S-1/temozolomide versus S-1/temozolomide plus thalidomide in advanced pancreatic and non-pancreatic neuroendocrine tumours (STEM): A randomised, open-label, multicentre phase 2 trial.

Background: There are currently limited systemic treatment options for patients with advanced neuroendocrine tumours (NETS) and the efficacy of existing treatments is sub-optimal. We evaluated the efficacy and safety of Tegafur/gimeracil/oteracil/potassium capsules (S-1)/Temozolomide with or without thalidomide for the treatment of NETS (STEM trial). Methods: A randomised, controlled, open-label, phase 2 trial conducted at eight hospitals in China. Adults (≥18 years) with unresectable/metastatic, pancreatic or non-pancreatic NETS, with an Eastern Cooperative Oncology Group (ECOG) PS of 0-1, and progression on ≤2 previous therapies were randomised (1:1, using hierarchical block randomization with block length 4, stratified by pancreatic/non-pancreatic disease to receive S-1 40-60 mg orally twice daily on days 1-14 plus temozolomide 200 mg orally daily on days 10-14 in a 21-day cycle OR S-1 and temozolomide plus thalidomide orally nightly (100 mg on days 1-7, 200 mg on days 8-14, and 300 mg from day 15), until disease progression, death, intolerable toxicity, withdrawal of informed consent or at the investigator's discretion. The primary endpoint was objective response rate (ORR) by RECIST 1.1 in an intention-to-treat population. Safety was assessed in all patients who received treatment. The study was registered at ClinicalTrials.gov: NCT03204019 (pancreatic group) and NCT03204032 (non-pancreatic group). Findings: Between March 23, 2017 and November 16, 2020, 187 patients were screened and 140 were randomly assigned to S-1/temozolomide plus thalidomide (n = 69) or S-1/temozolomide (n =71). After a median follow-up of 12·1 months (IQR: 8·4-16·6), the ORR was comparable in the S-1/temozolomide plus thalidomide and S-1/temozolomide groups 26·1% [95% CI 17·2-37·5] versus 25·4% [95% CI 16·7-36·6]; odds ratio: 1·03 [95% CI 0·48-2·22]; P = 0·9381). In the S-1/temozolomide plus thalidomide group, the most common grade 3-4 treatment-related adverse event was fatigue (2/68, 3%), and in the control group were thrombocytopenia and diarrhea (both 1/71, 2%). There were no treatment-related deaths in either group. Interpretation: S-1/temozolomide with or without thalidomide leads to a comparable treatment response in patients with advanced/metastatic NETS. Funding: This work was supported by CAMS Innovation Fund for Medical Sciences (CIFMS,2021-I2M-1-066, 2017-I2M-4-002, 2021-I2M-1-019, 2017-I2M-1-001), the National Natural Science Foundation of China (81972311, 82141127, 31970794,), the State Key Project on Infection Diseases of China (2017ZX10201021-007-003), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT310026), Sanming Project of Medicine in Shenzhen (SZSM202011010), and the State Key Laboratory Special fund from the Ministry of Science (2060204).

Ki-67 index of 5% could better predict the clinical prognosis of well-differentiated pancreatic neuroendocrine tumours.

BACKGROUND: The pathological classification of well-differentiated pancreatic neuroendocrine tumour (pNET) is based largely upon Ki-67 index. However, current controversies abound about the classification of pNETG1/pNETG2. PATIENTS AND METHODS: Clinicopathological data were retrospectively analysed for 153 pNETG1/pNETG2 patients hospitalized at China-Japan Friendship Hospital. The critical values of pNETG1/pNETG2 were examined by using the area under the receiver operating characteristic curve and survival analysis was used to compare the clinical prognosis of pNETG1/G2. RESULTS: Among them, 52.3% were males. The median age was 49 (18-81) years and the clinical types were pNETG1 (n = 38) and pNETG2 (n = 115). According to the receiver operating characteristic curve, the optimal cut-off value was 5.5% for classifying pNETG1/pNETG2. Significant differences between pNETG1 (n = 101) and pNETG2 (n = 52) existed in overall survival (P = 0.001) and disease-free survival (P = 0.013) when Ki-67 index was 5%. Yet no significant differences existed in overall survival (P = 0.378) or disease-free survival (P = 0.091) between pNETG1 and pNETG2 when Ki-67 index was 3%. Furthermore, multivariate analysis indicated that the revised pathological grade was an independent risk factor for mortality and post-operative recurrence of pNET patients (P = 0.003 and 0.014; hazard ratio (HR) = 4.005 and 2.553). CONCLUSION: Thus, differentiating pNETG1/pNETG2 with Ki-67 index (5%) is proposed as the cut-off value and a new Ki-67 index (5%) is a better predictor of pNET mortality and post-operative recurrence than Ki-67 index (3%).

