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This study aimed to assess portal and hepatic venous volumes as related to the planning of complex liver resections and segmental liver transplant.We analyzed 3-dimensional computed tomography of portal and hepatic vein territorial maps of 140 potential living related liver donors. Portal and hepatic vein maps were simulated both separately and in overlap (cross-mapping) to calculate inflow and outflow volumes.In total liver volume, the right hemiliver was always dominant (mean 64.7 ± 4.8%) and the right medial sector (mean 36.4 ± 6.8%) and segment 8 (mean 19.1 ± 4.3%) accounted for the largest volumes, whereas the left medial sector(mean 13.5 ± 3.1%) and segment 4A (mean 5.8 ± 1.8%) accounted for the smallest volumes (with exclusion of caudate lobe). The right hepatic vein was dominant for both right hemiliver and right lateral sector and had the largest drainage volume in total liver volume (mean 40.0 ± 11.2%). The left hepatic vein was dominant for both left hemiliver and left lateral sector but had the smallest drainage volume fortotal liver volume (mean 21.3 ± 5.0%). The middle hepatic vein drained 50.2 ± 12.5% of the right medial sector and 75.8 ± 15.4% of the left medial sector. In 67 cases, an accessory vein (inferior hepatic vein) drained 16.5 ± 13.2% ofthe right hemiliver, 31.4 ± 25.1% ofthe right lateral sector, 26.6 ± 23.2% of segment 7, and 37.4 ± 31.3% of segment 6.The portal and hepatic vein territorial anatomy was characterized by extensive individual variability. An extremely smallremnant volume (25% of total liver volume) precluded a minority of virtual extended left and a majority of extended right hepatectomies. Left trisectionectomy was associated with risky drainage from the middle hepatic vein, extensive segment 6 remnant congestion volume in 8% of cases, and right lateral sector-favorable inferior hepatic vein large drainage pattern in 13% of livers.

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 Supplementary Information The online version contains supplementary material available at 10.1007/s00277-020-04325-7.

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

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.

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.

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.

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.

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 drugrefractory 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.

Introduction Detailed knowledge of the biliary anatomy is essential to avoid complications in living donor liver transplantation. The aim of this study was to determine the optimal dosage of Gd-EOB-DTPA for contrast-enhanced magnetic resonance cholangiography (ce-MRC) with reference to contrast-enhanced CT cholangiography (ce-CTC). Materials and methods 30 potential living liver donors (PLLD) underwent both ce-CTC and ce-MRC. Ten candidates each received single, double or half-dose Gd-EOB-DTPA. Ce-MRC images with and without inversion recovery pulses (T1w ± IR) were acquired 20–30 min after intravenous contrast injection. Image data was quantitatively and qualitatively reviewed by two radiologists based on a on a 5-point scale. Data sets were compared using a Mann–Whitney- U -test or Wilcoxon-rank-sum-test. Kappa values were also calculated. Results All image series provided sufficient diagnostic information both showing normal biliary anatomy and variant bile ducts. Ce-CTC showed statistically significant better results compared to all ce-MRC data sets. T1w MRC with single dose Gd-EOB-DTPA proved to be superior to half and double dose in subjective and objective evaluation without a statistically significant difference. Conclusions Ce-MRC is at any dosage inferior to ce-CTC. As far as preoperative planning of bile duct surgery is focused on the central biliary anatomy, ce-MRC can replace harmful ce-CTC strategies, anyway. Best results were seen with single dose GD-EOB-DTPA on T1w MRC+IR.

Prognostic effect of calreticulin mutations in patients with myelofibrosis after allogeneic hematopoietic stem cell transplantation

The aim of this study was to investigate the feasibility of dynamic contrast-enhanced 7 T MRI of the liver using an eight-channel radiofrequency (RF) transmit/receive body-coil. 16 healthy subjects were examined on a 7 T MR system utilizing a custom-built eight-channel RF body-coil suitable for RF-shimming. The following data were acquired: (1) steady state free precession imaging, (2) T2w turbo spin echo imaging, (3) T1w in and opposed-phase imaging, (4) T1w 3D FLASH images pre-contrast and in arterial, portal-venous and venous phase and (5) a fat-saturated pre- and post-contrast 2D FLASH sequence. Visual evaluation of (1) the delineation of liver vasculature, (2) the overall image quality, and (3) artifact presence and consequent image impairment was performed. SNR of the liver parenchyma was measured for the contrast-enhanced 2D and 3D FLASH sequences. For statistical analysis, a Wilcoxon-Rank Test was used. Best delineation of non-enhanced liver vasculature and overall image quality was found for 2D FLASH MRI, with only slight improvement in vessel conspicuity after the application of contrast media. T2-weighted TSE imaging remained strongly impaired, falling short of diagnostic relevance and precluding a clinical application. Our results demonstrate the feasibility and diagnostic potential of dedicated contrast-enhanced 7 T liver MRI as well as the potential for non-contrast-enhanced angiographic application.

