Advancing Cardiovascular Drug Screening Using Human Pluripotent Stem Cell-Derived Cardiomyocytes.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have emerged as a promising tool for studying cardiac physiology and drug responses. However, their use is largely limited by an immature phenotype and lack of high-throughput analytical methodology. In this study, we developed a high-throughput testing platform utilizing hPSC-CMs to assess the cardiotoxicity and effectiveness of drugs. Following an optimized differentiation and maturation protocol, hPSC-CMs exhibited mature CM morphology, phenotype, and functionality, making them suitable for drug testing applications. We monitored intracellular calcium dynamics using calcium imaging techniques to measure spontaneous calcium oscillations in hPSC-CMs in the presence or absence of test compounds. For the cardiotoxicity test, hPSC-CMs were treated with various compounds, and calcium flux was measured to evaluate their effects on calcium dynamics. We found that cardiotoxic drugs withdrawn due to adverse drug reactions, including encainide, mibefradil, and cetirizine, exhibited toxicity in hPSC-CMs but not in HEK293-hERG cells. Additionally, in the effectiveness test, hPSC-CMs were exposed to ATX-II, a sodium current inducer for mimicking long QT syndrome type 3, followed by exposure to test compounds. The observed changes in calcium dynamics following drug exposure demonstrated the utility of hPSC-CMs as a versatile model system for assessing both cardiotoxicity and drug efficacy. Overall, our findings highlight the potential of hPSC-CMs in advancing drug discovery and development, which offer a physiologically relevant platform for the preclinical screening of novel therapeutics.

Arthroscopic Superior Capsular Reconstruction With Tensor Fascia Lata Allograft for Irreparable Rotator Cuff Tears: Clinical and Radiologic Outcomes for a Minimum 1-Year Follow-Up.

PURPOSE: To confirm the radiologic and clinical outcomes after performing arthroscopic superior capsular reconstruction (ASCR) using a tensor fascia lata (TFL) allograft. METHODS: Thirty-three patients with irreparable rotator cuff tears were treated with ASCR with a TFL allograft. The mean age and follow-up period were 62 years and 20.1 months, respectively. TFL allografts were used as 3, 4, and 6 layers, and the graft thickness was 3.7, 3.9, and 5.4 mm, respectively. Range of motion, visual analog scale (VAS) pain score, American Shoulder and Elbow Surgeons score, and Constant score were evaluated preoperatively and at the final follow-up. The pre-, postoperative, and final acromiohumeral distances (AHD) were compared. The graft integrity was checked through a follow-up magnetic resonance imaging at least 6 months after surgery. RESULTS: Torn grafts were identified in 6 cases (19%). AHD significantly increased from 5.0 to 8.0 mm postoperatively (P < .0001). However, there was no significant difference of 5.0 mm at the final follow-up AHD. Five cases (83%) of torn grafts were induced in the 3-layered graft sheet group, but the difference was not statistically significant (P = .067). Visual analog scale, forward elevation, internal rotation, American Shoulder and Elbow Surgeons, and Constant scores significantly improved at the last follow-up. Two cases of early infection were confirmed and the graft materials were all removed. CONCLUSIONS: Despite the possibility of early infection, ASCR using TFL allograft is a reliable procedure for the irreparable rotator cuff tear. In particular, if the number of layers of TFL allograft increases, it is judged that it could become a more effective graft. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Nanoscale imaging reveals miRNA-mediated control of functional states of dendritic spines.

Dendritic spines are major loci of excitatory inputs and undergo activity-dependent structural changes that contribute to synaptic plasticity and memory formation. Despite the existence of various classification types of spines, how they arise and which molecular components trigger their structural plasticity remain elusive. microRNAs (miRNAs) have emerged as critical regulators of synapse development and plasticity via their control of gene expression. Brain-specific miR-134s likely regulate the morphological maturation of spines, but their subcellular distributions and functional impacts have rarely been assessed. Here, we exploited atomic force microscopy to visualize in situ miR-134s, which indicated that they are mainly distributed at nearby dendritic shafts and necks of spines. The abundance of miR-134s varied between morphologically and functionally distinct spine types, and their amounts were inversely correlated with their postulated maturation stages. Moreover, spines exhibited reduced contents of miR-134s when selectively stimulated with beads containing brain-derived neurotropic factor (BDNF). Taken together, in situ visualizations of miRNAs provided unprecedented insights into the "inverse synaptic-tagging" roles of miR-134s that are selective to inactive/irrelevant synapses and potentially a molecular means for modifying synaptic connectivity via structural alteration.

