Severe aplastic anaemia in children: Impact of histopathology profile and treatment on very long-term outcomes.

AIM: To assess very long-term outcomes of children with severe aplastic anaemia (SAA) and impact of histopathology and of different treatments over time. METHODS: We conducted a retrospective study of 57 consecutive patients with SAA during 1973-2019. According to period, treatment consisted of androgens, immunosuppressive treatment (IST) and haematopoietic cell transplantation (HCT) in 14, 31 and 13 patients, respectively. Histopathology immune profiles were studied on bone marrow (BM). RESULTS: Response rate (RR) to androgens was 35%, with long-term survivorship in 4 of 5 responders. RR and 10-year overall survival (OS) after IST was 65% and 80%, respectively. RR was higher in girls (92% vs 43% in boys, P = .02). Mean baseline BM values of CD34 + and of B-lymphocytes in responders vs non-responders were 1.3% vs 0 (P = .08) and 14.1% vs 9.7% (P = .07), respectively. After IST, BM cellularity gradually increased and cytotoxic T-lymphocytes decreased (time variation P = .003 and 0.07, respectively). Outcome did not differ between patients with IST or frontline HCT. Ten-year OS improved over time, increasing from 35.3% to 77.1% and 77% during 1973-1985, 1986-2003 and 2004-2019, respectively. CONCLUSION: Histopathology may refine response prediction to IST. The course of SAA in children, a previously fatal disease, was altered in recent times.

Incidence, time trends and survival patterns of childhood pilocytic astrocytomas in Southern-Eastern Europe and SEER, US.

Pilocytic astrocytomas (PA) comprise the most common childhood central nervous system (CNS) tumor. Exploiting registry-based data from Southern and Eastern Europe (SEE) and SEER, US, we opted to examine incidence, time trends, survival and tentative outcome disparities of childhood PA by sociodemographic and clinical features. Childhood PA were retrieved from 12 SEE registries (N = 552; 1983-2014) and SEER (N = 2723; 1973-2012). Age-standardized incidence rates (ASR) were estimated and survival was examined via Kaplan-Meier and Cox regression analysis. ASR of childhood PA during 1990-2012 in SEE was 4.2/106, doubling in the USA (8.2/106). Increasing trends, more prominent during earlier registration years, were recorded in both areas (SEE: +4.1 %, USA: +4.6 %, annually). Cerebellum comprised the most common location, apart from infants in whom supratentorial locations prevailed. Age at diagnosis was 1 year earlier in SEE, whereas 10-year survival was 87 % in SEE and 96 % in SEER, improving over time. Significant outcome predictors were age <1 year at diagnosis diagnosis (hazard ratio, HR [95% confidence intervals]: 3.96, [2.28-6.90]), female gender (HR: 1.38, [1.01-1.88]), residence in SEE (HR: 4.07, [2.95-5.61]) and rural areas (HR: 2.23, [1.53-3.27]), whereas non-cerebellar locations were associated with a 9- to 12-fold increase in risk of death. The first comprehensive overview of childhood PA epidemiology showed survival gains but also outcome discrepancies by geographical region and urbanization pointing to healthcare inequalities. The worse prognosis of infants and, possibly, females merits further consideration, as it might point to treatment adjustment needs, whereas expansion of systematic registration will allow interpretation of incidence variations.

Filaggrin and Periostin Expression Is Altered in Eosinophilic Esophagitis and Normalized With Treatment.

OBJECTIVES: Previous data have suggested that filaggrin (FLG) and periostin (POSTN) genes may be dysregulated in eosinophilic esophagitis (EoE). We aimed to further evaluate the expression patterns of FLG and POSTN proteins in esophageal tissue samples of patients with EoE, as compared to those of patients with gastroesophageal reflux disease (GERD) and normal controls. METHODS: A total of 61 prospectively collected cases, including 40 children with EoE and 21 children with GERD, and a control group of 14 sex- and age-matched healthy children were enrolled. Patients with EoE were treated with skin testing-driven elimination diet and/or corticosteroids. The immunohistochemical expression of FLG and POSTN was evaluated in esophageal biopsies obtained from patients and controls, and the results were correlated with EoE-related clinicopathological parameters. RESULTS: Positive FLG and negative POSTN staining were observed in all esophageal biopsies from normal controls. In contrast, FLG and POSTN stained negative and positive, respectively, in all pretreatment biopsies obtained from patients with EoE, whereas FLG and POSTN stained positive in 57.1% and 95.2% of GERD cases, respectively (P < 0.001). A statistically significant decrease of the proportion of cases with negative FLG and positive POSTN staining was observed from the first (pretreatment) to the second (post-treatment) biopsy in the subgroup of patients with EoE (P < 0.001 in both correlations). CONCLUSIONS: FLG and POSTN expression may be downregulated and upregulated, respectively, in the esophageal mucosa of patients with active EoE, and these changes may be restored with treatment in a significant percentage of cases.