Ineffective hematopoiesis is a major characteristic of myelodysplastic syndromes (MDS) causing relevant morbidity and mortality. Mesenchymal stromal cells (MSC) have been shown to physiologically support hematopoiesis, but their contribution to the pathogenesis of MDS remains elusive. We show that MSC from patients across all MDS subtypes (n=106) exhibit significantly reduced growth and proliferative capacities accompanied by premature replicative senescence. Osteogenic differentiation was significantly reduced in MDS-derived MSC, indicated by cytochemical stainings and reduced expressions of Osterix and Osteocalcin. This was associated with specific methylation patterns that clearly separated MDS-MSC from healthy controls and showed a strong enrichment for biological processes associated with cellular phenotypes and transcriptional regulation. Furthermore, in MDS-MSC, we detected altered expression of key molecules involved in the interaction with hematopoietic stem and progenitor cells (HSPC), in particular Osteopontin, Jagged1, Kit-ligand and Angiopoietin as well as several chemokines. Functionally, this translated into a significantly diminished ability of MDS-derived MSC to support CD34+ HSPC in long-term culture-initiating cell assays associated with a reduced cell cycle activity. Taken together, our comprehensive analysis shows that MSC from all MDS subtypes are structurally, epigenetically and functionally altered, which leads to impaired stromal support and seems to contribute to deficient hematopoiesis in MDS.

Salvage therapy with azacitidine increases regulatory T cells in peripheral blood of patients with AML or MDS and early relapse after allogeneic blood stem cell transplantation

BACKGROUND Preoperative imaging and donor selection are cardinal components of adult-to-adult live donor liver transplantation (ALDLT). The purpose of this study was to evaluate our three-dimensional (3D) computed tomography image-derived computer-assisted surgical planning (3D CASP) in ALDLT. METHODS Eighty-three consecutive ALDLTs (71 right and 12 left) were planned with 3D CASP. Graft, remnant, and total liver volume compliance were calculated and compared with actual intraoperative values. Computed risk analysis encompassing territorial liver mapping, functional (safely drained) volumes, and outflow congestion volumes in grafts and remnants allowed for the individualized management of the middle hepatic vein (MHV). RESULTS Graft volume compliance was 13.5%±4.4%. Three small-for-size (SFS) grafts with lethal SFS syndrome (SFSS) had nonsignificant volume compliance with maximal graft volume-body weight ratios of less than 0.83. Seven SFS grafts with reversible or absent SFSS showed maximal graft volume-body weight ratios of 0.9 to 1.16. Significant differences were identified for (a) virtual graft and remnant congestion volumes of risky versus nonrisky MHV types (49%±6% and 34%±7% vs. 29%±8% and 33%±12%, P

The Bismuth-Corlette (BC) classification is the current preoperative standard to assess hilar cholangiocarcinomas (HC). The aim of this study is to evaluate the accuracy, sensitivity, and prognostic value of the BC classification. Data of patients undergoing resection for HC were analyzed. Endoscopic retrograde cholangiography and standard computed tomography were undertaken in all cases. Additional 3D-CT-reconstructions, magnetic resonance imaging, and percutaneous transhepatic cholangiography were obtained in selected patients. A systematic review and meta-analysis of the literature was performed. Ninety patients underwent resection of the hilar bile duct confluence, with right or left hemihepatectomy in 68 instances. The overall accuracy of the BC classification was 48 per cent. Rates of BC under- and over-estimation were 29 per cent and 23 per cent, respectively. The addition of MRI, 3D-CT-reconstructions, or percutaneous transhepatic cholangiography improved the accuracy to 49 per cent ( P = 1.0), 53 per cent ( P = 0.074), and 64 per cent ( P < 0.001), respectively. Lowest sensitivity rates were for BC Type IIIA/IIIB tumors. Meta-analysis of published BC data corresponding to 540 patients did not reach significance. The BC classification has low accuracy and no prognostic value in cases of HC undergoing resection.