Minimizing Motion Artifacts in Intravital Microscopy Using the Sedative Effect of Dexmedetomidine.

Among intravital imaging instruments, the intravital two-photon fluorescence excitation microscope has the advantage of enabling real-time 3D fluorescence imaging deep into cells and tissues, with reduced photobleaching and photodamage compared with conventional intravital confocal microscopes. However, excessive motion of organs due to involuntary movement such as breathing may result in out-of-focus images and severe fluorescence intensity fluctuations, which hinder meaningful imaging and analysis. The clinically approved alpha-2 adrenergic receptor agonist dexmedetomidine was administered to mice during two-photon fluorescence intravital imaging to alleviate this problem. As dexmedetomidine blocks the release of the neurotransmitter norepinephrine, pain is suppressed, blood pressure is reduced, and a sedation effect is observed. By tracking the quality of focus and stability of detected fluorescence in two-photon fluorescence images of fluorescein isothiocyanate-sensitized liver vasculature in vivo, we demonstrated that intravascular dexmedetomidine can reduce fluorescence fluctuations caused by respiration on a timescale of minutes in mice, improving image quality and resolution. The results indicate that short-term dexmedetomidine treatment is suitable for reducing involuntary motion in preclinical intravital imaging studies. This method may be applicable to other animal models.

The potential of locking plate with intramedullary fibular allograft to manage proximal humeral fracture with an unstable medial column.

PURPOSE: To evaluate the potential of locking compression plate with intramedullary fibular allograft in managing proximal humeral fractures with an unstable medial column. METHODS: Between March 2007 and March 2015, we retrospectively analyzed 63 patients who underwent locking plate fixation for proximal humeral fracture with an unstable medial column. All patients were assigned into group 1 (patients treated with locking plate) and group 2 (patients treated with locking plate with intramedullary fibular allograft). Groups 1 and 2 were composed of 29 and 34 patients, respectively. We analyzed bone union, the neck-shaft angle, the Constant score, the range of motion, and complications. RESULTS: The mean average bone union time of the patients was 13.9 weeks in group 1 and 11.3 weeks in group 2. The average Constant score was 67.4 in group 1 and 73.6 in group 2 (p < 0.05). The mean preoperative NSA, postoperative NSA, and NSA at the last follow-up were 104.4°, 125.8°, and 115.8°, respectively, in group 1, and 109.0°, 130.3°, and 127.1°, respectively, in group 2. The mean forward flexion, abduction, external rotation, and internal rotation were 109.0°, 48.2°, 34.0°, and L5, respectively, in group 1, and 127.5°, 118.2°, 38.7°, and L1, respectively, in group 2. In group 1, avascular necrosis occurred in one patient and screw cutout in two patients. In group 2, screw cutout occurred in one patient. CONCLUSION: In patients aged over 65 years with proximal humeral fractures, an unstable medial column was associated with poor clinical results owing to varus collapse. To prevent this, an intramedullary fibular allograft was used, and radiologic and clinical results were better with this approach than with a locking plate alone. Therefore, locking plate fixation using a fibular allograft is one of the possible treatments for patients with an unstable medial column.

Binary Structure of Amyloid Beta Oligomers Revealed by Dual Recognition Mapping.

Amyloid beta (Aß) oligomers are widely considered to be the causative agent of Alzheimer's disease (AD), a progressive neurodegenerative disorder. Determining the structure of oligomers is, therefore, important for understanding the disease and developing therapeutic agents; however, elucidating the structure has been proven difficult due to heterogeneity, noncrystallinity, and variability. Herein, we investigated homo- and hetero-oligomers of Aß40 and Aß42 using atomic force microscopy (AFM) and revealed characteristics of the molecular structure. By examining the surface of individual oligomers with sequential N- and C-terminus specific antibody-tethered tips, we simultaneously mapped the N- and C-terminus distributions and the elastic modulus. Interestingly, both the N- and C-termini of Aß peptides were recognized on the oligomer surface, and the termini detected pixel regions exhibited a lower elastic modulus than silent pixel regions. These two types of regions were randomly distributed on the oligomer surface.

