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Objectives: This study explored factors related to Korean adults' smoking patterns and also the reasons for using new types of tobacco products., Study Design: Cross-sectional survey., Methods: Data from the Korea National Health and Nutrition Examination Survey from 2013 to 2021 were used. The prevalence of the use of electronic cigarettes (e-cigarettes) or heated tobacco products (HTPs) alone or in combination with conventional cigarettes (CC) and the reasons for using new tobacco products are presented. Factors associated with using new types of tobacco products alone or in combination with CC compared to exclusive CC users were identified using multinomial logistic regression analysis., Results: The prevalence of current smoking was 25.54% in 2013 and 23.05% in 2021, with no significant change. The prevalence of CC decreased from 23.39% in 2013 to 15.77% in 2021. The prevalence of new tobacco use in combination with CC did not show a definite trend. The prevalence of exclusive use of new tobacco was <1% until 2018 and has rapidly increased thereafter. Of the HTPs users, 46.68% responded with 'no cigarette smell' as the main reason for HTPs use, followed by 'It seems less harmful than cigarette' (19.19%), and 'It seems to be helpful for quitting smoking' (15.04%). Of the e-cigarette users, 45.19% responded 'It seems to be helpful for quitting smoking' as the main reason for e-cigarette use, followed by 'It is less harmful than cigarettes' (19.98%). Compared to CC users, new tobacco users were younger, had a higher household income or education, and used more nutritional supplements., Conclusion: Regulations for newer tobacco products are more lenient than for traditional cigarettes, leading to misunderstandings, especially among women and young people. To increase awareness of the risks of these products, specific policies such as disclosure of ingredients, ban on online sales, and increase in consumption tax, are needed., (Copyright © 2023 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Objectives: A multicenter randomized clinical trial in Hong Kong Accident and Emergency (A&E) departments concluded that intramuscular (IM) olanzapine is noninferior to haloperidol and midazolam, in terms of efficacy and safety, for the management of acutely agitated patients in A&E setting. Determining their comparative cost-effectiveness will further provide an economic perspective to inform the choice of sedative in this setting., Methods: This analysis used data from a randomized clinical trial conducted in Hong Kong A&E departments between December 2014 and September 2019. A within-trial cost-effectiveness analysis comparing the 3 sedatives was conducted, from the A&E perspective and a within-trial time horizon, using a decision-analytic model. Sensitivity analyses were also undertaken., Results: In the base-case analysis, median total management costs associated with IM midazolam, haloperidol, and olanzapine were Hong Kong dollar (HKD) 1958.9 (US dollar [USD] 251.1), HKD 2504.5 (USD 321.1), and HKD 2467.6 (USD 316.4), respectively. Agitation management labor cost was the main cost driver, whereas drug costs contributed the least. Midazolam dominated over haloperidol and olanzapine. Probabilistic sensitivity analyses supported that midazolam remains dominant > 95% of the time and revealed no clear difference in the cost-effectiveness of IM olanzapine versus haloperidol (incremental cost-effectiveness ratio 667.16; 95% confidence interval -770.89, 685.90)., Conclusions: IM midazolam is the dominant cost-effective treatment for the management of acute agitation in the A&E setting. IM olanzapine could be considered as an alternative to IM haloperidol given that there is no clear difference in cost-effectiveness, and their adverse effect profile should be considered when choosing between them., (Copyright © 2022. Published by Elsevier Inc.)

Background: Current treatment options for peripheral T-cell lymphomas (PTCLs) in the relapsed/refractory setting are limited and demonstrate modest response rates with rare achievement of complete response (CR)., Patients and Methods: This phase I/II study (NCT03052933) investigated the safety and efficacy of copanlisib, a phosphatidylinositol 3-kinase-α/-δ inhibitor, in combination with gemcitabine in 28 patients with relapsed/refractory PTCL. Patients received escalating doses of intravenous copanlisib on days 1, 8, and 15, administered concomitantly with fixed-dose gemcitabine (1000 mg/m 2 on days 1 and 8) in 28-day cycles., Results: Dose-limiting toxicity was not observed in the dose-escalation phase and 60 mg copanlisib was selected for phase II evaluation. Twenty-five patients were enrolled in phase II of the study. Frequent grade ≥3 adverse events (AEs) included transient hyperglycemia (57%), neutropenia (45%), thrombocytopenia, (37%), and transient hypertension (19%). However, AEs were manageable, and none were fatal. The overall response rate was 72% with a CR rate of 32%. Median duration of response was 8.2 months, progression-free survival was 6.9 months, and median overall survival was not reached. Combination treatment produced a greater CR rate in patients with angioimmunoblastic T-cell lymphoma than those with PTCL-not otherwise specified (55.6% versus 15.4%, respectively, P = 0.074) and progression-free survival was significantly longer (13.0 versus 5.1 months, respectively, P = 0.024). In an exploratory gene mutation analysis of 24 tumor samples, TSC2 mutation was present in 25% of patients and occurred exclusively in responders., Conclusion: The combination of copanlisib and gemcitabine is a safe and effective treatment option in relapsed/refractory PTCLs and represents an important new option for therapy in this rare group of patients., Competing Interests: Disclosure D-HY reports receipt of institutional research funding from Bayer HealthCare Pharmaceuticals, Inc. All remaining authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Objectives: This study aimed to evaluate the effect of the prospective drug utilization review (DUR) system introduced in Korea in December 2010 as a real-time method to improve patient safety, in terms of changes in prescribing practices, adverse drug events (ADEs), and ADE-related healthcare expenditure, using non-steroidal anti-inflammatory drugs (NSAIDs) and their common ADEs as a guide., Study Design: We used an interrupted time-series study design using generalized estimating equations to evaluate changes in prescription rate and ADE-related healthcare expenditure. Cox regression analysis was used to evaluate the probability of NSAID-associated ADEs., Methods: A total of 154,585 outpatients with musculoskeletal or connective tissue disorders, without pre-existing gastric bleeding or ulcers were included in this study. The primary outcome was the level and trend change in prescription rate, drug-drug interactions, coprescribed gastro-protective drugs, and defined daily dose (DDD) of NSAIDs. The secondary outcome was the probability of ADEs and changes in ADE-related healthcare expenditure., Results: There was a significant trend change after introducing the DUR system in terms of drug-drug interactions (-3.6%) and coprescribed gastro-protective drugs (+0.6%). The mean DDD of NSAIDs increased by 0.2. The probability of ADEs decreased overall (-1.7%) and in the high-risk group (age ≥65 years; -9.6%); however, only the latter was significant. There was no significant trend or level change in ADE-related health expenditure., Conclusions: The introduction of the DUR system was associated with more efficient prescribing, including a reduction in drug-drug interactions and an increase in the use of gastro-protective drugs. The system had a positive effect on patient outcome but was not associated with reduced ADE-related costs. Further studies are needed to evaluate the long-term effects of the DUR system in Korea., (Copyright © 2018 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