Objective The purpose of this study was (1) to compare 2-dimensional computed tomographic (2D-CT) and 3D-CT computer-assisted preoperative surgical planning, and (2) to define the indications for the latter method. Background The determination of functional residual liver volumes and the imaging of intrahepatic anatomy are critical when planning complex liver resections. Patients and methods Prospective study of 202 consecutive patients who underwent high-risk procedures (extended right/left hepatectomies, central resections, polysegmentectomies, large atypical resections, repeated resections, and hepatectomies in the setting of abnormal liver parenchyma). Preoperative evaluation included 3D-CT computer-assisted surgical planning (3D-CASP) and conventional 2D-CT imaging. Endpoints of the study were (1) determination of resectability and (2) changes in operative strategy (resection modifications/extensions/intrahepatic vascular reconstructions). Results Thirty-four of 202 cases were considered nonresectable on the basis of both 2D and 3D imaging results. In 56 (33%) instances, 3D-CASP either changed the 2D strategy (expansion of resection, n = 40; intrahepatic vascular reconstructions, n = 13) or provided an entirely different approach (n = 3). Eleven (5.4%) cases were considered unresectable at laparotomy on the basis of poor liver quality (n = 8) or unfeasible vascular reconstructions resulting in remnants too small to sustain physiologic function (n = 3). Significant differences between resectional 2D and functional 3D remnant liver volumes were observed in extended left hepatectomies and left trisectionectomies. Conclusions 3D-CASP was particularly helpful in patients with unconventional resection planes and in those with central left tumors. Its main advantages were the individualized inflow/outflow virtual analyses and the accurate determination of safely perfused/drained retained liver volumes.

Background. The knowledge of "venous dominance" is essential to prevent serious venous congestion in live donor liver transplantation and extended liver resections. Aims. The purpose of our study was to delineate our proposed anatomic-functional classification of hepatic venous drainage. Methods. One hundred forty consecutive live liver donor candidates underwent three-dimensional computed tomography reconstructions and three-dimensional virtual hepatectomies. Five different venous dominance types were defined on drainage volumes or territories. "Risky" configurations were identified and classified. Results. The right hepatic vein (RHV) was dominant for the entire liver and right hemiliver (RHH) in most (83.5%) cases irrespective of the presence of inferior (accessory) hepatic veins (IHVs). The middle hepatic vein (MHV) was dominant for the total liver (TL) in 15.5% of cases and for the RHH in 27% of cases. The left hepatic vein was almost always (92%) dominant for the left hemiliver. When associated with a large IHV drainage volume, a RHV/IHV complex dominant for the TL led to a RHH dominant MHV (mean 59.5%RHH) if the IHV was not reconstructed. Conclusions. Our proposed anatomic-functional classification provides a valuable insight into hepatic vein dominance patterns. RHH venous drainage patterns at "high risk" for venous congestion include (1) a dominant MHV for the TL and (2) a dominant RHV/IHV complex with a large IHV drainage volume.

Background The aim of this study was to delineate an algorithm for donor and recipient criteria and middle hepatic vein (MHV) management in right-graft live-donor liver transplantation (LDLT) on the basis of computerized 3-dimensional computed tomographic image analysis. Methods Data on 94 consecutive right-graft LDLTs were prospectively collected. Graft and remnant data for the first 23 cases were retrospectively evaluated by means of 3-dimensional computed tomographic reconstructions, and on the basis of that preliminary series, a graft selection algorithm using 3 parameters—hepatic vein dominance classification, graft and remnant graft volume/body weight ratios, and congestion volumes—was created. It was subsequently applied to the next 71 right-graft LDLTs. Results Fifty-nine right grafts contained the MHV. Four of the 12 grafts with no MHVs required MHV reconstructions. In 18 cases, small liver grafts were used. The postoperative function of liver grafts and remnants with versus without MHVs was not statistically different. Conclusions The proposed algorithm favored the inclusion of the MHV with the right grafts. It also allowed for the procurement of grafts that were potentially small for size without compromising donor or recipient safety.