Giant Atypical Intraventricular Meningioma in a Child.

We present the case of a 14-year-old boy with a giant tumor of the lateral ventricle. The patient was operated upon. Histopathology showed the presence of an atypical meningioma. Postoperative imaging confirmed the complete tumor excision. Meningiomas although frequent in adults are rare in children. Intraventricular meningiomas are exceedingly rare. Complete surgical excision should be the goal of treatment and is usually associated with a favorable outcome.

The Role of Fast Cell Cycle Analysis in Pediatric Brain Tumors.

Cell cycle analysis by flow cytometry has not been adequately studied in pediatric brain tumors. We investigated the value of a modified rapid (within 6 min) cell cycle analysis protocol for the characterization of malignancy of pediatric brain tumors and for the differentiation of neoplastic from nonneoplastic tissue for possible intraoperative application. We retrospectively studied brain tumor specimens from patients treated at our institute over a 5-year period. All tumor samples were histopathologically verified before flow-cytometric analysis. The histopathological examination of permanent tissue sections was the gold standard. There were 68 brain tumor cases. All tumors had significantly lower G0/G1 and significantly higher S phase and mitosis fractions than normal brain tissue. Furthermore low-grade tumors could be differentiated from high-grade tumors. DNA aneuploidy was detected in 35 tumors. A correlation between S phase fraction and Ki-67 index was found in medulloblastomas and anaplastic ependymomas. Rapid cell cycle analysis by flow cytometry is a promising method for the identification of neoplastic tissue intraoperatively. Low-grade tumors could be differentiated from high-grade tumors. Thus, cell cycle analysis can be a valuable adjunct to the histopathological evaluation of pediatric brain tumors, whereas its intraoperative application warrants further investigation.

The prevalence of Helicobacter pylori gastritis in newly diagnosed children with inflammatory bowel disease.

BACKGROUND: Recent studies have shown that patients with inflammatory bowel disease (IBD) are less likely to be infected with Helicobacter pylori compared with non-IBD patients. We aimed to study the prevalence of H. pylori-positive and H. pylori-negative gastritis in newly diagnosed children with IBD in comparison to those with non-IBD in Greece. MATERIALS AND METHODS: All children who underwent first esophagogastroduodenal endoscopy between 2002 and 2011 were retrospectively included. Four groups were studied: patients with Crohn's disease (CD), ulcerative colitis (UC), IBD unclassified (IBDU), and non-IBD individuals (non-IBD). Helicobacter pylori infection was defined by positive culture or by positive histology and CLO test. Those children with negative or not available culture and only one positive test (histology or CLO) were further evaluated by urea breath test, and the positives were also included in the infected group. RESULTS: We studied 159 patients with IBD (66 CD, 34 UC, and 59 IBDU) and 1209 patients in non-IBD individuals. Helicobacter pylori gastritis was less frequent in the IBD group (3.8% vs 13.2% in the control group, p < .001), whereas IBD patients were significantly older than non-IBD children (p < .001). Children with H. pylori-negative gastritis were 3.3 times more likely to belong in the IBD group compared with H. pylori-positive patients (p = .006). CONCLUSIONS: Occurrence of H. pylori gastritis is less frequent in children with IBD compared with controls. Our study confirms an inverse association between H. pylori and IBD. Future studies are needed to distinguish between a true protective role of H. pylori and a confounding effect due to previous antibiotic use in children with IBD.

Successful Treatment of Disseminated Fusariosis in a 15-Month-Old Boy With Refractory Acute Lymphoblastic Leukemia Using High-Dose Voriconazole.