The incidence of acute kidney injury (AKI) and its impact on chronic kidney disease (CKD) following pediatric nonkidney solid organ transplantation is unknown. We aimed to determine the incidence of AKI and CKD and examine their relationship among children who received a heart, lung, liver, or multiorgan transplant at the Hospital for Sick Children between 2002 and 2011. AKI was assessed in the first year posttransplant. Among 303 children, perioperative AKI (within the first week) occurred in 67% of children, and AKI after the first week occurred in 36%, with the highest incidence among lung and multiorgan recipients. Twenty-three children (8%) developed CKD after a median follow-up of 3.4 years. Less than 5 children developed end-stage renal disease, all within 65 days posttransplant. Those with 1 AKI episode by 3 months posttransplant had significantly greater risk for developing CKD after adjusting for age, sex, and estimated glomerular filtration rate at transplant (hazard ratio: 2.77, 95% confidence interval, 1.13-6.80, P trend = .008). AKI is common in the first year posttransplant and associated with significantly greater risk of developing CKD. Close monitoring for kidney disease may allow for earlier implementation of kidney-sparing strategies to decrease risk for progression to CKD., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: In stage I/II natural killer (NK)/T-cell lymphoma, concurrent chemoradiotherapy (CCRT) had previously been shown to result in superior outcome compared with anthracycline-containing regimens, which have since been considered ineffective. The role of CCRT in comparison with approaches employing nonanthracycline-containing chemotherapy (CT) and sequential radiotherapy (RT) in such patients remains to be defined., Patients and Methods: Three hundred and three untreated patients (207 men, 96 women; median age: 51, 18-86 years) with stage I/II NK/T-cell lymphoma who had received nonanthracycline-containing regimens were collected from an international consortium and retrospectively analyzed. Treatment included single modality (CT and RT), sequential modalities (CT + RT; RT + CT) and concurrent modalities (CCRT; CCRT + CT). The impact of clinicopathologic parameters and types of treatment on complete response (CR) rate, progression-free-survival (PFS) and overall-survival (OS) was evaluated., Results: For CR, stage (P = 0.027), prognostic index for NK/T-cell lymphoma (PINK) (P = 0.026) and types of initial treatment (P = 0.011) were significant prognostic factors on multivariate analysis. On Cox regression analysis, ECOG performance score (P = 0.021) and PINK-EBV DNA (PINK-E) (P = 0.002) significantly impacted on PFS; whereas ECOG performance score (P = 0.008) and stage (P < 0.001) significantly impacted on OS. For comparing CCRT ± CT and sequential CT + RT, CCRT ± CT patients (n = 190) were similar to sequential CT + RT patients (n = 54) in all evaluated clinicopathologic parameters except two significantly superior features (higher proportion of undetectable circulating EBV DNA on diagnosis and lower PINK-E scores). Despite more favorable pre-treatment characteristics, CCRT ± CT patients had CR rate, PFS and OS comparable with sequential CT + RT patients on multivariate and Cox regression analyses., Conclusions: In stage I/II NK/T-cell lymphomas, when effective chemotherapeutic regimens were used, CCRT and sequential CT + RT gave similar outcome., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Population-based cancer screening recommendations are also suggested for solid organ transplant recipients (SOTR); however, recommendation adherence is unknown. In a population-based cohort of SOTR in Ontario between 1997 and 2010, we determined the uptake of breast, cervical, and colorectal cancer screening tests and identified factors associated with up-to-date screening using recurrent event analysis. We identified 4436 SOTR eligible for colorectal, 2252 for cervical, and 1551 for breast cancer screening. Of those, 3437 (77.5%), 1572 (69.8%), and 1417 (91.4%), respectively, were not up-to-date for cancer screening tests during the observation period. However, these rates are likely an overestimate due to the inability to differentiate between tests done for screening or for diagnosis. SOTR with fewer comorbidities had higher rates of becoming screen up-to-date. Assessment by a primary care provider (PCP) was associated with becoming up-to-date with cancer screening (breast relative risk [RR] = 1.40, 95% confidence interval [CI]: 1.12-1.76, cervical RR = 1.29, 95% CI: 1.06-1.57, colorectal RR = 1.30, 95% CI: 1.15-1.48). Similar results were observed for continuity of care by transplant specialist at a transplant center. In conclusion, cancer screening for most SOTR does not adhere to standard recommendations. Involvement of PCPs in posttransplant care and continuity of care at a transplant center may improve the uptake of screening., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Current standard treatment, including non-anthracycline-based chemotherapy and optimal combining of radiotherapy, has dramatically improved outcomes of patients with extranodal natural killer/T-cell lymphoma (ENKTL) during the last decade. This study was conducted to investigate the clinical outcome of ENKTL patients with relapsed or progressive disease after initial current standard therapy., Patients and Methods: We retrospectively reviewed patients diagnosed with ENKTL at six centers in four countries (China, France, Singapore, and South Korea) from 1997 to 2015 and analyzed 179 patients who had relapsed or progressed after initial current standard therapy., Results: After a median follow-up of 58.6 months (range 27.9-89.2), the median second progression-free survival (PFS) was 4.1 months [95% confidence interval (CI) 3.04-5.16] and overall survival (OS) was 6.4 months (95% CI 4.36-8.51). Multivariate Cox-regression analysis revealed that elevated lactate dehydrogenase, multiple extranodal sites (≥2), and presence of B symptoms were associated with inferior OS (P < 0.05). OS and PFS were significantly different according to both prognostic index of natural killer lymphoma (PINK) and PINK-E (Epstein-Barr virus) models. Salvage chemotherapy with l-asparaginase (l-Asp)-based regimens showed a significantly better clinical benefit to response rate and PFS, although it did not lead to OS improvement. First use of l-Asp in the salvage setting and l-Asp rechallenge at least 6 months after initial treatment were the best candidates for salvage l-Asp containing chemotherapy., Conclusions: Most patients with relapsed or refractory ENKTL had poor prognosis with short survival. Further studies are warranted to determine the optimal treatment of patients with relapsed or refractory ENKTL., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In the United States, kidney transplant rates vary significantly across end-stage renal disease (ESRD) networks. We conducted a population-based cohort study to determine whether there was variability in kidney transplant rates across renal programs in a health care system distinct from the United States. We included incident chronic dialysis patients in Ontario, Canada, from 2003 to 2013 and determined the 1-, 5-, and 10-year cumulative incidence of kidney transplantation in 27 regional renal programs (similar to U.S. ESRD networks). We also assessed the cumulative incidence of kidney transplant for "healthy" dialysis patients (aged 18-50 years without diabetes, coronary disease, or malignancy). We calculated standardized transplant ratios (STRs) using a Cox proportional hazards model, adjusting for patient characteristics (maximum possible follow-up of 11 years). Among 23 022 chronic dialysis patients, the 10-year cumulative incidence of kidney transplantation ranged from 7.4% (95% confidence interval [CI] 4.8-10.7%) to 31.4% (95% CI 16.5-47.5%) across renal programs. Similar variability was observed in our healthy cohort. STRs ranged from 0.3 (95% CI 0.2-0.5) to 1.5 (95% CI 1.4-1.7) across renal programs. There was significant variation in kidney transplant rates across Ontario renal programs despite patients having access to the same publicly funded health care system., (© 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Solid organ transplant recipients (SOTRs) are at increased risk of developing and dying from cancer. However, controversies exist around cancer screening in this population owing to reduced life expectancy and competing causes of death. This systematic review assesses the availability, quality and consistency of cancer screening recommendations in clinical practice guidelines (CPGs). We systematically searched bibliographic databases and gray literature to identify CPGs and assessed their quality using AGREE II. Recommendations were extracted along with their supporting evidence. Thirteen guidelines were included in the review. CPGs for kidney recipients were the most frequent source of screening recommendations, and recommendations for skin cancer screening were most frequently presented. Some screening recommendations differed from those for the general population, based on literature demonstrating higher cancer incidence among SOTRs versus direct evidence of screening effectiveness. Relevant stakeholders such as oncology specialists, primary care providers and public health experts were not involved in the formulation of the screening recommendations. In conclusion, although several guidelines make recommendations for cancer screening in SOTRs, the availability of cancer screening recommendations varied considerably by transplanted organ. More studies are required to inform cancer screening recommendations in SOTRs, and guideline development should involve transplant patients, oncologists and cancer screening specialists., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Persistent sciatic artery (PSA) is a relatively rare congenital variant of the lower limb vasculature and can have highly variable clinical presentations. The purpose of this study was to analyze the relationship between PSA anatomy and clinical presentation, and to suggest an optimal management strategy., Methods: Between 2001 and 2014, 24 PSAs in 19 patients were diagnosed by computed tomography and referred to the vascular surgery department. Patient demographics, types of PSA and femoral artery, aneurysmal changes, symptoms, and treatment methods were assessed. Additionally, all English literature from 1964 to 2014 was reviewed and compared using the PubMed database (224 PSAs in 171 patients)., Results: PSA was diagnosed in 10 men (52.6%) and nine women (47.4%). PSAs were bilateral in five patients (26.3%) and symptomatic in 12 patients, while in seven patients PSA was found incidentally. According to the Pillet-Gauffre classification, Type 2a was the most common variant (n = 15/24, 62.5%), with unclassifiable types in two limbs. Compared with cases in the literature, the PSA occlusion rate in this study was higher (n = 10/24, 41.7% vs. n = 54/224, 27.5%), but aneurysm incidence was higher in the literature cases (n = 5/24, 20.8% vs. n = 112/224; 50.7%). In this study, 16 limbs (66.6%) were treated conservatively, and six limbs were treated by open surgery, including four bypasses, one amputation, and one thrombo-embolectomy. Endovascular coil embolization was performed in one limb, and a hybrid procedure with stent graft was performed in one limb with PSA aneurysm. Based on the present series and the literature review, a new classification system and treatment option is proposed according to the anatomic status and the presence of aneurysm. According to the new classification, class III was the most common in both the present study (18/24; 75%) and the literature review, and the presence of aneurysm was the most important determinant of surgical treatment., Conclusions: The new classification system is simple and provides guidance for management. Limb anatomy of the femoral artery system and the presence of PSA aneurysm should be considered when selecting the optimal treatment. The risk of embolism from the presence of aneurysm is an important factor for treatment, and bypass surgery is mostly required in classes III and IV., (Copyright © 2016. Published by Elsevier Ltd.)

