Allogeneic hematopoietic cell transplantation is equally effective in secondary acute lymphoblastic leukemia (ALL) compared to de-novo ALL-a report from the EBMT registry.

Secondary acute lymphoblastic leukemia (s-ALL) comprises up to 10% of ALL patients. However, data regarding s-ALL outcomes is limited. To answer what is the role of allogeneic hematopoietic cell transplantation (HCT) in s-ALL, a matched-pair analysis in a 1:2 ratio was conducted to compare outcomes between s-ALL and de novo ALL (dn-ALL) patients reported between 2000-2021 to the European Society for Blood and Marrow Transplantation registry. Among 9720 ALL patients, 351 (3.6%) were s-ALL, of which 80 were in first complete remission (CR1) with a known precedent primary diagnosis 58.8% solid tumor (ST), 41.2% hematological diseases (HD). The estimated 2-year relapse incidence (RI) was 19.1% (95%CI: 11-28.9), leukemia-free survival (LFS) 52.1% (95%CI: 39.6-63.2), non-relapse mortality (NRM) 28.8% (95%CI: 18.4-40), GvHD-free, relapse-free survival (GRFS) 39.4% (95%CI: 27.8-50.7), and overall survival (OS) 60.8% (95%CI: 47.9-71.4), and did not differ between ST and HD patients. In a matched-pair analysis, there was no difference in RI, GRFS, NRM, LFS, or OS between s-ALL and dn-ALL except for a higher incidence of chronic GvHD (51.9% vs. 31.4%) in s-ALL. To conclude, patients with s-ALL who received HCT in CR1 have comparable outcomes to patients with dn-ALL.

Sequential vs myeloablative vs reduced intensity conditioning for patients with myelodysplastic syndromes with an excess of blasts at time of allogeneic haematopoietic cell transplantation: a retrospective study by the chronic malignancies working party of the EBMT.

The optimal conditioning for patients with higher risk MDS receiving potentially curative allogeneic haematopoietic stem cell transplant(allo-HCT) remains to be defined. This is particularly the case for patients with excess of blasts at time of allo-HCT. Sequential (Seq) conditioning, whereby chemotherapy is followed rapidly by transplant conditioning, offers an opportunity to decrease disease burden, potentially improving outcomes allo-HCT outcomes. Herein we present the only analysis comparing Seq to myeloablative (MAC) and reduced intensity conditioning (RIC) specifically focussed on MDS patients with excess of blasts at allo-HCT. 303 patients were identified in the EBMT registry, receiving RIC (n = 158), Seq (n = 105), and MAC (n = 40). Median follow-up was 67.2 months and median age at allo-HCT was 59.5 years (IQR 53.5-65.6). For the entire cohort, 3 y overall survival (OS) was 50% (95% CI 45-56%) and relapse free survival (RFS) 45% (95% CI 40-51%). No significant differences in OS (log-rank p = 0.13) and RFS (log-rank p = 0.18) were observed between conditioning protocols. On multivariable analysis, lower performance status, worse IPSS-R cytogenetics, sibling donor (compared to 8/8 MUD) and ≥20% blasts at allo-HCT were associated with worse outcomes. In conclusion, the Seq protocol did little to influence the outcome in this high-risk group of patients, with outcomes mostly determined by baseline disease risk and patient characteristics such as performance status.

Artificial intelligence methods to estimate overall mortality and non-relapse mortality following allogeneic HCT in the modern era: an EBMT-TCWP study.

Allogeneic haematopoietic cell transplantation (alloHCT) has curative potential counterbalanced by its toxicity. Prognostic scores fail to include current era patients and alternative donors. We examined adult patients from the EBMT registry who underwent alloHCT between 2010 and 2019 for oncohaematological disease. Our primary objective was to develop a new prognostic score for overall mortality (OM), with a secondary objective of predicting non-relapse mortality (NRM) using the OM score. AI techniques were employed. The model for OM was trained, optimized, and validated using 70%, 15%, and 15% of the data set, respectively. The top models, "gradient boosting" for OM (AUC = 0.64) and "elasticnet" for NRM (AUC = 0.62), were selected. The analysis included 33,927 patients. In the final prognostic model, patients with the lowest score had a 2-year OM and NRM of 18 and 13%, respectively, while those with the highest score had a 2-year OM and NRM of 82 and 93%, respectively. The results were consistent in the subset of the haploidentical cohort (n = 4386). Our score effectively stratifies the risk of OM and NRM in the current era but do not significantly improve mortality prediction. Future prognostic scores can benefit from identifying biological or dynamic markers post alloHCT.