Background There is limited information on the regional inflammatory effects of mechanical ventilation and endotoxemia on the production of acute lung injury. Measurement of F-fluorodeoxyglucose (F-FDG) uptake with positron emission tomography allows for the regional, in vivo and noninvasive, assessment of neutrophilic inflammation. The authors tested whether mild endotoxemia combined with large tidal volume mechanical ventilation bounded by pressures within clinically acceptable limits could yield measurable and anatomically localized neutrophilic inflammation. Methods Sheep were mechanically ventilated with plateau pressures = 30-32 cm H2O and positive end-expiratory pressure = 0 for 2 h. Six sheep received intravenous endotoxin (10 ng x kg x min), whereas six did not (controls), in sequentially performed studies. The authors imaged with positron emission tomography the intrapulmonary kinetics of infused N-nitrogen and F-FDG to compute regional perfusion and F-FDG uptake. Transmission scans were used to assess aeration. Results Mean gas fraction and perfusion distribution were similar between groups. In contrast, a significant increase in F-FDG uptake was observed in all lung regions of the endotoxin group. In this group, F-FDG uptake in the middle and dorsal regions was significantly larger than that in the ventral regions. Multivariate analysis showed that the F-FDG uptake was associated with regional aeration (P < 0.01) and perfusion (P < 0.01). Conclusions Mild short-term endotoxemia in the presence of heterogeneous lung aeration and mechanical ventilation with pressures within clinically acceptable limits produces marked spatially heterogeneous increases in pulmonary neutrophilic inflammation. The dependence of inflammation on aeration and perfusion suggests a multifactorial basis for that finding. F-FDG uptake may be a sensitive marker of pulmonary neutrophilic inflammation in the studied conditions.

Intrahepatic anatomic variations have been associated with both morbidity and mortality associated with live donor liver transplantation. The aim of our study was to evaluate central hilar and peripheral segmental vascular/biliary anatomy in right graft living donor liver transplantation. From January 2003 to August 2007, three-dimensional (3D) computed tomography (CT) reconstructions and virtual 3D hepatectomies were performed in 71 consecutive right graft live liver donors. A combined two-level classification system addressing the four possible combinations of normal (N) and abnormal (A) central hilar and peripheral features based on both the existing classification and our own classification for portal (portal vein, PV), arterial (hepatic artery, HA) and biliary (bile duct, BD) systems was defined as follows: type I, N/N; type II, N/A; type III, A/N; and type IV, A/A. A simultaneous normal central hilar and peripheral segmental (N/N) anatomy for each system (PV, HA, BD) was found in

The effect of body posture on regional ventilation during bronchoconstriction is unknown. In five subjects with asthma, we measured spirometry, low-frequency (0.15-Hz) lung elastance, and resistance and regional ventilation by intravenous 13NN-saline positron emission tomography before and after nebulized methacholine. The subjects were imaged prone on 1 day and supine on another, but on both days the methacholine was delivered while prone. From the residual 13NN after washout, ventilation defective areas were defined, and their location, volume, ventilation, and fractional gas content relative to the rest of the lung were calculated. Independent of posture, all subjects developed ventilation defective areas. Although ventilation within these areas was similarly reduced in both postures, their volume was smaller in prone than supine (25 vs. 41%, P < 0.05). The geometric center of the ventilation defective areas was gravitationally dependent relative to that of the lung in both postures. Mean lung fractional gas content was greater in the prone position before methacholine and did not increase as much as in the supine position after methacholine. In the prone position at baseline, areas that became ventilation defects had lower gas content than the rest of the lung. In both positions at baseline, there was a gradient of gas content in the vertical direction. In asthma, the size and location of ventilation defects is affected by body position and likely affected by small differences in lung expansion during bronchoconstriction.