Humanin is the first newly discovered peptide encoded in the mitochondrial genome in over three decades. It is the first member of a novel class of mitochondrial derived peptides. This small, 24 amino acid peptide was initially discovered to have neuroprotective effects and subsequent experiments have shown that it is beneficial in a diverse number of disease models including stroke, cardiovascular disease, and cancer. Over a decade ago, our lab found that humanin bound IGFBP-3 and more recent studies have found it to decrease circulating IGF-I levels. In turn, IGF-I also seems to regulate humanin levels and in this review, we cover the known interaction between humanin and IGF-I. Although the exact mechanism for how humanin and IGF-I regulate each other still needs to be elucidated, it is clear that humanin is a new player in IGF-I signaling., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Competing events (or risks) preclude the observation of an event of interest or alter the probability of the event's occurrence and are commonly encountered in transplant outcomes research. Transplantation, for example, is a competing event for death on the waiting list because receiving a transplant may significantly decrease the risk of long-term mortality. In a typical analysis of time-to-event data, competing events may be censored or incorporated into composite end points; however, the presence of competing events violates the assumption of "independent censoring," which is the basis of standard survival analysis techniques. The use of composite end points disregards the possibility that competing events may be related to the exposure in a way that is different from the other components of the composite. Using data from the Scientific Registry of Transplant Recipients, this paper reviews the principles of competing risks analysis; outlines approaches for analyzing data with competing events (cause-specific and subdistribution hazards models); compares the estimates obtained from standard survival analysis, which handle competing events as censoring events; discusses the appropriate settings in which each of the two approaches could be used; and contrasts their interpretation., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