Predictive Parameters in Patients Undergoing Percutaneous Hepatic Perfusion with Melphalan for Unresectable Liver Metastases from Uveal Melanoma: A Retrospective Pooled Analysis.

PURPOSE: The aim of this study was to identify positive predictors for survival in uveal melanoma (UM) patients treated with percutaneous hepatic perfusion with melphalan (M-PHP), by retrospectively pooling data from three centers. MATERIALS AND METHODS: Retrospective analysis including patients ([Formula: see text] 18 years) treated with M-PHP between February 2014 and December 2019 for unresectable liver-dominant or liver-only metastases from UM. Predictors for OS were assessed using uni- and multivariate analyses. Other study outcome measures were response rate, progression-free survival (PFS), liver progression-free survival (LPFS), overall survival (OS) and complications according to CTCAEv5.0. RESULTS: In total, 101 patients (47.5% males; median age 59.0 years) completed a minimum of one M-PHP. At a median follow-up time of 15.0 months, complete response (CR), partial response (PR), stable disease (SD) and progressive disease were seen in five (5.0%), 55 (54.5%), 30 (29.7%) and 11 (10.9%) patients, respectively, leading to a 89.1% disease control rate. Median PFS, LPFS and OS were 9.0, 11.0 and 20.0 months, respectively. Survival analyses stratified for radiological response demonstrated significant improved survival in patients with CR or PR and SD category. Treatment of the primary tumor with radiotherapy, ≥ 2 M-PHP and lactate dehydrogenase (LDH) < 248 U/L were correlated with improved OS. Thirty-day mortality was 1.1% (n = 2). Most common complication was hematological toxicity (self-limiting in most cases). CONCLUSION: M-PHP is safe and effective in patients with UM liver metastases. Achieving CR, PR or SD is associated with improved survival. Primary tumor treatment with radiotherapy, normal baseline LDH and > 1 M-PHP cycles are associated with improved OS.

Therapy-related myeloid neoplasms following treatment for multiple myeloma-a single center analysis.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) can be late complications following mutagenic treatment. Limited data is available on the outcome of patients developing therapy-related MDS and AML after treatment for multiple myeloma (MM). We identified 250 patients with therapy-associated MDS or AML in the Duesseldorf MDS registry. Of those, 50 patients were previously diagnosed with multiple myeloma (mm-MDS/AML). We compared them to patients with de novo MDS (n = 4862) and to patients with MDS following other underlying diseases (tMDS) (n = 200). mm-MDS patients and tMDS patients showed similar karyotypes and degrees of cytopenia. However, mm-MDS patients had significantly higher blast counts and more often belonged to the high-risk group according to the International Prognostic Scoring System (IPSS) (both p < 0.05). Although the rate of progression to AML was similar in mm-MDS and tMDS, both transformed significantly more often than de novo MDS (p < 0.05). Median overall survival of patients with mm-MDS (13 months; range: 1-99) and tMDS (13 months; range 0-160) was also similar yet significantly shorter than patients with de novo MDS (32 months; range 0-345 months; p < 0.05). Furthermore, survival of mm-MDS patients was not affected by myeloma activity. Despite significantly more high-risk disease and higher blast cell counts, myeloma-associated MDS-patients show features akin to other tMDS. Survival is similar to other tMDS and irrespective of myeloma remission status or transformation to AML. Thus, patient outcome is not determined by competing clones but rather by MDS governing the stem cell niche.

First-line high-dose therapy and autologous blood stem cell transplantation in patients with primary central nervous system non-Hodgkin lymphomas-a single-centre experience in 61 patients.