BACKGROUND: Infections due to rare molds, such as Fusarium spp., cause severe and difficult-to-control diseases with increasing frequency. Data on fusariosis in children and on the use of voriconazole (VCZ), considered a drug of choice, are scarce in infants and children <2 years of age. CASE PRESENTATION: We present the first, to our knowledge, pediatric case of disseminated mycosis due to Fusarium musae in a 15-month-old boy with relapsed/refractory acute lymphoblastic leukemia, diagnostics and outcome. Herein, at this severely immunocompromised patient, after prompt diagnosis, disseminated fusariosis was successfully treated with high-dose VCZ at a final dose of 15 mg/kg of body weight twice a day. This occurred by achieving adequate drug exposures as determined by drug susceptibility testing and followed by therapeutic drug monitoring without observed toxicity. CONCLUSIONS: Appropriate diagnostic approach and timely administration of optimal antifungal therapy with VCZ were important for the successful treatment of disseminated fusariosis. Therapeutic drug monitoring, especially in <2-year-old children, is necessary to achieve sufficient drug exposure for optimal therapeutic response without toxicity.

Expression of DNA Repair Genes in Ewing Sarcoma.

Background/Aim: Ewing sarcoma is an aggressive mesenchymal malignancy commonly affecting children and young adolescents. The molecular basis of this neoplasia is well reported with the formation of the EWSR1/FLI1 fusion gene being the most common genetic finding. However, this fusion gene has not been targeted therapeutically nor is being used as a prognostic marker. Its relevance regarding the molecular steps leading to Ewing sarcoma genesis are yet to be defined. The generation of the oncogenic EWSR1/FLI1 fusion gene, can be attributed to the simultaneous introduction of two DNA double-strand breaks (DSBs). The scope of this study is to detect any association between DNA repair deficiency and the clinicopathological aspects of Ewing's sarcoma disease. Patients and Methods: We have conducted an expression analysis of 35 patients diagnosed with Ewing sarcoma concerning the genes involved in non-homologous end joining (NHEJ) and homologous recombination (HR) repair pathways. We have analyzed the expression levels of 6 genes involved in NHEJ (XRCC4, XRCC5, XRCC6, POLλ, POLµ) and 9 genes involved in HR (RAD51, RAD52, RAD54, BRCA1, BRCA2, FANCC, FANCD, DNTM1, BRIT1) using real time PCR. Age, sex, location of primary tumor, tumor size, KI67, mitotic count, invasion of adjacent tissues and treatment were the clinicopathological parameters included in the statistical analysis. Results: Our results show that both these DNA repair pathways are deregulated in Ewing sarcoma. In addition, low expression of the xrcc4 gene has been associated with better overall survival probability (p=0.032). Conclusion: Our results, even though retrospective and in a small number of patients, highlight the importance of DSBs repair and propose a potential therapeutic target for this type of sarcoma.

Prognostic factors in high-grade pediatric osteosarcoma among children and young adults: Greek Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST) data along with a systematic review and meta-analysis.

The 5-year overall survival of children and adolescents with osteosarcoma has been in plateau during the last 30 years. The present systematic review (1976-2023) and meta-analysis aimed to explore factors implicated in the prognosis of children and young adults with high-grade osteosarcoma. Original studies including patients ≤30 years and the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST) data (2010-2021) referred to children ≤14 years were analysed. Individual participant data (IPD) and summary estimates were used to assess the n-year survival rates, as well as the association of risk factors with overall survival (OS) and event-free survival (EFS). IPD and the n-year survival rates were pooled using Kaplan-Meier and Cox regression models, and random effects models, respectively. Data from 8412 patients, including 46 publications, NARECHEM-ST data, and 277 IPD from 10 studies were analysed. The summary 5-year OS rate was 64% [95% confidence interval (95%CI): 62%-66%, 37 studies, 6661 patients] and the EFS was 52% (95%CI: 49%-56%, 30 studies, 5010 patients). The survival rates generally differed in the pre-specified subgroups. Limb-salvage surgery showed a higher 5-year OS rate (69%) versus amputation (47%). Good responders had higher OS rates at 3 years (94%) and 5 years (81%), compared to poor responders at 3 years (66%), and 5 years (56%). Patients with metastatic disease had a higher risk of death [Hazard Ratio (HR): 3.60, 95%CI: 2.52, 5.15, 11 studies]. Sex did not have an impact on EFS (HR females/males: 0.90, 95%CI: 0.54, 1.48, 3 studies), whereas age>18 years seems to adversely affect EFS (HR 18+/<10 years: 1.36, 95%CI: 1.09, 1.86, 3 studies). Our results summarize the collective experience on prognostic factors of high-grade osteosarcoma among children and young adults. Poor response to neoadjuvant chemotherapy and metastatic disease at diagnosis were confirmed as primary risk factors of poor outcome. International collaboration of osteosarcoma study groups is essential to improve survival.