Introduction The aim of this study was to analyze vascular and biliary variants at the hilar and sectorial level in right graft adult living donor liver transplantation. Methods From January 2003 to June 2007, 139 consecutive live liver donors underwent three-dimensional computed tomography (3-D CT) reconstructions and virtual 3-D liver partitioning. We evaluated the portal (PV), arterial (HA), and biliary (BD) anatomy. Results The hilar and sectorial biliary/vascular anatomy was predominantly normal (70%–85% and 67%–78%, respectively). BD and HA showed an equal incidence (30%) of hilar anomalies. BD and PV had a nearly identical incidence of sectorial abnormalities (64.7% and 66.2%, respectively). The most frequent “single” anomaly was seen centrally in HA (21%) and distally in BD (18%). A “double” anomaly involved BD/HA (7.2%) in the hilum, and HA/PV and BD/PV (6.5% each) sectorially. A “triple” anomaly involving all systems was found at the hilum in 1.4% of cases, and at the sectorial level in 9.4% of instances. Simultanous central and distal abnormalities were rare. In this study, 13.7% of all donor candidates showed normal hilar and sectorial anatomy involving all 3 systems. A simultaneous central and distal “triple” abnormality was not encountered. A combination of “triple” hilar anomaly with “triple” sectorial normality was observed in 2 cases (1.4%). A central “triple” normality associated with a distal “triple” abnormality occurred in 7 livers (5%). Conclusions Our data showed a variety of “horizontal” (hilar or sectorial) and “vertical” (hilar and sectorial) vascular and biliary branching patterns, providing comprehensive assistance for surgical decision-making prior to right graft hepatectomy.

Rationale and Objectives Dynamic positron emission tomographic imaging of the radiotracer 2-deoxy-2-[ 18 F]fluoro- d -glucose ( 18 F-FDG) is increasingly used to assess metabolic activity of lung inflammatory cells. To analyze the kinetics of 18 F-FDG in brain and tumor tissues, the Sokoloff model has been typically used. In the lungs, however, a high blood-to-parenchymal volume ratio and 18 F-FDG distribution in edematous injured tissue could require a modified model to properly describe 18 F-FDG kinetics. Materials and Methods We developed and validated a new model of lung 18 F-FDG kinetics that includes an extravascular/noncellular compartment in addition to blood and 18 F-FDG precursor pools for phosphorylation. Parameters obtained from this model were compared with those obtained using the Sokoloff model. We analyzed dynamic PET data from 15 sheep with smoke or ventilator-induced lung injury. Results In the majority of injured lungs, the new model provided better fit to the data than the Sokoloff model. Rate of pulmonary 18 F-FDG net uptake and distribution volume in the precursor pool for phosphorylation correlated between the two models ( R 2 = 0.98, 0.78), but were overestimated with the Sokoloff model by 17% ( P P 18 F-FDG distribution volumes was up to 13% and 49% of lung tissue volume in smoke- and ventilator-induced lung injury, respectively. Conclusion The lung-specific model predicted 18 F-FDG kinetics during acute lung injury more accurately than the Sokoloff model and may provide new insights in the pathophysiology of lung injury.

RATIONALE: In a pulmonary process characterized by spatially heterogeneous loss of aeration, the impairment of gas exchange is expected to depend on the regional distribution of perfusion relative to that of aeration. OBJECTIVES: To investigate how regional aeration, shunt, and perfusion are interrelated at different levels of end-expiratory pressure and how their interplay relates to global shunt fraction in acute lung injury. METHODS: Regional shunt and perfusion were assessed by imaging with positron emission tomography the pulmonary kinetics of [(13)N]nitrogen infused in saline solution in five sheep after lung lavage. The lung field was divided in six horizontal regions. MEASUREMENTS AND MAIN RESULTS: Each animal showed an inverse relation between regional shunt (Fs) and gas (Fg) fractions: Fs = -m . Fg + Fs(0). This relation was similar among animals (m = 1.25 +/- 0.14, Fs(0) = 0.75 +/- 0.15) and invariant with end-expiratory pressure, despite lack of correlation between global shunt and gas fractions and large interanimal variability in global shunt fraction. When this relation was used to estimate global shunt fraction as a perfusion-weighted average of the estimates of regional shunt fraction derived from regional gas fraction, 72% of the interanimal variability in global shunt fraction could be explained. CONCLUSIONS: Despite large interanimal variability in global shunt fraction, there was a consistent inverse relation between regional shunt and gas fractions, independent of end-expiratory pressure. Most of the interanimal variability in global shunt fraction could be explained by the combined effect of this relation and the distribution of perfusion on regional shunt, rather than by differences in global aeration.