Primary central nervous system non-Hodgkin lymphomas (PCNS-NHLs) are extranodal B-cell lymphomas with poor prognosis. The role of high-dose therapy (HDT) followed by autologous blood stem cell transplantation (ASCT) as first-line therapy is still not clear. We retrospectively collected long-term follow up data of 61 consecutive patients with PCNS-NHL at the University Hospital Düsseldorf from January 2004 to December 2016. Thirty-six patients were treated with conventional chemoimmunotherapy (cCIT) only (CT-group). Seventeen patients received an induction cCIT followed by HDT and ASCT. In the CT-group, the overall response rate (ORR) was 61% (CR 47%, PR 14%), and there were 8% treatment-related deaths (TRD). Progression-free survival (PFS) was 31.8 months, and overall survival (OS) was 57.3 months. In the HDT-group, the ORR was 88% (59% CR, 29% PR), and there were 6% TRD. Median PFS and OS were not reached at 5 years. The 5-year PFS and OS were 64.7%. After a median follow up of 71 months, 10 patients (59%) were still alive in CR/PR following HDT and ASCT, one patient was treated for progressive disease (PD), and 7 had died (41%, 6 PD, 1 TRD). All patients achieving CR prior to HDT achieved durable CR. In the CT-group, 8 patients (22%) were alive in CR/PR after a median follow-up of 100 months. Twenty-eight patients died (78%, 24 PD, 2 TRD, 2 deaths in remission). In the univariate analysis, the HDT-group patients had significantly better PFS (not reached vs 31.8 months, p = 0.004) and OS (not reached vs 57.3 months, p = 0.021). The multivariate analysis showed HDT was not predictive for survival. Treatment with HDT + ASCT is feasible and offers the chance for long-term survival with low treatment-related mortality in younger patients. In this analysis, ORR, PFS and OS were better with HDT than with conventional cCIT alone. This result was not confirmed in the multivariate analysis, and further studies need to be done to examine the role of HDT in PCNSL.

The WHO 2016 diagnostic criteria for Acute Myeloid leukemia with myelodysplasia related changes (AML-MRC) produce a very heterogeneous entity: A retrospective analysis of the FAB subtype RAEB-T.

We studied 79 patients with AML-MRC or RAEB-T, who were later reclassified according to the WHO classification. Marrow slides were examined cytomorphologically with regard to dysplasia. Patients were followed up until March 2020. Thirty-one patients underwent allogeneic stem cell transplantation (median survival (ms) 16 months), 14 were treated with induction chemotherapy (ms 8.4 months), 18 received hypomethylating agents (ms 9.2 months), 16 received low dose chemotherapy or best supportive care (ms 2.4 months). Only 30.4 % fulfilled the morphologic WHO criteria. 46.8 % were classified as AML-MRC by an antecedent MDS, 54.4 % of the pts were classified by MDS-related chromosomal abnormalities. 5 % did not fulfill any of the criteria and were entered based on 20-29 % medullary blasts. There was no difference in ms between pts presenting with > 50 % dysplasia as compared to pts with dysplasia between 10 % and 50 % (ms 9.1 vs 9.9 months, p = n.s.) or for pts with antecedent MDS (ms 9.1 vs 8.9 months, p = n.s.). Myelodysplasia-related cytogenetic abnormalities were associated with a worse outcome (ms 8.1 vs 13.5 months, p = 0.026). AML-MRC in its current definition is a heterogenous entity. Dysplasia of ≥ 50 % in ≥ two lineages is not helpful for diagnostics and prognostication and therefore should be deleted in future classifications. We recommend utilizing the WHO guidelines for defining dysplasia (10 % or greater in ≥ 1 of the three myeloid cell lines) assisting in establishing the diagnosis of MDS.

Analysis of the impact of adherence to guidelines and expert advice in patients with myelodysplastic syndromes.