BRAF alterations in pediatric low grade gliomas and mixed neuronal-glial tumors.

Low grade astrocytomas are the most common brain tumor in children. Recent studies have identified alterations in the BRAF serine/threonine kinase gene that result in mitogen activated protein kinase pathway activation. Herewith, we investigated the genetic changes of BRAF in pediatric low grade gliomas and their relation to pathological findings and Ki-67 proliferation index. The results showed gene fusions between KIAA1549 and BRAF in 66.7 % of tumors. The majority involved the KIAA1549-BRAF exon 16-exon 9 variant. Fusion junction between KIAA1549 exon 15 and BRAF exon 9 was found in five tumors, in which the myxoid component was the predominant. This has not been previously reported. No significant correlation was found between specific KIAA1549 and BRAF fusion junctions and Ki-67 index. All of the samples included in this study were tested for the presence of the BRAF(V600E) mutation, and no positive sample was found.

Extraintestinal manifestations in an infant with microvillus inclusion disease: complications or features of the disease?

UNLABELLED: Microvillus inclusion disease (MVID), a rare severe congenital enteropathy characterized by intracytoplasmic microvillous inclusions and variable brush border atrophy on intestinal epithelial cells histology, is associated with defective synthesis or abnormal function of the motor protein myosin Vb encoded by the MYO5B gene. Although MYO5B gene is expressed in all epithelial tissues, it is unclear so far whether organs other than intestine are affected in MVID patients. We report a case of an infant with MVID who presented liver dysfunction, hematuria, and Pneumocystis jiroveci pneumonia during the course of the disease. It is discussed whether extraintestinal manifestations in this patient are secondary consequences of MVID or might be features of the disease associated with altered MYO5B function. CONCLUSIONS: MVID is classically included in the differential diagnosis of congenital diarrhea of secretory type. Recent advances in our knowledge regarding the role of myosin Vb in the pathophysiology of MVID is expected to clarify the clinical spectrum of the disease and the possible primary involvement of organs other than intestine.

Survival patterns of childhood neuroblastoma: an analysis of clinical data from Southern-Eastern European countries.

The prognosis of children with neuroblastoma (NBL) can be dismal with significant variations depending on the stage and biology of the tumor. We assessed the event-free (EFS) and overall (OS) survival using harmonized data from three Southern-Eastern European (SEE) countries. Data for 520 incident NBL cases (2009-2018) were collected from Greece, Slovenia and Russia. Kaplan-Meier curves were fitted, and EFS/OS were derived from Cox proportional models by study variables including the protocol-based risk-group (low/observation, intermediate, high). Over one-third of cases were coded in the high-risk group, of which 23 children (4.4%) received treatment with anti-ganglioside 2 (GD2) mAb. Survival rates were inferior in older (OS 5-year; 1.5-4.9 years: 61%; EFS 5-year; 1.5-4.9 years: 48%) compared to children younger than 1.5 years (OS 5-year; <1.5 years: 91%; EFS 5-year; <1.5 years: 78%). Predictors of poor OS included stage 4 (hazard ratio, HR OS : 18.12, 95% confidence intervals, CI: 3.47-94.54), N-myc amplification (HR OS : 2.16, 95% CI: 1.40-3.34), no surgical excision (HR OS : 3.27, 95% CI: 1.91-5.61) and relapse/progression (HR OS : 5.46, 95% CI: 3.23-9.24). Similar unfavorable EFS was found for the same subsets of patients. By contrast, treatment with anti-GD2 antibody in high-risk patients was associated with decreased risk of death or unfavorable events (HR OS : 0.11, 95% CI: 0.02-0.79; HR EFS : 0.19, 95% CI: 0.07-0.52). Our results confirm the outstanding prognosis of the early NBL stages, especially in children <1.5 years, and the improved outcomes of the anti-GD2 treatment in high-risk patients. Ongoing high-quality clinical cancer registration is needed to ensure comparability of survival across Europe and refine our understanding of the NBL biology.