As the criteria for liver donation have been extended to include marginal donors, liver grafts are becoming particularly vulnerable to hepatic ischemia-reperfusion injury (IRI). However, no specific measures have been validated to ameliorate hepatic IRI. In this article, we explored whether everolimus has protective effects against hepatic IRI in relation with autophagy. The effects of everolimus were investigated in both in vitro and in vivo hepatic IRI models. Mouse hepatocyte AML12 cells and BALB/c mice were utilized for the establishment of each model. In the IRI-induced AML12 cells, everolimus treatment increased the expressions of autophagic markers (microtubule-associated protein 1 light chain 3 and p62) and decreased pro-apoptotic proteins (cleaved caspase 3 and cleaved poly-ADP ribose polymerase). The blockage of autophagy, using either bafilomycin A1 or si-autophagy-related protein 5, abrogated these anti-apoptosis effects of everolimus. Subsequently, everolimus administration to the hepatic IRI-induced mice provided hepatoprotective effects in terms of (1) decreasing the expressions of pro-apoptotic proteins, (2) inhibiting the release of pro-inflammatory cytokines (IL-6 and tumor necrosis factor-α), (3) reducing elevated liver enzymes (aspartate transaminase, alanine transaminase, and ammonia), and (4) restoring liver histopathology. These findings suggest that everolimus protects the liver against hepatic IRI by way of activating autophagy, and thus could be a potential therapeutic agent for hepatic IRI., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The use of imatinib combined with chemotherapy has demonstrated improved outcome in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). However, a substantial proportion of patients continue to die as a result of disease progression., Patients and Methods: We assessed the minimal residual disease (MRD)-based effect and long-term outcome of first-line incorporation of dasatinib (100 mg once daily) into chemotherapy alternatively for adults with Ph-positive ALL. The primary end point was the major molecular response (MMR) rate by the end of the second dasatinib cycle. Patients with a donor proceeded to allogeneic stem cell transplantation (SCT) as early as possible. MRD monitoring was centrally evaluated by real-time quantitative polymerase chain reaction (4.5-log sensitivity) using bone marrow samples., Results: Fifty-one patients (median age, 46 years) were enrolled and treated with this strategy. After the first dasatinib cycle, 50 patients (98.0%) achieved complete remission (CR). By the end of the second dasatinib cycle, 46 (93.9%) of 49 assessable patients had persistent CR, and 38 (77.6%) had MMR (32.7%) or undetectable MRD (44.9%). On the basis of the MRD kinetics by this time point, the numbers of early-stable, late, and poor molecular responders were 23 (46.9%), 15 (30.7%), and 11 (22.4%), respectively. Thirty-nine patients (76.5%) underwent allogeneic SCT in CR1. After a median follow-up of 54 months, the 4-year cumulative incidence of relapse and disease-free survival (DFS) rate for all patients were 30.0% and 52.0%, respectively, and the corresponding outcomes among those receiving allogeneic SCT in CR1 were 20.5% and 64.1%, respectively. Poor molecular responders had a higher risk of relapse and DFS than those of early-stable molecular responders., Conclusion: This dasatinib-based protocol was effective for achieving a good quality molecular response and durable DFS in adults with Ph-positive ALL., Trial Registration: clinicaltrials.gov, NCT01004497., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Everolimus, an oral mTOR inhibitor, has single-agent activity against relapsed lymphomas. Thus, we carried out a phase II study of everolimus in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) as a first-line treatment for patients with peripheral T-cell lymphoma (PTCL) based on our phase I study results., Patients and Methods: Participants (n = 30) received CHOP with 5 mg everolimus per day from day 1 to 14 every 21 days for a total of six cycles. The primary end point was the overall response rate (ORR), which included complete response (CR) and partial response (PR) to this regimen. Immunohistochemistry was used to evaluate the expression of phosphatase and tensin homology (PTEN) and phosphorylated S6 kinase (pS6K) as a response., Results: The objective response rate was 90% with CR (n = 17) and PR (n = 10). The CR rate was different among subtypes; angioimmunoblastic T-cell lymphoma (AITL, n = 3) had a CR whereas PTCL-not-otherwise specified and ALK-negative anaplastic large-cell lymphoma (ALCL) patients showed 63% (12/19) and 29% (2/7) of CR rate, respectively. This difference in CR rate among subtypes was associated with PTEN loss because PTEN loss was not seen in AITL but 33% of ALCL patients. The most common toxicity was hematological, with 80% of patients experiencing at least one event of grade 3/4 neutropenia, and 60% of patients had grade 3/4 thrombocytopenia., Conclusion: The everolimus plus CHOP was effective for PTCL patients, and its efficacy might be related with the preservation of PTEN., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Romidepsin, a histone deacetylase (HDAC) inhibitor, has been approved for the treatment of relapsed and refractory peripheral T-cell lymphoma. However, the efficacy and safety of romidepsin has never been studied in patients with relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma (ENKTL)., Patients and Methods: We conducted an open-label, prospective pilot study to evaluate the efficacy and feasibility of romidepsin in the treatment of patients with ENKTL. The treatment was intravenous infusion of romidepsin (14 mg/m(2)) for 4 h on days 1, 8, and 15 of a 28-day cycle, and was repeated until disease progression or the occurrence of unacceptable toxicity., Results: A total of five patients enrolled on to this pilot study. However, three patients developed fever and elevated liver enzyme and bilirubin levels immediately after their first administration of romidepsin. We suspected that these events were associated with Epstein-Barr virus (EBV) reactivation because of the rapidly elevated EBV DNA titers in blood from these patients. An in vitro study with the ENKTL cell line SNK-6 cells also showed that HDAC inhibitors including romidepsin increased the copy number of EBV DNA in a dose-dependent manner. These findings suggested that romidepsin-induced histone acetylation reversed the repressed state of the genes required for EBV reactivation and that romidepsin treatment may have caused EBV reactivation in EBV-infected tumor cells in ENKTL patients. Therefore, we discontinued the enrollment of patients into this pilot study., Conclusions: Our study suggests that the use of romidepsin may cause severe EBV reactivation in patients with ENKTL., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Recipients of pancreas transplant alone (PTA) may be at increased risk for developing end-stage renal disease (ESRD). The survival experience of PTA recipients developing ESRD has not been described. Furthermore, the relative survival of these patients as compared to diabetics on chronic dialysis is unknown. We studied all adult PTA recipients from January 1, 1990 to September 1, 2008 using the Scientific Registry of Transplant Recipients. Each PTA recipient developing ESRD was matched to 10 diabetics on chronic dialysis from the United States Renal Data System. Cox proportional hazards models were fitted to determine the relation between ESRD and mortality among PTA recipients, and the relation between PTA and mortality among diabetics on chronic dialysis. There were 1597 PTA recipients in the study, of which 207 developed ESRD. Those with ESRD had a threefold increase in mortality versus those without (adjusted hazard ratio 3.28 [95% confidence interval: 2.27, 4.76]). There was no significant difference in the risk of death among PTA recipients with ESRD versus diabetics on dialysis. PTA recipients developing ESRD are three times more likely to die than PTA recipients without ESRD; however, the risk of death in these patients was similar to diabetics on chronic dialysis without PTA., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Apoptosis during engraftment and inflammation induce poor islet xenograft survival. We aimed to determine whether overexpression of human heme oxygenase-1 (HO-1) or soluble tumor necrosis factor-α receptor type I with human IgG1 Fc (sTNF-αR-Fc) in porcine islets could improve islet xenograft survival. Adult porcine islets were transduced with adenovirus containing human HO-1, sTNF-αR-Fc, sTNF-αR-Fc/HO-1 or green fluorescent protein (control). Humanized mice were generated by injecting human cord blood-derived CD34(+) stem cells into NOD-scid-IL-2Rγ(null) mice. Both HO-1 and sTNF-αR-Fc reduced islet apoptosis under in vitro hypoxia or cytokine stimuli and suppressed RANTES induction without compromising insulin secretion. Introduction of either gene into islets prolonged islet xenograft survival in pig-to-humanized mice transplantation. The sTNF-αR-Fc/HO-1 group showed the best glucose tolerance. Target genes were successfully expressed in islet xenografts. Perigraft infiltration of macrophages and T cells was suppressed with decreased expression of RANTES, tumor necrosis factor-α and IL-6 in treatment groups; however, frequency of pig-specific interferon-γ-producing T cells was not decreased, and humoral response was not significant in any group. Early apoptosis of islet cells was suppressed in the treatment groups. In conclusion, overexpression of HO-1 or sTNF-αR-Fc in porcine islets improved islet xenograft survival by suppressing both apoptosis and inflammation. HO-1 or sTNF-αR-Fc transgenic pigs have potential for islet xenotransplantation., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Pig islets are an alternative source for islet transplantation to treat type 1 diabetes (T1D), but reproducible curative potential in the pig-to-nonhuman primate (NHP) model has not been demonstrated. Here, we report that pig islet grafts survived and maintained normoglycemia for >6 months in four of five consecutive immunosuppressed NHPs. Pig islets were isolated from designated pathogen-free (DPF) miniature pigs and infused intraportally into streptozotocin-induced diabetic rhesus monkeys under pretreatment with cobra venom factor (CVF), anti-thymocyte globulin (ATG) induction and maintenance with anti-CD154 monoclonal antibody and low-dose sirolimus. Ex vivo expanded autologous regulatory T cells were adoptively transferred in three recipients. Blood glucose levels were promptly normalized in all five monkeys and normoglycemia (90-110 mg/dL) was maintained for >6 months in four cases, the longest currently up to 603 days. Intravenous glucose tolerance tests during the follow-up period showed excellent glucose disposal capacity and porcine C-peptide responses. Adoptive transfer of autologous regulatory T cells was likely to be associated with more stable and durable normoglycemia. Importantly, the recipients showed no serious adverse effects. Taken together, our results confirm the clinical feasibility of pig islet transplantation to treat T1D patients without the need for excessive immunosuppressive therapy., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objective: Middle aortic syndrome (MAS) is a rare condition characterized by severe stenosis of the distal thoracic or abdominal aorta. The aims of this study are to define the anatomic characteristics of MAS and to review the various surgical methods and their outcomes in terms of long-term durability, Materials and Methods: Ten adult patients were diagnosed with MAS caused by Takayasu arteritis (TA) or midaortic dysplastic syndrome and underwent surgical treatment between July 1992 and January 2013., Result: The aortic lesions were mostly suprarenal (n = 7) and stenoses were commonly found in the celiac axis (n = 6), SMA (n = 7), and renal artery (n = 6). Indications for operation were uncontrolled hypertension in six patients and lower extremity claudication in four. Eight aortic bypasses, one supraceliac aortic interposition graft, and one bilateral aorto-renal bypass were performed. Adjunctive renal bypass with saphenous vein graft (n = 4) and IMA reimplantation (n = 2) were performed simultaneously. There was no post-operative mortality, and one complication of iliac dissection at the distal anastomosis site was detected and treated by stenting. Hypertension was cured or improved in five of the six patients, and lower extremity claudication improved in all of them. With a median follow up of 60 months (range, 12-263), all the aortic bypasses were patent and one adjunctive renal artery bypass graft with aortic bypass was occluded 29 months post-operatively., Conclusions: Aortic bypass for MAS is safe and shows excellent long-term durability. Considering the patients are relatively young with a long life expectancy, aggressive surgical treatment could be beneficial. Lifelong follow up to monitor complications and disease progression is necessary., (Copyright © 2015 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Lactoferrin (LF), a pleiotropic iron-binding glycoprotein, is known to modulate the humoral immune response. However, its exact role in Ig synthesis has yet to be elucidated. In this study, we investigated the effect of LF on Ig production by mouse B cells and its underlying mechanisms. LF, like transforming growth factor (TGF)-β1, stimulated B cells to produce IgA and IgG2b, while downregulating other isotypes. Using limiting dilution analysis, LF was shown to increase the frequency of IgA-secreting B-cell clones. This was paralleled by an increase in Ig germ-line α (GLα) transcripts, indicating that LF plays a role as an IgA switch factor. Interestingly, LF directly interacted with betaglycan (TGF-β receptor III, TβRIII) and in turn induced phosphorylation of TβRI and Smad3 through formation of the TβRIII/TβRII/TβRI complex, leading to IgA isotype switching. Peroral administration of LF increased intestinal/serum IgA production as well as number of IgA plasma cells in lamina propria. Finally, we found that LF has an adjuvant activity when nontoxigenic Salmonella typhimurium was inoculated perorally, conferring protection against intragastrical infection of toxigenic S. typhimurium. These results suggest that LF has an important effect on the mucosal/systemic IgA response and can contribute to protection against intestinal pathogens.