Circulating miRNA-202-3p is a potential novel biomarker for diagnosis of type 1 gastric neuroendocrine neoplasms.

BACKGROUND: Currently, there are no circulating diagnostic biomarkers for gastric neuroendocrine neoplasms (g-NENs). In previous studies, we found that miRNA-202-3p is overexpressed in the tumour tissue of type 1 g-NEN. We speculated that miRNA-202-3p is also likely to be highly expressed in circulating blood. METHODS: A total of 27 patients with type 1 g-NEN and 27 age- and sex-matched control participants were enrolled in this study. The miRNA-202-3p levels in serum obtained from the participants were measured by qRT-PCR. The expression level of miRNA-202-3p in the samples was calculated by comparison with a standard curve. RESULTS: The clinical characteristics of the patients were similar to those of the patient samples in previous reports. Expression of miRNA-202-3p was significantly higher in the patient group (3.84 × 107 copies/nl) than in the control group (0.635 × 107 copies/nl). The area under the ROC curve (AUC) was 0.878 (95% CI: 0.788-0.968), and the optimal cut-off point was approximately 1.12 × 107 copies/nl. The sensitivity and specificity were 88.9% and 77.8%, respectively. CONCLUSION: This study suggests that miRNA-202-3p is potentially useful as a biomarker of type 1 g-NEN; further investigation and verification should be performed in future research.

Clinicopathological characteristics and prognosis of 77 cases with type 3 gastric neuroendocrine tumours.

BACKGROUND: For the rarity of type 3 gastric neuroendocrine tumours (g-NETs), their clinicopathological characteristics and prognosis are not well illustrated. AIM: To describe the clinicopathological features and outcome of type 3 g-NETs in the Chinese population. METHODS: Based on the 2019 WHO pathological classification, the clinicopathological characteristics and prognosis of patients with type 3 g-NETs in China were retrospectively analysed. RESULTS: A total of 77 patients (55.8% of females) with type 3 g-NETs were analysed, with a median age of 48 years (range: 28-79 years). The tumours were mainly located in the gastric fundus/body (83.1%) and were mostly solitary (83.1%), with a median size of 1.5 cm (0.8-3.5 cm). Of these, there were 37 G1 tumours (48.1%), 31 G2 (40.3%), and 9 G3 (11.7%). Ten (13.0%) and 24 (31.2%) patients had lymph node and distant metastasis, respectively. In addition, type 3 g-NETs were heterogeneous. Compared with G1 NETs, G2 NETs had a higher lymph node metastasis rate, and G3 NETs had a higher distant metastasis rate. G1 and G2 NETs with stage I/II disease (33/68) received endoscopic treatment, and no tumour recurrence or tumour-related death was observed within a median follow-up time of 36 mo. Grade and distant metastasis were identified to be independent risk factors for prognosis in multivariable analysis. CONCLUSION: Type 3 g-NETs are obviously heterogeneous, and the updated WHO 2019 pathological classification may be used to effectively evaluate their biological behaviors and prognosis. Also, endoscopic treatment should be considered for small (< 2 cm), low grade, superficial tumours.

A Prospective and Retrospective Clinical Controlled Observation of Chinese Herbal Decoction (SMLJ01) for Type 1 Gastric Neuroendocrine Tumors.