Immunohistochemical expression of cell-cycle regulators in pediatric embryonal brain tumors.

Embryonal tumors constitute the most common malignant brain tumor group in children. Experimental results indicate that genes involved in cell cycle and signal transduction are deregulated in medulloblastoma (MB) and atypical teratoid/rhabdoid tumors (AT/RT). The cell cycle is regulated by protein complexes composed of a regulatory subunit called Cyclin and a catalytic domain named Cyclin-dependent kinase (CDK). Cyclins and CDKs are in turn regulated by cyclin-dependent kinase inhibitors (CDKI) which inhibit cell-cycle progression. Cyclins D and Cyclin E are important for the passage of cells through G1 to S phase. P-27, a member of the universal CDKI family, is important in regulating the G1/S transition. Thus, the purpose of this study was to investigate the expression of p-27, Cyclin D3, and Cyclin E, and their possible prognostic significance in pediatric embryonal brain tumors. We retrospectively evaluated 51 children with embryonal tumors that were treated surgically in our institute. All patients had regular follow up examinations. The streptavidin-biotin HRP method was performed on paraffin sections for detection of p-27, Cyclin D3, and Cyclin E. There were 42 cases of MB and nine cases of AT/RT. Cyclin D3 expression was detected in 11/42 MB and 3/9 AT/RT patients. Cyclin E expression was detected in 28/42 MB and 8/9 AT/RT patients. High expression of Ki-67 (>50 %) and p-27 (>50 %) was observed in 23.8-73.8 % of MB patients. Combined high Ki-67 and p-27 expression was observed in 21.4 % cases of MB. In these cases there was expression of Cyclin E in 88.8 % and Cyclin D3 in 22.2 % of MB. No significant correlation was found between Ki-67 and p-27, Cyclin D3, and E. No correlation was found between Cyclin D3, Cyclin E, p-27, and overall survival. Increased p-27 and Cyclin E expression was detected in a substantial number of MB patients and in nearly all AT/RT patients. Further studies on a larger number of patients are needed to clarify a possible correlation of p-27 and Cyclin E with tumor behavior.

An unusual case of Cat-Eye syndrome phenotype and extragonadal mature teratoma: review of the literature.

BACKGROUND Cat-Eye syndrome (CES) with teratoma has not been previously reported. We present the clinical and molecular findings of a 9-month-old girl with features of CES and also a palpable midline neck mass proved to be an extragonadal mature teratoma, additionally characterized by array comparative genomic hybridization (aCGH). RESULTS High resolution oligonucleotide-based aCGH confirmed that the supernumerary marker chromosome (SMC) derived from chromosome 22, as was indicated by molecular cytogenetic analysis with fluorescence in situ hybridization (FISH). Additionally, aCGH clarified the size, breakpoints, and gene content of the duplication (dup 22q11.1q11.21; size:1.6 Mb; breakpoints: 15,438,946-17,041,773; hg18). The teratoma tissue was also tested with aCGH, in which the CES duplication was not found, but the analysis revealed three aberrations: del Xp22.3 (108,864-2788,689; 2.7 Mb hg18), dup Yp11.2 (6688,491-7340,982; 0.65 Mb, hg18), and dup Yq11.2q11.23 (12,570,853-27,177,133; 14.61 Mb, hg18). These results indicated 46 XY (male) karyotype of the teratoma tissue, making this the second report of mature extragonadal teratoma in a female neonate, probably deriving from an included dizygotic twin of opposite sex (fetus in fetu). CONCLUSIONS Our findings extend the phenotypic spectrum of CES syndrome, a disorder with clinical variability, pointing out specific dosage-sensitive genes that might contribute to specific phenotypic features.

Medulloblastoma in a child with fragile X syndrome.

Fragile X syndrome is the most common cause of inherited intellectual impairment and has been associated with decreased incidence of cancer. We present the case of an 11-year-old boy with a diagnosis of fragile X syndrome who presented with gait imbalance, headache, and episodes of vomiting. Radiological investigation revealed the presence of a posterior fossa tumor. The patient was operated upon and the tumor proved to be a medulloblastoma (MB). To the best of our knowledge this is the first reported case of MB in a child with fragile X syndrome.