The European Leukemia Net (ELN) guidelines for treatment of myelodysplastic syndromes (MDS) connect heterogeneous MDS subgroups with a number of therapeutic options ranging from best supportive care to allogeneic stem cell transplantation (alloSCT). However, it is currently unknown whether adherence to guideline recommendations translates into improved survival. The sizeable database of the Duesseldorf MDS Registry allowed us to address this question. We first performed a retrospective analysis including 1698 patients (cohort 1) to whom we retrospectively applied the ELN guidelines. We compared patients treated according to the guidelines with patients who deviated from it, either because they received a certain treatment though it was not recommended or because they did not receive that treatment despite being eligible. We also performed a prospective study with 381 patients (cohort 2) who were seen in our department and received guideline-based expert advice. Again, we compared the impact of subsequent guideline-adherent versus non-adherent treatment. For the majority of treatment options (best supportive care, lenalidomide, hypomethylating agents, low-dose chemotherapy, and intensive chemotherapy), we found that adherence to the ELN guidelines did not improve survival in cohort 1. The same was true when patient management was prospectively enhanced through guideline-based treatment advice given by MDS experts (cohort 2). The only exceptions were alloSCT and iron chelation (ICT). Patients receiving ICT and alloSCT as recommended fared significantly better than those who were eligible but received other treatment. Our analysis underscores the limited survival impact of most MDS therapies and suggests to pursue alloSCT in all suitable candidates. Graphical abstract.

Therapy-related myelodysplastic syndromes deserve specific diagnostic sub-classification and risk-stratification-an approach to classification of patients with t-MDS.

In the current World Health Organization (WHO)-classification, therapy-related myelodysplastic syndromes (t-MDS) are categorized together with therapy-related acute myeloid leukemia (AML) and t-myelodysplastic/myeloproliferative neoplasms into one subgroup independent of morphologic or prognostic features. Analyzing data of 2087 t-MDS patients from different international MDS groups to evaluate classification and prognostication tools we found that applying the WHO classification for p-MDS successfully predicts time to transformation and survival (both p < 0.001). The results regarding carefully reviewed cytogenetic data, classifications, and prognostic scores confirmed that t-MDS are similarly heterogeneous as p-MDS and therefore deserve the same careful differentiation regarding risk. As reference, these results were compared with 4593 primary MDS (p-MDS) patients represented in the International Working Group for Prognosis in MDS database (IWG-PM). Although a less favorable clinical outcome occurred in each t-MDS subset compared with p-MDS subgroups, FAB and WHO-classification, IPSS-R, and WPSS-R separated t-MDS patients into differing risk groups effectively, indicating that all established risk factors for p-MDS maintained relevance in t-MDS, with cytogenetic features having enhanced predictive power. These data strongly argue to classify t-MDS as a separate entity distinct from other WHO-classified t-myeloid neoplasms, which would enhance treatment decisions and facilitate the inclusion of t-MDS patients into clinical studies.

Mapping distribution of brain metastases: does the primary tumor matter?

PURPOSE: Prior reports on the location and sizes of brain metastases almost entirely focus on patients with primary breast and pulmonary cancer. This is the first study comparing multiple other types of cancer that metastasize to the brain. METHODS: This monocentric retrospective study includes 369 untreated patients with 3313 intraaxial brain metastases. Following semi-manual segmentation of metastases on post-contrast T1WI, cumulative spatial probability distribution maps of brain metastases were created for the whole group and for all primary tumors. Furthermore, mixed effects logistic regression model analysis was performed to determine if the primary tumor, patient age, and patient sex influence lesion location. RESULTS: The cerebellum as location of brain metastases was proportionally overrepresented. Breast and pulmonary cancer caused higher number of brain metastases to what would normally be expected. Multivariate analyses revealed a significant accumulation of brain metastases from skin cancer in a frontal and from breast and gastrointestinal cancer in a cerebellar location. CONCLUSION: Distribution of brain metastases is very heterogeneous for the distinct primaries, possibly reflecting the diversity of mechanisms involved in brain metastases formation. In daily clinical practice distribution patters may be beneficial to predict the primary cancer site, if unknown.

Myelodysplastic syndromes without peripheral monocytosis but with evidence of marrow monocytosis share clinical and molecular characteristics with CMML.