Bronchoconstriction in asthma results in patchy ventilation forming ventilation defects (VDefs). Patchy ventilation is clinically important because it affects obstructive symptoms and impairs both gas exchange and the distribution of inhaled medications. The current study combined functional imaging, oscillatory mechanics and theoretical modelling to test whether the degrees of constriction of airways feeding those units outside VDefs were related to the extent of VDefs in bronchoconstricted asthmatic subjects. Positron emission tomography was used to quantify the regional distribution of ventilation and oscillatory mechanics were measured in asthmatic subjects before and after bronchoconstriction. For each subject, ventilation data was mapped into an anatomically based lung model that was used to evaluate whether airway constriction patterns, consistent with the imaging data, were capable of matching the measured changes in airflow obstruction. The degree and heterogeneity of constriction of the airways feeding alveolar units outside VDefs was similar among the subjects studied despite large inter-subject variability in airflow obstruction and the extent of the ventilation defects. Analysis of the data amongst the subjects showed an inverse relationship between the reduction in mean airway conductance, measured in the breathing frequency range during bronchoconstriction, and the fraction of lung involved in ventilation defects. The current data supports the concept that patchy ventilation is an expression of the integrated system and not just the sum of independent responses of individual airways.

Accurate preoperative prediction of functional donor and remnant hemiliver volumes in live donor liver transplantation is essential in preventing postoperative liver failure and optimizing safety. Our aim was (1) to evaluate volume variability associated with multiphasic CT imaging and (2) to determine over- or under-estimations of 3-D CT graft-volume assessments based on 'largest' versus 'smallest' CT phases with respect to intraoperative findings. Native, arterial and venous phase CT images from 83 potential live liver donors were subject to 3-D CT liver volume calculations and virtual 3-D liver partitioning. Estimates were compared to intraoperative volumes obtained in 43 cases. Calculated (preoperative) graft-volume-body-weight-ratios (GVBWR) versus measured (intraoperative) graft-weight-body-weight-ratios (GWBWR) were analyzed. Significant differences in total liver volume- and in graft-liver volume calculations were found among the largest (venous) and smallest (native) CT phases. High significant overestimations were observed in graft-volume determinations and in GVBWR-calculations based on the 'largest' CT phase when compared to intraoperatively obtained graft-weight and -GWBWR values. In contrast, differences among intraoperative measurements and preoperative calculations based on the 'smallest' CT phase yielded less significant overestimations. While 3-D CT volumetry based on the 'largest' (venous) CT phase is associated with considerable overestimation, 3-D volumetry based on the 'smallest' (native) CT phase accurately matches the intraoperative findings.

Reply to ‘Allogeneic hematopoietic cell transplantation for concurrent multiple myeloma and myelodysplastic syndrome’

Frequency and prognostic impact of casein kinase 1A1 mutations in MDS patients with deletion of chromosome 5q

AIM: To investigate middle hepatic vein (MHV) management in adult living donor liver transplantation and safer remnant volumes (RV). METHODS: There were 59 grafts with and 12 grafts without MHV (including 4 with MHV-5/8 reconstructions). All donors underwent our five-step protocol evaluation containing a preoperative protocol liver biopsy Congestive vs non-congestive RV, remnant-volume-body-weight ratios (RVBWR) and postoperative outcomes were evaluated in 71 right graft living donors. Dominant vs non-dominant MHV anatomy in total liver volume (d-MHV/TLV vs nd-MHV/TLV) was constellated with large/small congestion volumes (CV-index). Small for size (SFS) and non-SFS remnant considerations were based on standard cut-off- RVBWR and RV/TLV. Non-congestive RVBWR was based on non-congestive RV. RESULTS: MHV and non-MHV remnants showed no significant differences in RV, RV/TLV, RVBWR, total bilirubin, or INR. SFS-remnants with RV/TLV < 30% and non-SFS-remnants with RV/TLV ≥ 30% showed no significant differences either. RV and RVBWR for non-MHV (n = 59) and MHV-containing (n = 12) remnants were 550 ± 95 mL and 0.79 ± 0.1 mL vs 568 ± 97 mL and 0.79 ± 0.13, respectively (P = 0.423 and P = 0.919. Mean left RV/TLV was 35.8% ± 3.9%. Non-MHV (n = 59) and MHV-containing (n = 12) remnants (34.1% ± 3% vs 36% ± 4% respectively, P = 0.148. Eight SFS-remnants with RVBWR < 0.65 had a significantly smaller RV/TLV than 63 non-SFS-remnants with RVBWR ≥ 0.65 [SFS: RV/TLV 32.4% (range: 28%-35.7%) vs non-SFS: RV/TLV 36.2% (range: 26.1%-45.5%), P < 0.009. Six SFS-remnants with RV/TLV < 30% had significantly smaller RVBWR than 65 non-SFS-remnants with RV/TLV ≥ 30% (0.65 (range: 0.6-0.7) vs 0.8 (range: 0.6-1.27), P < 0.01. Two (2.8%) donors developed reversible liver failure. RVBWR and RV/TLV were concordant in 25%-33% of SFS and in 92%-94% of non-SFS remnants. MHV management options including complete MHV vs MHV-4A selective retention were necessary in n = 12 vs n = 2 remnants based on particularly risky congestive and non-congestive volume constellations. CONCLUSION: MHV procurement should consider individual remnant congestive- and non-congestive volume components and anatomy characteristics, RVBWR-RV/TLV constellation enables the identification of marginally small remnants.