INTRODUCTION: Type 1 gastric neuroendocrine tumors (g-NETs) have a good prognosis but a high recurrence rate. AIM: To observe the clinical efficacy of the treatment of type 1 g-NETs with the Chinese herbal decoction SMLJ01. MATERIALS AND METHODS: A prospective and retrospective, clinical, controlled observation was conducted in 4 Chinese centers from 2012 to 2019. Patients with type 1 g-NETs were nonrandomly divided into treatment and control groups after endoscopic treatment based on herbal treatment administered according to their wishes. The treatment group received oral SMLJ01, with follow-up every 6 to 12 months, while the control group received follow-up alone. Patient follow-up (via telephone) from 2012 to 2017 was mainly retrospective. All patients after 2017 were followed prospectively. The recurrence times and rates were compared after treatment for at least 6 months. Symptom improvements were evaluated in the treatment group. The follow-up ended on October 31, 2019. RESULTS: During a median follow-up of 22 months (range: 2-86 months), the survival rate was 100%, and no metastases occurred. Twenty-one of the 82 treated patients (25.6%) had recurrence after a median of 22 months, and 22 of the 54 control patients (40.7%) had recurrence after a median of 8 months (P = .063). The Kaplan-Meier curve analysis showed that the patients in the treatment group had a significantly longer median recurrence-free survival (RFS) time than those in the control group (P = .001). The risk of recurrence in the treatment group was 0.38 relative to that in the control group (95% CI: 0.20-0.70). The symptom score of the patients after taking Chinese medicine was 19.5 (10.3, 28.0), which was significantly lower than before treatment (31.5 (19.3, 38.0)). The difference was statistically significant (P < .01). CONCLUSION: SMLJ01, with the effects of soothing the liver, strengthening the spleen, increasing acid and harmonizing the stomach, may help reduce the recurrence rate, relieve symptoms and prolong the recurrence time in patients with type 1 g-NETs and is worthy of evaluation with further randomized research with large sample sizes and longer follow-up periods.

Association between MGMT status and response to alkylating agents in patients with neuroendocrine neoplasms: a systematic review and meta-analysis.

BACKGROUND: O6-methylguanine-DNA methyltransferase (MGMT) is a specific DNA damage reversal repair protein. The influence of MGMT status on alkylating agent sensitivity in patients with neuroendocrine neoplasms (NENs) is controversial. We conducted a meta-analysis to assess the influence of MGMT status on the therapeutic sensitivity of alkylating agents in patients with NENs. METHODS: We searched PubMed, EmBase, and Cochrane library public databases through 3 July 2019. The objective response rate (ORR) was the outcome data of interest. Subgroup analysis was performed according based on MGMT methylation and expression of MGMT protein. RESULTS: Eleven studies were included in the meta-analysis. The proportion of patients with NENs that achieved an ORR after alkylating agent treatment was higher in the MGMT-deficient group than the non-deficient group (OR: 5.00; 95% CI: 3.04-8.22; P < 0.001; I2: 3%). Similar results were noted in the MGMT methylation and MGMT protein expression subgroups. CONCLUSION: Patients with NENs and MGMT methylation or low protein expression had a higher ORR proportion than patients without MGMT methylation or high protein expression. The MGMT status can be used as a biological indicator of the response to alkylating agent treatment in patients with NENs.

Clinicopathological characteristics and risk factors for recurrence of well-differentiated pancreatic neuroendocrine tumors after radical surgery: a case-control study.

BACKGROUND: Well-differentiated pancreatic neuroendocrine tumors (PanNETs) usually have a good prognosis; however, there are patients that experience recurrence after curative resection. AIM: To explore recurrence-related risk factors by analyzing clinicopathological data of PanNETs after radical surgery. METHODS: Clinical and pathological data from 47 patients with well-differentiated PanNETs at China-Japan Friendship Hospital from January 2012 to March 2016 were analyzed retrospectively. Univariate and multivariate analyses of the risk factors of PanNETs for postoperative recurrence were conducted. RESULTS: Among the 47 patients with well-differentiated PanNETs, there were 38 cases with non-functioning tumors, 9 cases with functional tumors (6 insulinomas, 1 gastrinoma, 1 glucagonoma, and 1 VIPomas). There are 17 cases (36.2%) in the pancreatic head, 17 (36.2%) in the body and tail, 9 (19.1%) in the tail, and 4 (8.5%) in the body. The median tumor size was 3.65 (IQR 2-5.5) cm. Fourteen cases (29.8%) were NET G1, and 33 cases (70.2%) were NET G2. In regard to the clinical stage, 9 (19.1%) cases were IA, 14 (29.8%) cases were IB, 7 (14.9%) cases were IIA, 14 (29.8%) cases were IIB, and 3 cases unknown. There were 17 patients who presented with postoperative recurrence. Univariate analysis showed that AJCC TNM staging, Ki67 index, vascular invasion, margin status, and the regional stage of the tumors are related to the recurrence of patients with PanNETs (p < 0.05). The results of multivariate analysis showed that Ki67 index ≥ 10% is an independent risk factor for the postoperative recurrence of PanNETs (p < 0.05). CONCLUSION: The Ki67 index ≥ 10% is an independent risk factor for recurrence in well-differentiated PanNETs after radical surgery, and close surveillance for these patients may be needed.