Morphologic Factors Related to Repair Outcomes for Delaminated Rotator Cuff Tears: A Minimum 2-Year Retrospective Comparison Study.

PURPOSE: To evaluate clinical outcomes and repair integrity after en masse transosseous-equivalent suture bridge repair for delaminated rotator cuff tears and to analyze the morphologic factors related to clinical outcomes and repair integrity. METHODS: This study included 99 patients who underwent the technique of en masse transosseous-equivalent suture bridge repair for delaminated rotator cuff tears. Morphologic factors were estimated using magnetic resonance imaging, and clinical outcomes were evaluated using the University of California, Los Angeles score; American Shoulder and Elbow Surgeons score; and Constant shoulder score. The morphologic factors included the shape of delamination, retraction length of the bursal and articular layers, gap distance between the layers, and length of the intrasubstance cleavage. According to follow-up magnetic resonance imaging, cases were categorized into the intact or retear group. The morphologic factors were compared between the 2 groups, including the correlation between the morphologic factors and postoperative outcomes. RESULTS: Retears occurred in 26 of 99 cases (26%). In both the intact and retear groups, the University of California, Los Angeles, American Shoulder and Elbow Surgeons, and Constant scores improved postoperatively (P < .0001). The most common delamination shape was that of a more retracted articular layer in retears. We found no differences in retears in terms of the retraction length of the bursal layer, gap distance, and length of the intrasubstance cleavage. However, the retraction length of the articular layer differed significantly between the groups (P < .0001). No correlation between the morphologic factors and clinical outcomes was found. CONCLUSIONS: Arthroscopic en masse transosseous-equivalent suture bridge repair is a useful technique in delaminated tears to achieve optimal repair outcomes. In addition, although there was no correlation between the morphologic factors and postoperative clinical outcomes, the retraction length of the articular layer was identified as a significant factor influencing repair integrity. We recommend emphasizing the reduction of tension within the articular layer during the repair procedure. LEVEL OF EVIDENCE: Level III, retrospective comparison study.

Artemisia Extract Suppresses NLRP3 and AIM2 Inflammasome Activation by Inhibition of ASC Phosphorylation.

Artemisia princeps var. orientalis (Asteraceae, A. princeps) is a well-known traditional medicinal herb used for treating various inflammatory disorders in Korea, Japan, China, and other Asian countries. In the present study, we investigated the effects of A. princeps extract (APO) on interleukin- (IL-) 1ß regulation and inflammasome activation in bone marrow-derived macrophages (BMDMs) and monosodium urate- (MSU-) induced peritonitis mouse model in vivo. The APO treatment to BMDMs primed with lipopolysaccharide (LPS) attenuated the NLRP3 and AIM2 inflammasome activation induced by danger signals, such as ATP, nigericin, silica crystals, and poly (dA:dT), respectively. Mechanistic study revealed that APO suppressed the ASC oligomerization and speck formation, which are required for inflammasome activation. APO treatment also reduced the ASC phosphorylation induced by the combination of LPS and a tyrosine phosphatase inhibitor. In vivo evaluation revealed that intraperitoneal administration of APO reduced IL-1ß levels, significantly (p < 0.05) and dose dependently, in the MSU-induced peritonitis mouse model. In conclusion, our study is the first to report that the extract of A. princeps inhibits inflammasome activation through the modulation of ASC phosphorylation. Therefore, APO might be developed as therapeutic potential in the treatment of inflammasome-mediated inflammatory disorders, such as gouty arthritis.

Prominent synovial plicae in radiocapitellar joints as a potential cause of lateral elbow pain: clinico-radiologic correlation.