Bronchoconstriction in asthma leads to heterogeneous ventilation and the formation of large and contiguous ventilation defects in the lungs. However, the regional adaptations of pulmonary perfusion (Q) to such ventilation defects have not been well studied.We used positron emission tomography to assess the intrapulmonary kinetics of intravenously infused tracer nitrogen-13 ((13)NN), and measured the regional distributions of ventilation and perfusion in 11 patients with mild asthma. For each subject, the regional washout kinetics of (13)NN before and during methacholine-induced bronchoconstriction were analyzed. Two regions of interest (ROIs) were defined: one over a spatially contiguous area of high tracer retention (TR) during bronchoconstriction and a second one covering an area of similar size, showing minimal tracer retention (NR).Both ROIs demonstrated heterogeneous washout kinetics, which could be described by a two-compartment model with fast and slow washout rates. We found a systematic reduction in regional Q to the TR ROI during bronchoconstriction and a variable and nonsignificant change in relative Q for NR regions. The reduction in regional Q was associated with an increase in regional gas content of the TR ROI, but its magnitude was greater than that anticipated solely by the change in regional lung inflation.During methacholine-induced bronchoconstriction, perfusion to ventilation defects are systematically reduced by a relative increase in regional pulmonary vascular resistance.

Dibenzoylmethane derivatives with one (L1H2) or both (L2H3, L3H3) benzenes linked at their ortho positions to 4,6-di-tert-butylphenol moieties by two-carbon linkers have been synthesized. The mono-beta-diketone-monophenol ligand L1H2 is metalated by titanium alkoxides to form the homoleptic complex (L1)2Ti and heteroleptic complexes (L1)Ti([OCH2CH2]2NR) (R = H, CH3), and reacts with Cp3Sc to form CpSc(L1). These are the first examples of complexes of a beta-diketonate ligand which is further chelating to a single metal center. Crystallographic analysis of (L1)2Ti indicates that the 10-membered ring allows chelation of the phenoxide with little strain, and both fac and mer geometries are accessible in solution. Protonolysis of the second cyclopentadienyl ring of Cp3Sc appears to take place by an indirect, Cp3Sc-catalyzed pathway.

The objective of our study was to determine the diagnostic performance of MRI based on a HASTE sequence for the detection of pulmonary nodules in comparison with MDCT.Thirty patients with known pulmonary nodules underwent both MRI and CT. CT of the lung served as the standard of reference and was performed on a 4-MDCT scanner using a routine protocol. MRI was performed with axial and coronal HASTE sequences using a high-performance 1.5-T MR scanner. Image data were analyzed in three steps after completion of all data acquisition. Step 1 was the analysis of all the CT image data. Step 2 was the analysis of all the MR image data while blinded to the results of the CT findings. Step 3 closed with a simultaneous review of all corresponding CT and MRI data, including a one-to-one correlation of the size and location of all the nodules that were detected.Compared with the sensitivity of CT, the sensitivity values for the HASTE MR sequence were as follows: 73% for lesions less than 3 mm, 86.3% for lesions between 3 and 5 mm, 95.7% for lesions between 6 and 10 mm, and 100% for lesions larger than 10 mm. The overall sensitivity of the HASTE sequence for the detection of all pulmonary lesions was 85.4%.An MRI examination that consists of a HASTE sequence allows one to detect, exclude, or monitor pulmonary lesions that are 5 mm and bigger. Suspicious lesions smaller than 5 mm still need to be validated using CT.