Background: Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly is defined only in adults older than 50 years. However, EBV-positive DLBCL can affect younger patients. We investigated the prevalence, clinical characteristics and survival outcomes of EBV-positive DLBCL in young adults., Patients and Methods: We analyzed patients with de novo DLBCL who were registered in the Samsung Medical Center (SMC) retrospective lymphoma cohort and prospective SMC Lymphoma Cohort Study I (ClinicalTrials.gov: NCT00822731)., Results: A total of 571 cases were included in the analysis. The prevalence of EBV positivity was 6.7% (13/195) and 9.3% (35/376) in the young group (≤50 years) and in the elderly group (>50 years), respectively. EBV status was closely associated with unique unfavorable clinical characteristics [older age, more advanced stage, two or more sites of extranodal involvement, higher International Prognostic Index (IPI), and age-adjusted IPI risk] only in the elderly group. Poor prognostic impact of EBV positivity on overall survival was observed only in the elderly group [hazard ratio (HR) 2.86; 95% confidence interval (CI) 1.83-4.47; P < 0.001], but not in the young group (HR 1.17; 95% CI 0.35-3.89; P = 0.801)., Conclusion: A substantial proportion of EBV-positive DLBCL of the elderly can occur in young adults. EBV positivity of DLBCL in young adults was not associated with unfavorable clinical characteristics or worse outcomes. We suggest that EBV-positive DLBCL should not be confined only in the elderly and 'EBV-positive DLBCL in young adults' needs to be considered as a clinically distinct disease entity. ClinicalTrials.gov: NCT02060435., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Scedosporium spp. is the most common mold infection in pneumonia resulting from near-drowning. Three fatal scedosporiosis cases developed after solid organ transplantation, probably transmitted from the nearly-drowned donor. One heart transplant recipient and two kidney transplant recipients developed fatal scedosporiosis following deceased donor transplantation from the same donor, a nearly-drowned victim of a suicide attempt. Genotypically, indistinguishable strains of Scedosporium auratiacum were recovered from the three recipients. Two liver transplant recipients from the same donor received prophylactic voriconazole without any subsequent signs of infection. To determine the safety of donation from nearly-drowned donors, a national traceback investigation was also performed of the causes of deaths in all transplant recipients who received organs from drowned donors between 2001 and 2013. Over 13 years, 2600 deceased donor transplants were performed in Korea. Among these 2600 deceased donor transplants, 27 (1%) victims of drowning donated their organs. From these 27 donors, 84 patients received organ transplants and 18 died, including the above three. We found no microbiologic evidence of invasive mold transmission from the nearly-drowned donors to the other 15 recipients. Although disseminated infection in the donor could not be demonstrated by culture, undiagnosed disseminated donor infection and transmission of Scedosporium spp. should be considered in near-drowning events., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The association of hyperuricemia with kidney allograft outcomes remains controversial. We studied this problem in 1170 kidney transplants from January 2000 to December 2010. The primary endpoint was total graft failure (i.e. graft loss or death). Conventional, time-dependent and marginal structural Cox proportional hazards models were fitted, the latter accounting for kidney function as a time-varying confounder affected by prior uric acid levels. Uric acid level was associated with an increased risk of total graft failure in time-fixed and time-varying models (HR 1.02 [95% CI: 1.003-1.04] and HR 1.02 [95% CI: 1.01-1.03], respectively, for every 10 µmol/L increase in uric acid). In contrast, the marginal structural model showed a modestly protective effect (HR 0.90 [95% CI: 0.85-0.94] for every 10 µmol/L increase in uric acid). Similar results were observed for death-censored graft failure and death with graft function. In summary, the absence of a deleterious association between elevated uric acid and graft outcome after accounting for graft function as a time-varying confounder suggests that uric acid is not an independent risk factor for graft failure. The modestly protective effect of uric acid may be an indicator of nutritional status but further study is warranted., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

We conducted a nested case-control study from a cohort of adult kidney transplant recipients to assess the risk of transplant glomerulopathy (TG) as a function of donor and recipient HLA-DR and -DQ incompatibility at the eplet level. Cases (n = 52) were defined as patients diagnosed with transplant glomerulopathy based on biopsies showing glomerular basement membrane duplication without immune complex deposition. Controls (n = 104) with a similar follow-up from transplantation were randomly selected from the remaining cohort. HLAMatchmaker was used to ascertain the number of DRB1/3/4/5, DQA1 and DQB1 related eplet mismatches (eplet load). Multivariable conditional logistic regression models demonstrated an increase in the odds of TG (odds ratios [OR] of 2.84 [95% confidence interval (CI): 1.03, 7.84] and 4.62 [95% CI: 1.51, 14.14]) in the presence of 27-43 and >43 HLA-DR + DQ related eplet mismatches versus <27 eplet mismatches, respectively. When the eplet load was modeled as a continuous variable, the OR for TG was 1.25 (95% CI: 1.04, 1.50) for every 10 additional HLA-DR + DQ eplet mismatches. Our study suggests that minimization of HLA-DR + DQ eplet mismatches may decrease the incidence of transplant glomerulopathy diagnosed by indication biopsies. The role of eplet immunogenicity/antigenicity as determinants of allograft outcomes requires further study., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