Capecitabine and Temozolomide as a Promising Therapy for Advanced Thymic Atypical Carcinoid.

BACKGROUND: Thymic atypical carcinoid (TAC) is a rare thymic neuroendocrine tumor that originates in the neuroendocrine system and lacks a standardized treatment. The combination of capecitabine (CAP) and temozolomide (TEM) is associated with an extremely high and long-lasting response rate in patients with metastatic pancreatic neuroendocrine tumors. However, there is little evidence showing that the CAPTEM regimen is effective for TAC. For patients with unresectable or metastatic atypical carcinoid of the thymus, few treatment options are available, and the treatment efficacy is not satisfactory. To explore the efficacy and safety of the CAPTEM regimen against TAC, we conducted a retrospective review. PATIENTS AND METHODS: A total of nine patients with advanced atypical carcinoid of the thymus in the China-Japan Friendship Hospital were treated with capecitabine (750 mg/m2 twice daily, days 1-14) and temozolomide (200 mg/m2 once daily, days 10-14) every 28 days between 2014 and 2018. The disease control rate (DCR), progression-free survival (PFS), and adverse effects after treatment were analyzed. The DCR was calculated by RECIST version 1.1. Progression-free survival was calculated by the Kaplan-Meier survival method. RESULTS: A total of nine patients (six male and three female) were included. The median age at CAPTEM initiation was 50 years (range, 26-58). The median number of CAPTEM cycles was 8 (range, 3-23). The DCR was 89% (8/9), with eight patients achieving stable disease. Only one patient (11%) showed progressive disease. The median PFS was 8 months. Because we applied vitamin B6 and ondansetron before administering the drugs, the side effects of this regimen were very small. Adverse reactions were all below grade 3 and included myelosuppression and digestive tract reaction. CONCLUSION: Our results suggest that the CAPTEM regimen may be effective and well tolerated for the treatment of TAC. More evidence is needed to validate the effectiveness of this regimen. IMPLICATIONS FOR PRACTICE: Capecitabine and temozolomide regimen is effective and well tolerated in patients with advanced thymic atypical carcinoid.

GPI-anchored protein-deficient T cells in patients with aplastic anemia and low-risk myelodysplastic syndrome: implications for the immunopathophysiology of bone marrow failure.

Glycosylphosphatidylinositol-anchored protein-deficient (GPI-AP(-) ) T cells can be detected in some patients with bone marrow failure (BMF), but the link between these cells and BMF pathophysiology remains to be elucidated. To clarify the significance of GPI-AP(-) T cells in BMF, peripheral blood from 562 patients was examined for the presence of CD48(-) CD59(-) CD3(+) cells using high-resolution flow cytometry (FCM), and the GPI-AP(-) T cells were characterized with regard to their phenotype and sensitivity to inhibitory molecules, including herpesvirus entry mediator (HVEM) and a myelosuppressive cytokine, TGF-ß. A multi-lineage FCM analysis detected CD48(-) CD59(-) CD3(+) T cells in 72 (12.8%) of the patients, together with GPI-AP(-) myeloid cells. Unexpectedly, 12 patients (10 with aplastic anemia and 2 with myelodysplastic syndrome-refractory anemia, 2.1%), who showed clinical features similar to those of other BMF patients with GPI-AP(-) myeloid cells, such as a good response to immunosuppressive therapy, displayed 0.01-0.3% GPI-AP(-) cells exclusively in T cells. The CD48(-) CD59(-) T cells consisted of predominantly effector memory (EM) and terminal effector cells, while CD48(-) CD59(-) T cells from non-BMF patients who had received anti-CD52 antibody only showed EM and central memory phenotypes. TGF-ß and HVEM capable of inhibiting T-cell proliferation via its GPI-AP CD160 ligation suppressed the in vitro proliferation of GPI-AP(+) T cells more potently than that of GPI-AP(-) T cells from the same patients. The presence of GPI-AP(-) T cells, as well as GPI-AP(-) myeloid cells, may therefore reflect the immunopathophysiology of BMF in which cytokine-mediated suppression of hematopoietic stem cells via GPI-AP-type receptors takes place.