Recent PET imaging data from bronchoconstricted sheep (Vidal Melo et al., 2005) showed that V /Q distributions were bimodal and topographically patchy, but including a substantial heterogeneity at scales2.2 ml. In this paper, we reanalyze the experimental data to establish the contribution of ventilation (V (r)) heterogeneity to the bimodality in V /Q . This analysis demonstrates that the distribution of V (r) during bronchoconstriction was bimodal with large patches of severe hypoventilation occupying an average of 41% of the imaged lung. The degree of hypoventilation to these regions was highly correlated with the degree of oxygenation impairment, but was quite variable amongst animals in spite of consistent degrees of mechanical obstruction. Remarkably, those regions were found to be hyperventilated before methacholine and their degree of hyperventilation was correlated with their degree of hypoventilation during bronchoconstriction. These data suggest that improving the uniformity of ventilation at baseline may be a desirable therapeutic target if the risk of severe hypoxemia during asthma attacks is to be minimized and/or the distribution of inhaled pharmaceuticals is to be optimized.

Multi–detector row computed tomography was performed for the preharvest evaluation of 14 potential living liver donors. Both a biliary contrast agent and a conventional iodinated contrast agent were administered intravenously. This protocol included acquisition of three subsequent scans and allowed accurate assessment of the hepatic parenchymal morphology and volumetrics and a detailed analysis of the biliary and vascular anatomies. © RSNA, 2002

Recently, somatic frameshift mutations in exon 9 of calreticulin (CALR) have been identified in a large proportion of JAK2- and MPL-negative myelofibrosis and essential thrombocythemia (ET) patients.1, 2 The calreticulin gene encoding a 48-kDa protein is located on chromosome 19p13.3 and is retained in the endoplasmic reticulum through its C-terminal KDEL motif,3 but is also found in the cell membrane and cytoplasm.4 Physiologic functions of CALR include control of proper protein folding as a chaperone,3 calcium homeostasis as a calcium-binding protein5 as well as interaction and regulation with nuclear hormone receptors.6 Thus, CALR regulates key cellular functions like proliferation and apoptosis.4

We read with great interest the paper of Lopez-Otero et al.,1 in which they describe a feasible approach of using high-dose chemotherapy and autologous transplantation in patients with multiple myeloma without cryopreservation of the PBSCs. In their study, they used a G-CSF-based steady-state mobilization strategy immediately followed by a single dose of high-dose melphalan (200 mg/m2, day −1) and transplantation of the fridge-stored (+4 °C) autologous, unmanipulated PBSCs on day 0. Using this regimen they observed response and survival rates comparable to those achieved by a classical transplantation strategy using cryopreserved autografts, which has also been previously demonstrated by Carey et al. and several other groups.2, 3

Introduction The purpose of this study was to determine the impact of our classification on right graft adult live donor liver transplantation (ALDLT) outcomes. Methods Three-dimensional computed tomography (CT) reconstructions were used to classify the hilar and sectorial biliary anatomy of 71 consecutive live liver donors. Four possible clinical types were defined, based on the normal (N) or abnormal (A) features of the corresponding hilar/sectorial ducts: type I, N/N; type II, N/A; type III, A/N; and type IV, A/A. We subsequently performed an analysis of the operative outcomes based on the donor anatomy. Results Type I was encountered in 47.9% of cases, type II in 29.6%, type III in 19.7%, and type IV in 2.8%. The highest incidence of biliodigestive anastomoses was observed with type III (50%) and type IV (100%) variants. Type I was associated with the highest incidence of single anastomoses (single vs multiple, P = .001) and of single bile duct anastomoses (single vs multiple, P = .004). Type III was associated with more multi-duct reconstructions compared with types I and II (P = .002 and P = .05, respectively). There were no significant differences in early (P = .08) or late (P = .33) biliary complications, or deaths due to a biliary etiology (P = .55) among the 4 types. Conclusions Complex biliary anatomy in the right liver graft usually requires biliodigestive anastomoses, which are often associated with complicated procedures. The precise delineation of the intrahepatic biliary anatomy provided by our clinical classification may contribute to better morbidity and mortality rates, especially for grafts at greatest anatomical risk.