MDS patients may present with monocytic marrow proliferation not fulfilling criteria for CMML. We analyzed MDS patients with or without a marrow monocytic proliferation by following up the amount of monocytic proliferation and characterizing their molecular profile. 315 MDS patients of Duesseldorf MDS registry were divided into two groups: A) 183 patients with monocytic esterase positive cells in marrow and monocytes between 101 and 900/µl in blood and B) 132 patients without monocytic esterase positive cells in marrow and monocytes in blood ≤100/µl. Twenty patients of each group were screened with regard to ASXL1, TET2, RUNX1, SETBP1, NRAS, and SRSF2 using Illumina myeloid panel. Group A patients were older, had significantly higher WBC, hemoglobin levels, neutrophils and platelets. CMML evolution rates were 4.9% and 1.5%, respectively (p=n.s.). TET2, NRAS and SRFS2 mutation frequencies were higher in group A and four patients had coexisting TET2 and SRFS2 mutation, which was shown to be characteristic but not specific for CMML. MDS patients with marrow monocytic proliferation have a more CMML-like pheno- and genotype and develop CMML more often. Those patients could potentially be very early stages of CMML or represent a CMML-like myeloid neoplasma with marrow adherence of the monocytic cell population.

Long-term survival of sorafenib-treated FLT3-ITD-positive acute myeloid leukaemia patients relapsing after allogeneic stem cell transplantation.

BACKGROUND: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia (AML) relapsing after allogeneic stem cell transplantation (allo-SCT) has a dismal prognosis with limited therapeutic options. FLT3-ITD kinase inhibition is a reasonable but palliative experimental treatment alternative in this situation. Information on long-term outcome is not available. METHODS: We performed a long-term follow-up analysis of a previously reported cohort of 29 FLT3-ITD-positive AML patients, which were treated in relapse after allo-SCT with sorafenib monotherapy. FINDINGS: With a median follow-up of 7.5 years, 6 of 29 patients (21%) are still alive. Excluding one patient who received a second allo-SCT, five patients (17%) achieved sustained complete remissions with sorafenib. Four of these patients are in treatment-free remission for a median of 4.4 years. INTERPRETATION: Sorafenib may enable cure of a proportion of very poor risk FLT3-ITD-positive AML relapsing after allo-SCT.

Assessment of Competence in EVAR Procedures: A Novel Rating Scale Developed by the Delphi Technique.

OBJECTIVE/BACKGROUND: To develop a procedure specific global rating scale for assessment of operator competence in endovascular aortic repair (EVAR). METHODS: A Delphi approach was used to achieve expert consensus. A panel of 32 international experts (median 300 EVAR procedures, range 200-3000) from vascular surgery (n = 21) and radiology (n = 11) was established. The first Delphi round was based on a review of endovascular skills assessment papers, stent graft instructions for use, and structured interviews. It led to a primary pool of 83 items that were formulated as global rating scale items with tentative anchors. Iterative Delphi rounds were executed. The panellists rated the importance of each item on a 5 point Likert scale. Consensus was defined as 80% of the panel rating an item 4 or 5 in the primary round and 90% in subsequent rounds. Consensus on the final assessment tool was defined as Cronbach's alpha > .8 after a minimum of three rounds. RESULTS: Thirty-two of 35 invited experts participated. Three rounds of surveys were completed with a completion rate of 100% in the first two rounds and 91% in round three. The 83 primary assessment items were supplemented with five items suggested by the panel and reduced to seven pivotal assessment items that reached consensus, Cronbach's alpha = 0.82. The seven item rating scale covers key elements of competence in EVAR stent placement and deployment. Each item has well defined grades with explicit anchors at unacceptable, acceptable, and superior performance on a 5 point Likert scale. CONCLUSION: The Delphi methodology allowed for international consensus on a new procedure specific global rating scale for assessment of competence in EVAR. The resulting scale, EndoVascular Aortic Repair Assessment of Technical Expertise (EVARATE), represents key elements in the procedure. EVARATE constitutes an assessment tool for providing structured feedback to endovascular operators in training.

Assessment of Competence in EVAR Stent Graft Sizing and Selection.