Autoantibodies specific to hnRNP K: a new diagnostic marker for immune pathophysiology in aplastic anemia.

To identify a new diagnostic marker for the immune pathophysiology of aplastic anemia (AA), we screened sera of immune-mediated AA patients for the presence of antibodies (Abs) specific to proteins derived from a leukemia cell line UT-7 using two-dimensional electrophoresis followed by immunoblotting. The target proteins were identified by peptide mass fingerprinting. Heterogeneous nuclear ribonucleoprotein (hnRNP) K was identified as a novel autoantigen. An enzyme-linked immunosorbent assay revealed high titers of anti-hnRNP K Abs in 85 (31%) of 273 patients with AA. Sixty-four patients received antithymocyte globulin and cyclosporine after undergoing screening for anti-hnRNP K Ab, anti-DRS-1 Ab, anti-moesin Ab, and paroxysmal nocturnal hemoglobinuria (PNH)-type cells. Twenty (87%) of 23 patients with the presence of anti-hnRNP K Abs responded to the immunosuppressive therapy (IST), while 19 (46%) of 41 patients without the presence of anti-hnRNP K Abs responded. A multivariate analysis showed only PNH-type cells and anti-hnRNP K Abs to be significant factors for the prediction of a good response to IST. The detection of anti-hnRNP K Abs as well as PNH-type cells may therefore be useful for diagnosing the immune pathophysiology of AA.

Hydroxyurea upregulates NKG2D ligand expression in myeloid leukemia cells synergistically with valproic acid and potentially enhances susceptibility of leukemic cells to natural killer cell-mediated cytolysis.

Valproic acid (VPA), a histone deacetylase inhibitor, upregulates NKG2D ligands (NKG2DLs) on some monocytic and lymphoid leukemic cells. However, its effect on myeloid leukemia cells and synergistic agents that can augment the effect of VPA remains unknown. Of the various myeloid cell lines examined, OUN-1, a chronic myelogenous leukemia cell line, showed the most prominent upregulation of MICA/B and ULBP2 in response to VPA. The NKG2DL upregulation was observed only in leukemic cells without apoptosis and the effect was abrogated by pretreatment of cells with caffeine, an inhibitor of ATM/ATR. Several activators of ATM/ATR were screened for their effect on NKG2DL expression, but only hydroxyurea (HU) efficiently upregulated both MICA/B and ULPB2 expression on the cell line. VPA and HU synergistically upregulated the NKG2DLs on OUN-1 cells as well as primary leukemic cells from some patients with acute myeloid leukemia. The upregulation of NKG2DLs by VPA and/or HU was associated with increased transcription of each NKG2DL gene. OUN-1 cells treated with VPA + HU were more susceptible to killing by natural killer (NK) cells than untreated cells and the enhanced cytotoxicity of NK cells was blocked by the treatment of NK cells with anti-NKG2D monoclonal antibodies. The same concentrations of VPA and HU did not affect the cytotoxicity of NK cells against OUN-1 cells. These data suggest that VPA and HU might enhance the NK cell-mediated antileukemia effect by increasing the susceptibility of myeloid leukemic cells to NK cells.

Origin and fate of blood cells deficient in glycosylphosphatidylinositol-anchored protein among patients with bone marrow failure.

Peripheral blood from 489 recently diagnosed patients with aplastic anaemia (AA) and 316 with refractory anaemia (RA) of myelodysplastic syndrome was evaluated to characterize CD55(-)CD59(-) [paroxysmal nocturnal haemoglobinuria (PNH)]-type blood cells associated with bone marrow (BM) failure. PNH-type cells were detected in 57% and 20% of patients with AA and RA, respectively. The percentages of PNH-type granulocytes ranged from 0.003% to 94.2% and the distribution was log-normal with a median of 0.178%. Serial analyses of 75 patients with PNH-type cells over 5 years revealed that the percentage of PNH-type cells constantly increased in 13 (17%), persisted in 44 (59%), disappeared in the remaining 18 (24%) although even in the 'Disappearance' group, PNH-type granulocytes persisted for at least 6 months. A scattergram profile of PNH-type cells unique to each patient persisted regardless of the response to immunosuppressive therapy and only single PIGA mutations were detected in PNH-type granulocytes sorted from four patients. These findings suggest that the PNH-type cells in patients with BM failure are derived from single PIGA mutant haematopoietic stem cells even when their percentages are <1% and their fate depends on the proliferation and self-maintenance properties of the individual PIGA mutants.