This study was designed to optimize a method to improve porcine parthenogenetic embryo hatching and trophoblast culture. Mature oocytes (D0PPA) and day 6 blastocysts (D6PPA) were perforated with a 20 μm diameter needle for assisted hatching. The two groups showed a significant difference in hatching rate and blastocyst cell doubling when compared to a non-perforated control group. D0PPA blastocysts were able to form tertiary trophoblast colonies but D6PPA and control groups were not able to grow beyond primary colonies. Quantitative real-time PCR analysis showed significant differences in BAX, BAX/BCL2L1 and HSP70-2 mRNA expression between the experimental groups., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to construct a novel prediction model for the pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) using immune-related gene expression data., Patients and Methods: DNA microarray data were used to perform a gene expression analysis of tumor samples obtained before NAC from 117 primary breast cancer patients. The samples were randomly divided into the training (n = 58) and the internal validation (n = 59) sets that were used to construct the prediction model for pCR. The model was further validated using an external validation set consisting of 901 patients treated with NAC from six public datasets., Results: The training set was used to construct an immune-related 23-gene signature for NAC (IRSN-23) that is capable of classifying the patients as either genomically predicted responders (Gp-R) or non-responders (Gp-NR). IRSN-23 was first validated using an internal validation set, and the results showed that the pCR rate for Gp-R was significantly higher than that obtained for Gp-NR (38 versus 0%, P = 1.04E-04). The model was then tested using an external validation set, and this analysis showed that the pCR rate for Gp-R was also significantly higher (40 versus 11%, P = 4.98E-23). IRSN-23 predicted pCR regardless of the intrinsic subtypes (PAM50) and chemotherapeutic regimens, and a multivariate analysis showed that IRSN-23 was the most important predictor of pCR (odds ratio = 4.6; 95% confidence interval = 2.7-7.7; P = 8.25E-09)., Conclusion: The novel prediction model (IRSN-23) constructed with immune-related genes can predict pCR independently of the intrinsic subtypes and chemotherapeutic regimens.

Background: Oncogenic phosphatidylinositol-3-kinase/serine-threonine kinase (PI3K/AKT) pathway plays a critical role in cell proliferation and growth. Phosphorylated AKT (p-AKT) has been reported to be abnormally overexpressed and to have poor prognostic impact in solid tumors., Patients and Methods: To define the clinical implications of p-AKT expression in diffuse large B-cell lymphoma (DLBCL), we calculated arbitrary units (AUs) by multiplying the intensity and the proportion of p-AKT expression and investigated the impact of p-AKT expression on clinical outcomes. We assessed 262 patients with DLBCL. Based on a cutoff value of the upper limit of the third quartile of AUs, 56 patients were classified as high p-AKT and the remaining 206 patients were classified as low p-AKT., Results: The high p-AKT group was closely associated with more advanced stage (stage III-IV, P = 0.02), two or more extranodal involvement (P = 0.03), lactic dehydrogenase elevation (P = 0.03), higher International Prognostic Index risk groups (high intermediate/high, P = 0.02), and the presence of B-symptoms (P = 0.01). The high p-AKT group showed substantially worse overall survival (OS) (median OS, 115.0 months versus not reached, P = 0.004) and progression-free survival (PFS) (median PFS, 25.5 versus 105.8 months, P = 0.019) compared with the low p-AKT group. Multivariate analysis revealed that high p-AKT expression retained its significant poor prognostic impact for OS (hazard ratio 1.7; 95% confidence interval, 1.0-2.7; P = 0.031). The subgroup with high p-AKT expression and concurrent Epstein-Barr virus positivity showed worst prognosis with the median OS and PFS of 15.2 and 7.4 months., Conclusion: DLBCL patients with high p-AKT expression showed distinct clinical features and followed a more rapidly deteriorating clinical course with worse OS and PFS. Thus, a more effective treatment option should be developed for this subset of DLBCL patients, and targeting PI3K/AKT pathway may be a promising therapeutic strategy.

A kidney stone in a person with a solitary kidney requires urgent attention, which may result in surgical and/or hospital attention. We conducted a matched retrospective cohort study to determine if living kidney donors compared to healthy nondonors have a higher risk of: (i) kidney stones with surgical intervention, and (ii) hospital encounters for kidney stones. We reviewed all predonation charts for living kidney donations from 1992 to 2009 at five major transplant centers in Ontario, Canada, and linked this information to healthcare databases. We selected nondonors from the healthiest segment of the general population and matched 10 nondonors to every donor. Of the 2019 donors and 20 190 nondonors, none had evidence of kidney stones prior to cohort entry. Median follow-up time was 8.4 years (maximum 19.7 years; loss to follow-up <7%). There was no difference in the rate of kidney stones with surgical intervention in donors compared to nondonors (8.3 vs. 9.7 events/10 000 person-years; rate ratio 0.85; 95% confidence interval [CI] 0.47-1.53). Similarly there was no difference in the rate of hospital encounters for kidney stones (12.1 vs. 16.1 events/10 000 person-years; rate ratio 0.75; 95% CI 0.45-1.24). These interim results are reassuring for the safety of living kidney donation., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: In this study, the prognostic impact of the presence of the multifocal or multicentric tumor (MMT) and its association with molecular subtypes were investigated., Patients and Methods: We investigated the breast cancer metastasis and survival in patients with multifocal or multicentric invasive foci in the same breast. The study population includes 2882 patients in the Seoul National University Hospital Breast Care Center (SNUHBCC) dataset and 41 179 patients in Korean Breast Cancer Registry (KBCR) dataset., Results: From SNUHBCC dataset, we observed a significant role of MMT in developing distant metastasis and death when the tumors were triple-negative subtype. This subtype-specific prognostic importance of MMT in overall survival was also seen in KBCR dataset (HR, 1.32; 95% CI, 1.02-1.69). In tumors <2 cm, the hazard ratios (HRs) for node metastasis and death were similar along the tumor size change in triple-negative subtype, while other subtypes showed a stepwise increment, suggesting the biologic importance of small invasive foci in this subtype., Conclusions: Our results demonstrate the prognostic importance of MMT in patients with triple-negative breast cancers. Small additional invasive foci in triple-negative breast cancer patients should be considered as clinically relevant tumor deposits.