BACKGROUND: Thickened synovial plicae in the radiocapitellar joint have been reported as a cause of lateral elbow pain. However, few reports regarding diagnosis based on detailed physical examination and magnetic resonance imaging (MRI) findings are available. The aims of this study were to characterize the clinical manifestations of this syndrome and to investigate the clinical outcomes of arthroscopic surgery. METHODS: We analyzed 20 patients who received a diagnosis of plica syndrome and underwent arthroscopic débridement between 2006 and 2011. The diagnosis was based on physical examination and MRI findings. Elbow symptoms were assessed using a visual analog scale for pain; the Mayo Elbow Performance Index; and the Disabilities of the Arm, Shoulder and Hand score at a minimum of 2 years after surgery. The thickness of plicae on MRI was compared with the normal data in the literature. RESULTS: Plicae were located on the anterior side in 1 patient, on the posterior side in 15, and on both sides in 4. Radiocapitellar joint tenderness and pain with terminal extension were observed in 65% of patients. MRI showed enlarged plicae consistent with intraoperative findings. The mean plica thickness on MRI was 3.7 ± 1.0 mm, which was significantly thicker than the normal value. The mean lengths (mediolateral length, 9.4 ± 1.6 mm; anteroposterior length, 8.2 ± 1.7 mm) were also greater than the normal values. The visual analog scale score for pain decreased from 6.3 to 1.0 after surgery. The Mayo Elbow Performance Index and Disabilities of the Arm, Shoulder and Hand scores improved from 66 to 89 and from 26 to 14, respectively. CONCLUSIONS: Specific findings of the physical examination and MRI provide clues for the diagnosis of plica syndrome. Painful symptoms were successfully relieved after arthroscopic débridement.

Factors affecting rotator cuff integrity after arthroscopic repair for medium-sized or larger cuff tears: a retrospective cohort study.

BACKGROUND: We wished to identify the preoperative prognostic factors associated with structural integrity after repair of medium-sized and larger rotator cuff tears and to determine the cutoff values using receiver operating characteristic curve analysis. METHODS: The study included 180 patients with medium-sized and larger rotator cuff tears. Each had a minimum 2-year postoperative follow-up by magnetic resonance imaging. We assessed several patient-related and disease-related preoperative factors using univariate and multivariate logistic regression analysis. To determine the cutoff value for the significant variables, receiver operating characteristic curve analysis was performed. RESULTS: Retears occurred in 28 of the 180 patients (15.6%). Univariate analysis found that retear was significantly affected by the type of work and pattern of tear. The rate of retear was significantly increased in diabetes and with increasing tear size, extent of retraction, delamination, and fatty infiltration. Furthermore, reduced remnant tendon length, distance from the musculotendinous junction to the face of the glenoid, occupation ratio, and acromiohumeral interval were also significant risk factors. In the multivariate analysis, body mass index, diabetes, dyslipidemia, extent of retraction, delamination, distance from musculotendinous junction to face of glenoid, occupation ratio, fatty infiltration of infraspinatus, and acromiohumeral interval remained significant risk factors. The extent of retraction (22.2 mm) and the occupation ratio (53.5%) showed highly accurate cutoff values for predicting retear. CONCLUSION: Multiple factors influenced the healing process after rotator cuff repair. The best predictors were the extent of retraction and occupation ratio, which could help assist in determining the prognosis after rotator cuff repairs.

Medialized repair for retracted rotator cuff tears.

BACKGROUND: The purpose of this study was to evaluate the functional outcomes of medialized rotator cuff repair and the continuity of repaired tendon in chronic retracted rotator cuff tears. METHODS: Thirty-five consecutive patients were selected from 153 cases that underwent arthroscopic rotator cuff repair for more than medium-sized posterosuperior rotator cuff tears between July 2009 and July 2012 performed with the medialized repair. All cases were available for at least 2 years of postoperative follow-up. The visual analog scale of pain, muscle strength, Constant score, American Shoulder and Elbow Surgeons (ASES) score, and University of California-Los Angeles score were evaluated. RESULTS: At the final follow-up, all clinical outcomes were significantly improved. The visual analog scale score for pain improved from 6 ± 1 preoperatively to 2 ± 1 postoperatively. The range of motion increased from preoperatively to postoperatively: active forward elevation, from 134° ± 49° to 150° ± 16°; active external rotation at the side, from 47° ± 15° to 55° ± 10°; and active internal rotation, from L3 to L1. The shoulder score also improved: Constant score, from 53.5 ± 16.7 to 79 ± 10; American Shoulder and Elbow Surgeons score, from 51 ± 15 to 82 ± 8; and University of California-Los Angeles score, from 14 ± 4 to 28 ± 4. The retear cases at the final follow-up were 6 (17%). CONCLUSIONS: Medialized repair may be useful in cases in which anatomic bone-to-tendon repair would be difficult because of the excessive tension of the repaired tendon and a torn tendon that does not reach the anatomic insertion.