A rare case of neonatal systemic xanthogranulomatosis with severe hepatic disease and metachronous skin involvement.

Juvenile xanthogranuloma (JXG) is a rare benign disorder of unknown pathogenesis, usually a self-limited condition. Extracutaneous systematic involvement is infrequent. We report one of the few documented cases of congenital systemic JXG, presenting with fever, jaundice, hepatosplenomegaly, ascites, pancytopenia, and delayed skin involvement. Liver biopsy established the diagnosis and JXG was not demonstrated in the bone marrow. Rapid deterioration of liver disease and pancytopenia, prompted us to administer immunosuppressive treatment (Langerhans cell histiocytosis-II Protocol). The patient's clinical condition improved and visceral and skin lesions showed gradual involution. The patient is still free of disease 4 years after the initial presentation.

Tumors of central and peripheral nervous system associated with inherited genetic syndromes.

There are several genetic syndromes that predispose to the development of tumors of the nervous system. In the present study, we provide a review of the tumors that are associated with neurofibromatosis type 1, neurofibromatosis type 2, tuberous sclerosis complex, von Hippel-Lindau disease, Li-Fraumeni syndrome, Cowden disease, Turcot syndrome, nevoid basal cell carcinoma syndrome (Gorlin syndrome) and rhabdoid predisposition syndrome, which are the most common.

Fish evaluation of additional cytogenetic aberrations and hyperdiploidy in childhood Burkitt lymphoma.

Beyond MYC rearrangement, Burkitt lymphoma (BL) often presents with additional aberrations. Biopsy touch imprints from 72 children with BL were tested with interphase fluorescence in-situ hybridization (i-FISH) for MYC, BCL2, BCL6, IGH, IGK and IGL rearrangements and copy-number aberrations involving 1q21/1p32, 7cen/7q31, 9cen/9p21, 13q14/13q34 and 17cen/17p13. Diploid status deviations were investigated with chromosome enumeration probes. MYC rearrangement was demonstrated in all cases. Additional aberrations included +1q (21/72:29.2%), +7q (14/72:19.4%), 13q- (14/72:19.4%), 9p-(6/72:8.3%) and hyperdiploidy (6/72:8.3%). Advanced clinical stage IV, +7q and 9p- were associated with shorter overall survival, with stage IV and +7q retaining prognostic significance on multivariate analysis. No relapse or death was reported among the hyperdiploid cases. This i-FISH investigation provides information on the genetic profile of BL and may prove valuable for patients with no karyotype analysis. Demonstration of hyperdiploidy could evolve research on clonal evolution pathways and probably identify a subgroup of children with favorable prognosis.

Rapid clinical-scale propagation of mesenchymal stem cells using cultures initiated with immunoselected bone marrow CD105+ cells.

Current clinical protocols used for isolation and purification of mesenchymal stem cells (MSC) are based on long-term cultures starting with bone marrow (BM) mononuclear cells. Using a commercially available immunoselection kit for enrichment of MSC, we investigated whether culture of enriched BM-CD105(+) cells could provide an adequate number of pure MSC in a short time for clinical use in the context of graft versus host disease and graft failure/rejection. We isolated a mean of 5.4 × 10(5) ± 0.9 × 10(5) CD105(+) cells from 10 small volume (10-25 ml) BM samples achieving an enrichment >100-fold in MSC. Seeding 2 × 10(3) immunoselected cells/cm(2) we were able to produce 2.5 × 10(8) ± 0.7 × 10(8) MSC from cultures with autologous serum enriched medium within 3 weeks. Neither haematopoietic nor endothelial cells were detectable even in the primary culture cell product. Expanded cells fulfilled both phenotypic and functional current criteria for MSC; they were CD29(+), CD90(+), CD73(+), CD105(+), CD45(-); they suppressed allogeneic T-cell reaction in mixed lymphocyte cultures and retained in vitro differentiation potential. Moreover, comparative genomic hybridization analysis revealed chromosomal stability of the cultured MSC. Our data indicate that adequate numbers of pure MSC suitable for clinical applications can be generated within a short time using enriched BM-CD105(+) cells.