The pharmacokinetics, efficacy and safety of once-daily tacrolimus formulation (Tac-OD) were assessed in 34 stable pediatric kidney transplant recipients. Enrolled patients received their dose of twice-daily tacrolimus formulation (Tac-BID) on study Days 0 through 7. On the morning of study Day 8, the total daily doses for patients were converted to Tac-OD on a 1:1 basis and maintained on a once-daily morning dosing regimen. Tacrolimus pharmacokinetic profiles were obtained on study Days 7, 14 and 28 (after dose adjustment). Although the mean C0 concentrations (4.10 ± 1.16-3.53 ± 1.10 ng/mL, p = 0.004), and AUC0-24 (151.8 ± 41.6-129.8 ± 39.3 ng h/mL, p < 0.001) were decreased significantly after a 1:1 based conversion, there was high interindividual variability. The dose of Tac-OD was decreased in 26.5% and increased in 44.1% of patients. The resultant tacrolimus dose and pharmacokinetic profiles on study Day 28 were comparable to those on Day 7. There were no serious adverse events. In conclusion, Tac-BID can be safely converted to Tac-OD in stable pediatric kidney transplant patients with the heightened therapeutic drug monitoring. Effects of drug conversion on the cardiovascular risk factors, neurological side effects and adherence should be further evaluated., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The outcomes of kidney transplants that simultaneously exhibit donation after cardiac death (DCD) and expanded criteria donor (ECD) characteristics have not been well studied. We examined the outcomes of DCD versus non-DCD kidney transplants as a function of ECD status and the kidney donor risk index (KDRI). A cohort study of 67 816 deceased donor kidney transplant recipients (KTR), including 562 ECD/DCD KTR, from January 1, 2000 to December 31, 2009 was conducted using the Scientific Registry of Transplant Recipients. In a multivariable Cox proportional hazards model, the modestly increased risk of total graft failure in DCD versus non-DCD KTR was not significantly modified by ECD status (hazard ratio1.07 [95% CI: 1.01, 1.15] for non-ECD vs. 1.21 [95% CI: 1.04, 1.40] for ECD, p for interaction = 0.14).Moreover, the hazard ratios did not significantly vary by KDRI quintiles (p = 0.40). Similar trends were seen for death-censored graft failure and death with graft function. In conclusion, ECD status or higher KDRI score did not appreciably increase the relative hazard of adverse graft and patient outcomes in DCD KTR. These findings suggest that the judicious use of ECD/DCD donor kidneys may be an appropriate strategy to expand the donor pool., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The aim of this study was to investigate the clinicopathological characteristics of GATA binding protein 3 (GATA3)-positive breast cancers as well as the association of GATA3 expression with response to chemotherapy., Patients and Methods: Tumor specimens obtained before neoadjuvant chemotherapy [paclitaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide)] from breast cancer patients (n = 130) were subjected to immunohistochemical and mutational analysis of GATA3 and DNA microarray gene expression analysis for intrinsic subtyping., Results: Seventy-four tumors (57%) were immunohistochemically positive for GATA3. GATA3-positive tumors were significantly more likely to be lobular cancer, estrogen receptor (ER)-positive, progesterone receptor (PgR)-positive, Ki67-negative, and luminal A tumors. Somatic mutations were found in only three tumors. Pathological complete response (pCR) was observed in 8 (11%) GATA3-positive tumors and in 22 (39%) GATA3-negative tumors. multivariate analysis showed that tumor size, human epidermal growth factor receptor 2 (her2), and gata3 were independent predictors of pcr., Conclusions: GATA3-positive breast cancers showed luminal differentiation characterized by high ER expression and were mostly classified as luminal-type tumors following intrinsic subtyping. Interestingly, GATA3 was an independent predictor of response to chemotherapy, suggesting that GATA3 might be clinically useful as a predictor of a poor response to chemotherapy.

Background: Clinical features and outcomes of extranodal natural killer/T-cell lymphoma (ENKL) arising from extranasal sites are not fully understood. The purpose of this study was to study the prognosis and treatment outcome of skin/soft tissue primary ENKL., Patients and Methods: This multicenter retrospective study included 48 patients with skin/soft tissue primary ENKL diagnosed from 1993 to 2010., Results: Patients with Ann Arbor stage I, T1-2N0M0 by International Society for Cutaneous Lymphomas-European Organization of Research and Treatment of Cancer TNM (tumour-node-metastasis) stage, International prognostic index score of 0-1, and a Korean prognostic index (KPI) score of 0-1 were associated with better survival. Four of five patients with T1-2N0M0 disease achieved complete response with radiation alone. In disseminated disease, only 6 of 13 patients responded to anthracycline-containing chemotherapy, and all the two patients receiving SMILE showed response., Conclusion: In conclusion, we identified the prognostic value of KPI, and we suggest a treatment recommendation according to the TNM (tumour-node-metastasis) stage. Radiotherapy with/without chemotherapy seemed to be optimal in localized disease. In advanced stages, a more aggressive treatment regimen with newer agents should be sought.

In kidney transplant recipients, cardiovascular disease (CVD) is the leading cause of death. The relationship of kidney function with CVD outcomes in transplant recipients remains uncertain. We performed a post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial to assess risk factors for CVD and mortality in kidney transplant recipients. Following adjustment for demographic, clinical and transplant characteristics, and traditional CVD risk factors, proportional hazards models were used to explore the association of estimated GFR with incident CVD and all-cause mortality. In 4016 participants, mean age was 52 years and 20% had prior CVD. Mean eGFR was 49 ± 18 mL/min/1.73 m(2) . In 3676 participants with complete data, there were 527 CVD events over a median of 3.8 years. Following adjustment, each 5 mL/min/1.73 m(2) higher eGFR at levels below 45 mL/min/1.73 m(2) was associated with a 15% lower risk of both CVD [HR = 0.85 (0.80, 0.90)] and death [HR = 0.85 (0.79, 0.90)], while there was no association between eGFR and outcomes at levels above 45 mL/min/1.73 m(2) . In conclusion, in stable kidney transplant recipients, lower eGFR is independently associated with adverse events, suggesting that reduced kidney function itself rather than preexisting comorbidity may lead to CVD., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: We established the cell cycle profiling (C2P) assay for specific activity (SA; activity/expression) of cyclin-dependent kinases (CDKs). C2P risk score (C2P-RS) based on CDK1 and CDK2 SAs was significantly associated with relapse in breast cancer (BC). This study was conducted to investigate the predictive value of C2P-RS for neoadjuvant chemotherapy (NAC)., Patients and Methods: Among 124 eligible patients, 122 were treated with weekly paclitaxel followed by 5-fluorouracil, epirubicin and cyclophosphamide (P-FEC) and 2 were treated with paclitaxel monotherapy. C2P-RS was determined via C2P using frozen biopsy samples before NAC., Results: Negative estrogen receptor (ER), negative progesterone receptor (PR), positive human epidermal growth factor receptor 2 (HER2), high Ki-67 expression and intermediate + high C2P-RS were significantly associated with high pathological complete response (pCR) rates compared with positive ER (30% versus 9%), positive PR (25% versus 6%), negative HER2 (34% versus 11%), low Ki-67 expression (24% versus 7%) or low C2P-RS (24% versus 9%), respectively. The combination of C2P-RS and Ki-67 had a stronger impact on pCR than each parameter alone, and a multivariate analysis showed that the combination was an independent predictor of pCR (odds ratio 3.3, 95% confidence interval 1.1-9.5)., Conclusions: C2P-RS was significantly associated with pCR after P-FEC and may be a useful predictor for chemotherapy in BCs.

Background: The incidence and risk factors of central nervous system (CNS) involvement in peripheral T-cell lymphomas (PTCLs) are still unclear., Patients and Methods: We analyzed 228 patients with PTCLs, excluding cases of extranodal natural killer/T-cell lymphoma and primary cutaneous T-cell lymphoma, by retrospectively collecting the clinical features and outcomes of the patients., Results: Twenty events (8.77%, 20/228) of CNS involvement were observed during a median follow-up period of 13.9 months (range 0.03-159.43). Based on univariate analysis, elevated serum lactate dehydrogenase (LDH) level [P = 0.019, relative risk (RR) 5.904, 95% confidence interval (CI) 1.334-26.123] and involvement of the paranasal sinus (P = 0.032, RR 3.137, 95% CI 1.105-8.908) adversely affect CNS involvement. In multivariate analysis, both were independently poor prognostic factors for CNS relapse [elevated LDH level: P = 0.011, hazard ratio (HR) 6.716, 95% CI 1.548-29.131; involvement of the paranasal sinus: P = 0.008, HR 3.784, 95% CI 1.420-10.083]. The survival duration of patients with CNS involvement was significantly shorter than that of the patients without CNS involvement (P = 0.009), with median overall survival of 7.60 months (95% CI of 4.92-10.28) versus 27.43 months (95% CI of 0.00-57.38), respectively., Conclusions: Elevated LDH level and involvement of the paranasal sinus are two risk factors for CNS involvement in patients with PTCLs. Considering the poor prognoses after CNS relapse, prophylaxis should be considered with the presence of any risk factor.