Fabrication of Glass Microchannel via Glass Imprinting using a Vitreous Carbon Stamp for Flow Focusing Droplet Generator.

This study reports a cost-effective method of replicating glass microfluidic chips using a vitreous carbon (VC) stamp. A glass replica with the required microfluidic microstructures was synthesized without etching. The replication method uses a VC stamp fabricated by combining thermal replication using a furan-based, thermally-curable polymer with carbonization. To test the feasibility of this method, a flow focusing droplet generator with flow-focusing and channel widths of 50 µm and 100 µm, respectively, was successfully fabricated in a soda-lime glass substrate. Deviation between the geometries of the initial shape and the vitreous carbon mold occurred because of shrinkage during the carbonization process, however this effect could be predicted and compensated for. Finally, the monodispersity of the droplets generated by the fabricated microfluidic device was evaluated.

Quantification of Fewer than Ten Copies of a DNA Biomarker without Amplification or Labeling.

Polymerase chain reaction (PCR) is a highly sensitive diagnosis technique for detection of nucleic acids and for monitoring residual disease; however, PCR can be unreliable for samples containing very few target molecules. Here, we describe a quantification method, using force-distance (FD) curve based atomic force microscopy (AFM) to detect a target DNA bound to small (1.4-1.9 µm diameter) probe DNA spots, allowing mapping of entire spots to nanometer resolution. Using a synthetic BCR-ABL fusion gene sequence target, we examined samples containing between one and 10 target copies. A high degree of correlation (r(2) = 0.994) between numbers of target copies and detected probe clusters was observed, and the approach could detect the BCR-ABL biomarker when only a single copy was present, although multiple screens were required. Our results clearly demonstrate that FD curve-based imaging is suitable for quantitative analysis of fewer than 10 copies of DNA biomarkers without amplification, modification, or labeling.

Visualization and Quantification of MicroRNA in a Single Cell Using Atomic Force Microscopy.

MicroRNAs (miRNAs) play critical roles in controlling various cellular processes, and the expression levels of individual miRNAs can be considerably altered in pathological conditions such as cancer. Accurate quantification of miRNA at the single-cell level will lead to a better understanding of miRNA function. Here, we present a direct and sensitive method for miRNA detection using atomic force microscopy (AFM). A hybrid binding domain (HBD)-tethered tip enabled mature miRNAs, but not premature miRNAs, to be located individually on an adhesion force map. By scanning several sections of a micrometer-sized DNA spot, we were able to quantify the copy number of miR-134 in a single neuron and demonstrate that the expression was increased upon cell activation. Moreover, we visualized individual miR-134s on fixed neurons after membrane removal and observed 2-4 miR-134s in the area of 1.0 × 1.0 µm(2) of soma. The number increased to 8-14 in stimulated neurons, and this change matches the ensemble-averaged increase in copy number. These findings indicate that miRNAs can be reliably quantified at the single cell level with AFM and that their distribution can be mapped at nanometric lateral resolution without modification or amplification. Furthermore, the analysis of miRNAs, mRNAs, and proteins in the same sample or region by scanning sequentially with different AFM tips would let us accurately understand the post-transcriptional regulation of biological processes.

Primary status, complementary status, and organizational survival in the U.S. venture capital industry.

We introduce a distinction between two kinds of status and examine their effects on the exit rates of organizations investing in the U.S. venture capital industry. Extending past work on status-based competition, we start with a simple baseline: we describe primary status as a network-related signal of an organization's quality in a leadership role, that is, as a function of the degree to which an organization leads others that are themselves well regarded as lead organizations in the context of investment syndicates. Combining Harary's (1959) image of the elite consultant with Goffman's (1956) concept of "capacity-esteem," we then discuss complementary status as an affiliation-based signal of an organization's quality in a supporting role. We measure complementary status as a function of the extent to which an organization is invited into syndicates by well-regarded lead organizations-that is, by those possessing high levels of primary status. Findings show that, conditioning on primary status, complementary status reduces the rate at which venture capital organizations exit the industry. Consistent with the premise that these kinds of status correspond to different roles and market identities, we also find that complementary status attenuates (and ultimately reverses) the otherwise favorable effect of primary status on an organization's life chances. Theoretically and methodologically oriented scope conditions, as well as implications for future research, are discussed.

