital stay are no longer definite. When PN with glutamine is compared with standard PN, patients may not leave hospital earlier, but do have reduced incidence of positive blood cultures, than those receiving standard PN. Where possible use of intravenous fluids and oral diet should be considered as a preference to parenteral nutrition, however, in the event of a patient suffering severe gastrointestinal failure even with a trial of enteral feeding, PN with the addition of glutamine could be considered.

The importance of risk factors for the prediction of patients with invasive pulmonary aspergillosis.

Invasive pulmonary aspergillosis (IPA) is a major challenge in the management of immunocompromised patients. Despite all the advances in diagnosis, it remains a problem. The purpose of our study was to investigate the risk factors associated with IPA seen in patients with hematological malignancies. A total of 152 febrile neutropenia (FEN) patients with hematological malignancies aged over 18 years and receiving high-dose chemotherapy or stem cell transplant between January 1, 2010, and December 31, 2012 were included in the study. Sixty-five (65) cases with IPA according to the European Organization for the Research and Treatment of Cancer and Infectious Diseases Mycoses Study Group criteria were enrolled as the case group, while 87 patients without IPA development during concomitant monitoring were enrolled as the control group. Incidence of IPA was 21.4% (3/14) in patients receiving bone marrow transplant (allogeneic 2, autologous 1) and those cases were also added into the case group. The two groups were compared in terms of demographic, clinical and laboratory findings and risk factors associated with IPA investigated retrospectively. Presence of relapse of primary disease, neutropenia for more than 3 weeks, presence of bacterial infection, and non-administration of antifungal prophylaxis were identified as risk factors associated with IPA. It may be possible to reduce the incidence of the disease by eliminating preventable risk factors. Predicting those risks would, per se, enable early diagnosis and treatment and, thus, the mortality rate of these patients would unquestionably decline.

Lysyl Hydroxylase 3 Localizes to Epidermal Basement Membrane and Is Reduced in Patients with Recessive Dystrophic Epidermolysis Bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is caused by mutations in COL7A1 resulting in reduced or absent type VII collagen, aberrant anchoring fibril formation and subsequent dermal-epidermal fragility. Here, we identify a significant decrease in PLOD3 expression and its encoded protein, the collagen modifying enzyme lysyl hydroxylase 3 (LH3), in RDEB. We show abundant LH3 localising to the basement membrane in normal skin which is severely depleted in RDEB patient skin. We demonstrate expression is in-part regulated by endogenous type VII collagen and that, in agreement with previous studies, even small reductions in LH3 expression lead to significantly less secreted LH3 protein. Exogenous type VII collagen did not alter LH3 expression in cultured RDEB keratinocytes and we show that RDEB patients receiving bone marrow transplantation who demonstrate significant increase in type VII collagen do not show increased levels of LH3 at the basement membrane. Our data report a direct link between LH3 and endogenous type VII collagen expression concluding that reduction of LH3 at the basement membrane in patients with RDEB will likely have significant implications for disease progression and therapeutic intervention.

A nonparametric analysis of waiting times from a multistate model using a novel linear hazards model approach

Traditional methods for the analysis of failure time data are often employed in the analysis of waiting times of transient states from multistate models. However, such methods can exhibit bias when waiting times among model states are dependent, even when censoring is random. Furthermore, right-censoring can occur prior to entry into the transient state of interest, preventing the observation of transitions from the state and providing another potential source of bias. We introduce a nonparametric linear hazards model for waiting times from multistate models, analogous to Aalen’s linear hazards model for failure time data, where proper estimation can be carried out via reweighting, a method flexible enough to incorporate general forms of induced and other dependent censoring. We illustrate the approximate unbiasedness of the proposed regression coefficient estimators through a simulation study, while also demonstrating the bias arising from traditional Aalen’s linear hazards model estimators obtained from correlated waiting time data. Theoretical results for the parameter estimators are provided. The reweighted estimators are used in the analysis of two data sets, to identify predictors of ambulatory recovery in a data set of spinal cord injury patients receiving activity-based rehabilitation and to identify prognostic indicators for patients receiving bone marrow transplant.