OBJECTIVES AND BACKGROUND: The aims of this study were to develop a test of competence in endovascular aortic repair (EVAR) stent graft sizing and selection; to examine the test for evidence of validity; and to explore the experience required for the task. METHODS: The test was developed based on a literature review resulting in 22 anatomical assessment points and a graft selection. Validity evidence was explored in an international cross sectional study. Twenty-two consultants with varying levels of experience in the field (novices, intermediates, and experts) were presented with computed tomography angiography of the aortic vessels from three patients. Test scores were based on summed z-scores using the anatomical measurements and graft choices of the experts as a reference. A proficiency score was established using the contrasting groups standard setting method. RESULTS: The assessment was shown to be reliable with an intraclass correlation coefficient of 0.83 (p<.001) and high internal consistency with a Cronbach's α of .91 (p<.001). Mann-Whitney U test showed that experts performed significantly better than novices and intermediates (p<.002 and p<.005, respectively). Regarding anatomical measurements, Mann-Whitney U test could discriminate between experts and novices (p=.002), between experts and intermediates (p=.010), and between novices and intermediates (p=.036). In stent selection the experts performed significantly better than both the novices and the intermediates (p=.002 and p=.007, respectively), while there was no significant difference between the two non-expert groups (p=1). A credible passing standard with appropriate consequences was established using the contrasting groups methods. CONCLUSION: This study presents a standardised and objective assessment tool of competence in vessel analysis and stent graft selection for endovascular aortic repair. This was supported by strong validity evidence with good internal consistency and discriminatory ability. The tool may be used to facilitate training and certification of future endovascular specialists.

A National Needs Assessment to Identify Technical Procedures in Vascular Surgery for Simulation Based Training.

OBJECTIVES AND BACKGROUND: Practical skills training in vascular surgery is facing challenges because of an increased number of endovascular procedures and fewer open procedures, as well as a move away from the traditional principle of "learning by doing." This change has established simulation as a cornerstone in providing trainees with the necessary skills and competences. However, the development of simulation based programs often evolves based on available resources and equipment, reflecting convenience rather than a systematic educational plan. The objective of the present study was to perform a national needs assessment to identify the technical procedures that should be integrated in a simulation based curriculum. DESIGN AND METHODS: A national needs assessment using a Delphi process was initiated by engaging 33 predefined key persons in vascular surgery. Round 1 was a brainstorming phase to identify technical procedures that vascular surgeons should learn. Round 2 was a survey that used a needs assessment formula to explore the frequency of procedures, the number of surgeons performing each procedure, risk and/or discomfort, and feasibility for simulation based training. Round 3 involved elimination and ranking of procedures. RESULTS: The response rate for round 1 was 70%, with 36 procedures identified. Round 2 had a 76% response rate and resulted in a preliminary prioritised list after exploring the need for simulation based training. Round 3 had an 85% response rate; 17 procedures were eliminated, resulting in a final prioritised list of 19 technical procedures. CONCLUSION: A national needs assessment using a standardised Delphi method identified a list of procedures that are highly suitable and may provide the basis for future simulation based training programs for vascular surgeons in training.

Transfer of minimally manipulated CMV-specific T cells from stem cell or third-party donors to treat CMV infection after allo-HSCT.

Cytomegalovirus (CMV) infection is a common, potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). We assessed prospectively the safety and efficacy of stem cell-donor- or third-party-donor-derived CMV-specific T cells for the treatment of persistent CMV infections after allo-HSCT in a phase I/IIa trial. Allo-HSCT patients with drug-refractory CMV infection and lacking virus-specific T cells were treated with a single dose of ex vivo major histocompatibility complex-Streptamer-isolated CMV epitope-specific donor T cells. Forty-four allo-HSCT patients receiving a T-cell-replete (D+ repl; n=28) or T-cell-depleted (D+ depl; n=16) graft from a CMV-seropositive donor were screened for CMV-specific T-cell immunity. Eight D+ depl recipients received adoptive T-cell therapy from their stem cell donor. CMV epitope-specific T cells were well supported and became detectable in all treated patients. Complete and partial virological response rates were 62.5% and 25%, respectively. Owing to longsome third-party donor (TPD) identification, only 8 of the 57 CMV patients transplanted from CMV-seronegative donors (D-) received antigen-specific T cells from partially human leukocyte antigen (HLA)-matched TPDs. In all but one, TPD-derived CMV-specific T cells remained undetectable. In summary, adoptive transfer correlated with functional virus-specific T-cell reconstitution in D+ depl patients. Suboptimal HLA match may counteract expansion of TPD-derived virus-specific T cells in D- patients.