Reading single DNA with DNA polymerase followed by atomic force microscopy.

The importance of DNA sequencing in the life sciences and personalized medicine is continually increasing. Single-molecule sequencing methods have been developed to analyze DNA directly without the need for amplification. Here, we present a new approach to sequencing single DNA molecules using atomic force microscopy (AFM). In our approach, four surface-conjugated nucleotides were examined sequentially with a DNA polymerase-immobilized AFM tip. By observing the specific rupture events upon examination of a matching nucleotide, we could determine the template base bound in the polymerase's active site. The subsequent incorporation of the complementary base in solution enabled the next base to be read. Additionally, we observed that the DNA polymerase could incorporate the surface-conjugated dGTP when the applied force was controlled by employing the force-clamp mode.

Prognostic significance of preoperative peripheral blood monocyte ratio in patients with hepatocellular carcinoma.

BACKGROUND: Leukocyte subsets in peripheral blood, which include neutrophils, lymphocytes, and monocytes, have not been well established as prognostic factors in patients with hepatocellular carcinoma (HCC). METHODS: Consecutive patients who underwent curative hepatic resection for HCC at the National Cancer Center, Republic of Korea, from 2001 to 2008 were enrolled in this retrospective study. Clinicopathologic factors, cancer-specific survival (CSS), and disease-free survival (DFS) were analyzed with respect to preoperative lymphocyte subsets, especially monocyte ratio. RESULTS: The 603 patients had a median follow-up of 40.0 months and a 5-year overall survival rate of 67.7 %. In univariate analysis of survivals, preoperative lymphocyte ratio ≤35 % and monocyte ratio >7 % were significantly poor prognostic factors. In multivariate analysis, preoperative monocyte ratio >7 %, satellite nodule, and microvascular invasion were independent risk factors for CSS and DFS (hazard ratio of monocyte ratio >7 % = 1.77, p = 0.02 and 1.57, p = 0.006, respectively). Considering monocyte ratio with preoperative α-fetoprotein level, patients with both abnormal α-fetoprotein levels (>12 ng/mL) and monocyte ratio >7 % showed significantly worse CSS and DFS than other groups (p < 0.001). Cirrhotic patients with monocyte ratio >7 % showed significantly poor CSS and DFS compared with non-cirrhotic patients (p = 0.033 and <0.001, respectively). CONCLUSIONS: A preoperative monocyte ratio >7 % of peripheral blood is an independent risk factor for CSS and DFS after hepatic resection for HCC. Preoperative monocyte ratio might be considered as a novel biomarker for HCC.

Pretransplant absolute monocyte count in peripheral blood predicts posttransplant tumor prognosis in patients undergoing liver transplantation for hepatocellular carcinoma.

BACKGROUND: Preoperative absolute monocyte count in peripheral blood (AMCPB) is closely associated with prognoses in not only various malignancies but also hepatocellular carcinoma (HCC). The purpose of this study was to evaluate whether pretransplant AMCPB predicts posttransplant outcomes in patients with HCC undergoing liver transplantation (LT). METHOD: We retrospectively analyzed relationships between clinicopathologic factors involving pretransplant AMCPB and tumor recurrence or survival in 256 patients who had undergone LT for HCC between January 2005 and April 2012. RESULTS: ROC curve analysis showed that AMCPB >200/mm(3) was a risk factor for tumor recurrence; 43 patients showed higher AMCPB (>200/mm(3)), whereas 213 showed lower AMCPB (≤200/mm(3)) at the time of LT. On multivariate analysis, pretransplant high AMCPB, positive findings in pretransplant (18)F-FDG PET/CT, pathological maximal tumor size >5 cm, intrahepatic metastasis, moderately or poorly differentiated tumor and microvascular invasion were independent factors affecting recurrence-free survival. When we performed subgroup analysis based on the Milan criteria, high AMCPB was an independent factor for predicting HCC recurrence in patients with tumor beyond the Milan criteria (P=0.004), and not for patients within the criteria. CONCLUSION: This study demonstrated that pretransplant AMCPB could predict tumor recurrence after LT for HCC, especially in patients with tumor beyond the Milan criteria.