Anti-moesin antibodies derived from patients with aplastic anemia stimulate monocytic cells to secrete TNF-alpha through an ERK1/2-dependent pathway.

Antibodies specific to moesin, which are frequently detectable in the serum of patients with aplastic anemia (AA), can induce tumor necrosis factor-alpha (TNF-alpha) secretion from monocytes and a human monocytic leukemia cell line THP-1. We investigated the mechanisms responsible for TNF-alpha secretion from monocytic cells induced by the auto-antibodies that are purified from the sera of AA patients. TNF-alpha induction by anti-moesin antibodies depended on the amount of cell surface moesin expressed by THP-1 cells. F(ab')(2) fragments prepared from the anti-moesin antibodies were able to stimulate THP-1 cells to secrete TNF-alpha and this stimulatory effect was enhanced by cross-linking of moesins with anti-human IgG F(ab')(2) fragment antibodies. Anti-moesin antibodies as well as their F(ab')(2) fragments induced the phosphorylation of ERK1/2 in monocytic cells and this effect was suppressed by the addition of an ERK1/2 inhibitor. Moreover, anti-moesin antibody treatment induced the phosphorylation of moesin proteins in the monocytes and THP-1 cells within 30 min. These results indicate that anti-moesin antibodies induce TNF-alpha secretion from monocytes through the activation of the ERK1/2 pathway provoked by direct binding to moesin on the cells.

Anti-moesin antibodies in the serum of patients with aplastic anemia stimulate peripheral blood mononuclear cells to secrete TNF-alpha and IFN-gamma.

Moesin is an intracellular protein that links the cell membrane and cytoskeleton, while also mediating the formation of microtubules and cell adhesion sites as well as ruffling of the cell membrane. To determine the roles of anti-moesin Abs derived from the serum of patients with aplastic anemia (AA) in the pathophysiology of bone marrow failure, we studied the expression of moesin on various blood cells and the effects of anti-moesin Abs on the moesin-expressing cells. The proteins recognized by anti-moesin mAbs were detectable on the surface of T cells, NK cells, and monocytes from healthy individuals as well as on THP-1 cells. The peptide mass fingerprinting of the THP-1 cell surface protein and the knock-down experiments using short hairpin RNA proved that the protein is moesin itself. Both the anti-moesin mAbs and the anti-moesin polyclonal Abs purified from the AA patients' sera stimulated THP-1 cells and the PBMCs of healthy individuals and AA patients to secrete 60-80% as much TNF-alpha as did LPS 100 ng/ml. Although the polyclonal Abs induced IFN-gamma secretion from the PBMCs of healthy individuals only when the PBMCs were prestimulated by anti-CD3 mAbs, the anti-moesin Abs were capable of inducing IFN-gamma secretion from the PBMCs of AA patients by themselves. Anti-moesin Abs may therefore indirectly contribute to the suppression of hematopoiesis in AA patients by inducing myelosuppressive cytokines from immunocompetent cells.

Expansion of donor-derived hematopoietic stem cells with PIGA mutation associated with late graft failure after allogeneic stem cell transplantation.

A small population of CD55(-)CD59(-) blood cells was detected in a patient who developed donor-type late graft failure after allogeneic stem cell transplantation (SCT) for treatment of aplastic anemia (AA). Chimerism and PIGA gene analyses showed the paroxysmal nocturnal hemoglobinuria (PNH)-type granulocytes to be of a donor-derived stem cell with a thymine insertion in PIGA exon 2. A sensitive mutation-specific polymerase chain reaction (PCR)-based analysis detected the mutation exclusively in DNA derived from the donor bone marrow (BM) cells. The patient responded to immunosuppressive therapy and achieved transfusion independence. The small population of PNH-type cells was undetectable in any of the 50 SCT recipients showing stable engraftment. The de novo development of donor cell-derived AA with a small population of PNH-type cells in this patient supports the concept that glycosyl phosphatidylinositol-anchored protein-deficient stem cells have a survival advantage in the setting of immune-mediated BM injury.