Older living kidney donors are regularly accepted. Better knowledge of recipient outcomes is needed to inform this practice. This retrospective cohort study observed kidney allograft recipients from Ontario, Canada between January 2000 and March 2008. Donors to these recipients were older living (≥ 60 years), younger living, or standard criteria deceased (SCD). Review of medical records and electronic healthcare data were used to perform survival analysis. Recipients received 73 older living, 1187 younger living and 1400 SCD kidneys. Recipients of older living kidneys were older than recipients of younger living kidneys. Baseline glomerular filtration rate (eGFR) of older kidneys was 13 mL/min per 1.73 m² lower than younger kidneys. Median follow-up time was 4 years. The primary outcome of total graft loss was not significantly different between older and younger living kidney recipients [adjusted hazard ratio, HR (95%CI): 1.56 (0.98-2.49)]. This hazard ratio was not proportional and increased with time. Associations were not modified by recipient age or donor eGFR. There was no significant difference in total graft loss comparing older living to SCD kidney recipients [HR: 1.29 (0.80-2.08)]. In light of an observed trend towards potential differences beyond 4 years, uncertainty remains, and extended follow-up of this and other cohorts is warranted., (©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: To analyze the clinical features, outcomes including efficacy of treatment, and prognostic factors of patients with immunoglobulin D multiple myeloma (IgD MM)., Design and Methods: Seventy-five patients diagnosed with IgD MM were selected from the Korean Myeloma Registry database (www.myeloma.or.kr)., Results: Median age was 57 years and the main presenting features were bone pain (77%). Renal function impairment and hypercalcemia were present in 40 (53%) and 20 (27%) patients. Sixty-seven patients (89%) had lambda light chains. Forty-eight patients (64%) were of stage III by International Staging System. Twenty-six patients (53%) had chromosomal abnormalities mostly by conventional cytogenetics. Thirty-nine patients (54%) were treated with vincristine, adriamycin, and dexamethasone chemotherapy; the overall response rate (ORR) of 56%. Sixteen patients (22%) received first-line chemotherapy including new drugs (bortezomib or thalidomide), with an ORR of 81%. At a median follow-up time of 28.6 months, median overall survival (OS) was 18.5 months. Age, extramedullary plasmacytoma, del(13) or hypoploidy, serum β(2) microglobulin level, and platelet count were significant prognostic factors for OS., Conclusions: IgD MM is an aggressive disease that is usually detected at an advanced stage. Despite a positive initial response, survival after relapse was dismal. Intensive treatment strategies before and following stem cell transplantation may improve outcomes in younger patients.

Purpose: Recently, Ki67 index (cell proliferation marker) has been attracting a considerable attention as a prognostic factor in breast cancer but the prognostic significance of Ki67 after neoadjuvant chemotherapy (NAC) has rarely been examined., Experimental Design: Primary breast cancer patients (n = 102) treated with NAC (sequential paclitaxel 12 cycles (q1w) and 5-FU/epirubicin/cyclophosphamide 4 cycles (q3w)) were recruited in the study. Ki67, estrogen receptor (ER) and progesterone receptor (PR) and breast cancer resistant protein (BCRP) and P-glycoprotein were determined by immunohistochemistry and HER2 was determined by FISH in tumor tissues obtained before and after NAC, and their association with patient prognosis (relapse-free survival) was examined., Results: Of the 102 patients, pCR was achieved in 30 (29.4%). In the 72 non-pCR patients, Ki67 index significantly (P < 0.001) decreased after NAC. Ki67 index after NAC, but not Ki67 index before NAC, was significantly associated with a patient prognosis (P = 0.022). Multivariate analysis has shown that Ki67 index after NAC is a marginally significant (P = 0.05) prognostic factor and that other biomarkers including ER, PR, BCRP, and P-glycoprotein before and after NAC are not significant., Conclusions: Ki67 after NAC, but not before NAC, is prognostic in breast cancer patients, and might be clinically useful in the prognosis prediction of patients who do not achieve pCR after NAC. On the other hand, BCRP and P-glycoprotein before and after NAC are unlikely to be useful as prognostic factors in these patients., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: The roles of arachidonic acid (AA) metabolites in hypoxia-induced pulmonary vasoconstriction (HPV), a critical physiological mechanism that prevents ventilation/perfusion mismatch, are still incompletely understood., Methods: Pulmonary arterial pressure was measured in ventilated/perfused rat lungs. Isometric tones of rat intralobar pulmonary arteries were also measured, using a myograph., Results: Hypoxia (Po₂, 3%)-induced pulmonary arterial pressure increases (ΔPAP(hypox)) were stable with blood-mixed perfusate, but decayed spontaneously. ΔPAP(hypox) was inhibited by 29%, 16%, and 28% by the thromboxane A₂ (TXA₂) antagonist SQ-29548, the 5-lipoxygenase inhibitor, MK886, and the leukotriene D₄ antagonist, LY-171883, respectively. The prostacyclin synthase inhibitor tranylcypromine augmented ΔPAP(hypox) by 5%, whereas inhibition of cytochrome P450 did not affect ΔPAP(hypox). Consistently, the TXA₂ analogue U46619 increased ΔPAP(hypox) whereas prostacyclin abolished ΔPAP(hypox). However, leukotriene D₄ had no direct effect on ΔPAP(hypox). In the isolated pulmonary arteries, pretreatment with U46619 was essential to demonstrate hypoxia-induced contraction., Conclusions: The above results suggest that TXA₂ and cysteinyl leukotrienes, other than leukotriene D₄, are endogenous factors that facilitate HPV in rats. The indispensable role of TXA₂-induced pretone in the HPV of isolated pulmonary arteries indicates that the signal from thromboxane receptors might be a critical component of oxygen sensation mechanisms.

Background: The optimal dose of remifentanil to attenuate the cardiovascular responses to tracheal intubation in pre-eclamptic patients undergoing Caesarean delivery under general anaesthesia has not been established. We compared the effects of two low doses of remifentanil on the cardiovascular responses to tracheal intubation and neonatal outcomes., Methods: Forty-eight women with severe pre-eclampsia were randomly assigned to receive either remifentanil 0.5 µg kg⁻¹ (R0.5 group, n=24) or 1 µg kg⁻¹ (R1.0 group, n=24) over 30 s before induction of anaesthesia using thiopental 5 mg kg⁻¹ and succinylcholine 1.5 mg kg⁻¹. Systolic arterial pressure (SAP), heart rate (HR), and plasma catecholamine concentrations were measured. Neonatal effects were assessed using Apgar scores and umbilical cord blood gas analysis., Results: SAP was decreased by induction of anaesthesia and increased by tracheal intubation in both groups. The peak SAP after intubation was greater in the R0.5 group than in the R1.0 group, whereas it did not exceed baseline values in either group. HR increased significantly above baseline in both groups with no significant differences between the groups. Three subjects in the R1.0 group received ephedrine due to hypotension (SAP < 90 mm Hg). Norepinephrine concentrations remained unaltered after intubation and increased significantly at delivery with no significant differences between the groups. Neonatal Apgar scores and umbilical arterial and venous pH and blood gas values were comparable between the groups., Conclusions: Both doses of remifentanil effectively attenuated haemodynamic responses to tracheal intubation with transient neonatal respiratory depression in pre-eclamptic patients undergoing Caesarean delivery under general anaesthesia. The 1.0 µg kg⁻¹ dose was associated with hypotension in three of 24 subjects.