Graft-to-recipient weight ratio lower to 0.7% is safe without portal pressure modulation in right-lobe living donor liver transplantation with favorable conditions.

BACKGROUND: The low graft-to-recipient weight ratio (GRWR) in adult-to-adult living donor liver transplantation (LDLT) is one of the major risk factors affecting graft survival. The goal of this study was to evaluate whether the lower limit of the GRWR can be safely reduced without portal pressure modulation in right-lobe LDLT. METHODS: From 2005 to 2011, 317 consecutive patients from a single institute underwent LDLT with right-lobe grafts without portal pressure modulation. Of these, 23 had a GRWR of less than 0.7% (group A), 27 had a GRWR of ≥0.7%, <0.8% (group B), and 267 had a GRWR of more than and equal to 0.8% (group C). Medical records, including recipient, donor, operation factors, laboratory findings and complications were reviewed retrospectively. RESULTS: The baseline demographics showed low model for end-stage liver disease score (mean 16.3+/-8.9) and high percentage of hepatocellular carcinoma (231 patients, 72.9%). Three groups by GRWR demonstrated similar characteristics except recipient body mass index and donor gender. For small-for-size syndrome, there were 3 (13.0%) in group A, 1 (3.7%) in group B, and 2 patients (0.7%) in group C (P<0.001). Hepatic artery thrombosis was more frequently observed in group A than in groups B and C (8.7% vs 3.7% vs 1.9%, P=0.047). However, among the three groups, graft survival rates at 1 year (100% vs 96.3% vs 93.6%) and 3 years (91.7% vs 73.2% vs 88.1%) were not different (P=0.539). In laboratory measurements, there was no group difference in total bilirubin and albumin. However, prothrombin time was longer in group A within postoperative 1 week and platelet count was lower in groups A and B within postoperative 1 month. CONCLUSION: A GRWR lower to 0.7% is safe and does not need to modulate portal pressure in adult-to-adult LDLT using the right-lobe in favorable conditions including low model for end-stage liver disease score.

Clinicopathological features and prognosis of combined hepatocellular carcinoma and cholangiocarcinoma after surgery.

BACKGROUND: Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is a rare subtype of primary liver cancer consisting of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Because of the rarity of this tumor, its feature is poorly understood. The present study aimed to evaluate the clinicopathological features and long-term prognosis of patients with cHCC-CC after surgery and to compare with those of the patients with stage-matched HCC and CC. METHODS: The clinicopathological features of the patients who underwent surgery for cHCC-CC at our center during the period of 2001-2010 were retrospectively analyzed and compared with those of stage-matched HCC and CC patients. Cancer staging was performed according to the AJCC Cancer Staging Manual (6th ed.). Overall survival and disease-free survival were compared among the groups and prognostic factors of cHCC-CC were evaluated. RESULTS: Significant differences were observed in clinicopathological features among 42 patients with cHCC-CC, 90 patients with HCC and 45 patients with CC. Similar to HCC patients, cHCC-CC patients had frequent hepatitis B virus antigen positivity, microscopic vessel invasion, cirrhosis and high level of serum alpha-fetoprotein. Similar to CC patients, cHCC-CC patients showed increased bile duct invasion and decreased capsule. The 1-, 3-, and 5-year overall survival and disease-free survival of patients with cHCC-CC were not significantly different from those with stage-matched patients with CC; but significantly poorer than those with HCC. In subanalysis of patients with stage II, the overall survival in patients with cHCC-CC or CC was significantly poorer than that in patients with HCC. We did not find the difference in patients with other stages. Univariate analysis of overall and disease-free survival of patients with cHCC-CC showed that the vascular invasion and intrahepatic metastasis were the significant predictive factors. CONCLUSION: Patients with cHCC-CC showed similar clinicopathological features as those with HCC or CC, and patients with cHCC-CC or CC had a poorer prognosis compared with those with HCC, especially at matched stage II.