Portal Supply and Venous Drainage of the Caudate Lobe in the Healthy Human Liver: Virtual Three-Dimensional Computed Tomography Volume Study.

OBJECTIVE: The venous vascular anatomy of the caudate lobe is exceptional. The purpose of this study was to assess portal inflow and venous outflow volumes of the caudate lobe. METHODS: Extrahepatic (provided by the first-order branches) versus intrahepatic (provided by the second- to third-order branches) portal inflow, as well as direct (via Spieghel veins) versus indirect (via hepatic veins) venous drainage patterns were analyzed in virtual 3-D liver maps in 140 potential live liver donors. RESULTS: The caudate lobe has a greater intrahepatic than extrahepatic portal inflow volume (mean 55 ± 26 vs. 45 ± 26%: p = 0.0763), and a greater extrahepatic than intrahepatic venous drainage (mean 54-61 vs. 39-46%). Intrahepatic drainage based on mean estimated values showed the following distribution: middle > inferior (accessory) > right > left hepatic vein. CONCLUSIONS: Sacrifice of extrahepatic caudate portal branches can be compensated by the intrahepatic portal supply. The dominant outflow via Spieghel veins and the negligible role of left hepatic vein in caudate venous drainage may suggest reconstruction of caudate outflow via Spieghel veins in instances of extended left hemiliver live donation not inclusive of the middle hepatic vein. The anatomical data and the real implication for living donors must be further verified by clinical studies.

Quantifying intrinsic and extrinsic control of single-cell fates in cancer and stem/progenitor cell pedigrees with competing risks analysis.

The molecular control of cell fate and behaviour is a central theme in biology. Inherent heterogeneity within cell populations requires that control of cell fate is studied at the single-cell level. Time-lapse imaging and single-cell tracking are powerful technologies for acquiring cell lifetime data, allowing quantification of how cell-intrinsic and extrinsic factors control single-cell fates over time. However, cell lifetime data contain complex features. Competing cell fates, censoring, and the possible inter-dependence of competing fates, currently present challenges to modelling cell lifetime data. Thus far such features are largely ignored, resulting in loss of data and introducing a source of bias. Here we show that competing risks and concordance statistics, previously applied to clinical data and the study of genetic influences on life events in twins, respectively, can be used to quantify intrinsic and extrinsic control of single-cell fates. Using these statistics we demonstrate that 1) breast cancer cell fate after chemotherapy is dependent on p53 genotype; 2) granulocyte macrophage progenitors and their differentiated progeny have concordant fates; and 3) cytokines promote self-renewal of cardiac mesenchymal stem cells by symmetric divisions. Therefore, competing risks and concordance statistics provide a robust and unbiased approach for evaluating hypotheses at the single-cell level.

Functional inhibition of mesenchymal stromal cells in acute myeloid leukemia.

Hematopoietic insufficiency is the hallmark of acute myeloid leukemia (AML) and predisposes patients to life-threatening complications such as bleeding and infections. Addressing the contribution of mesenchymal stromal cells (MSC) to AML-induced hematopoietic failure we show that MSC from AML patients (n=64) exhibit significant growth deficiency and impaired osteogenic differentiation capacity. This was molecularly reflected by a specific methylation signature affecting pathways involved in cell differentiation, proliferation and skeletal development. In addition, we found distinct alterations of hematopoiesis-regulating factors such as Kit-ligand and Jagged1 accompanied by a significantly diminished ability to support CD34+ hematopoietic stem and progenitor cells in long-term culture-initiating cells (LTC-ICs) assays. This deficient osteogenic differentiation and insufficient stromal support was reversible and correlated with disease status as indicated by Osteocalcin serum levels and LTC-IC frequencies returning to normal values at remission. In line with this, cultivation of healthy MSC in conditioned medium from four AML cell lines resulted in decreased proliferation and osteogenic differentiation. Taken together, AML-derived MSC are molecularly and functionally altered and contribute to hematopoietic insufficiency. Inverse correlation with disease status and adoption of an AML-like phenotype after exposure to leukemic conditions suggests an instructive role of leukemic cells on bone marrow microenvironment.