Ten-year epidemiology and risk factors of cytomegalovirus infection in hematopoietic stem cell transplantation patients in Taiwan.

BACKGROUND: Cytomegalovirus (CMV) can cause infection and critical diseases in hematopoietic stem cell transplantation (HSCT) recipients. This study aimed to explore the cumulative incidence and risk factors for CMV infection and disease among HSCT recipients in Taiwan. METHODS: This retrospective cohort study using the Taiwan Blood and Marrow Transplantation Registry (TBMTR) included HSCT recipients between 2009 and 2018 in Taiwan. The primary outcome was cumulative incidence of CMV infection or disease at day 100 after HSCT. Secondary outcomes included day 180 cumulative incidence of CMV infection or disease, infection sites, risk factors for CMV infection or disease, survival analysis, and overall survival after CMV infection and disease. RESULTS: There were 4394 HSCT recipients included in the study (2044 auto-HSCT and 2350 allo-HSCT). The cumulative incidence of CMV infection and disease was significantly higher in allo-HSCT than in auto-HSCT patients at day 100 (53.7% vs. 6.0%, P < 0.0001 and 6.1% vs. 0.9%, P < 0.0001). Use of ATG (HR 1.819, p < 0.0001), recipient CMV serostatus positive (HR 2.631, p < 0.0001) and acute GVHD grades ≥ II (HR 1.563, p < 0.0001) were risk factors for CMV infection, while matched donor (HR 0.856, p = 0.0180) and myeloablative conditioning (MAC) (HR 0.674, p < 0.0001) were protective factors. CONCLUSION: The study revealed a significant disparity in terms of the incidence, risk factors, and clinical outcomes of CMV infection and disease between auto and allo-HSCT patients. These findings underscore the importance of considering these factors in the management of HSCT recipients to improve outcomes related to CMV infections.

Correlation of low numbers of intratumoral FOXP3+ cells with worse progression-free survival in angioimmunoblastic T cell lymphoma.

AIMS: Angioimmunoblastic T cell lymphoma (AITL) is a T cell lymphoma with aberrant immune activity. It is characterised by inflammatory and immune reactions. However, the impact of regulatory T (Treg) cells on AITL remains unclear. METHODS: We retrospectively collected 46 AITL cases and performed immunohistochemical analysis of forkhead box P3 (FOXP3) expression. The number of immunostained FOXP3 cells was determined using a digital pathology system with whole-slide imaging. The average number of FOXP3+ cells per high-power field (HPF) was determined by randomly counting 20 HPFs. AITL cases were categorised into high-expression and low-expression groups based on the median count of FOXP3+ cells in all analysed samples. The relationship between FOXP3 expression and clinicopathological features was assessed. RESULTS: Among the studied patients, 14 (30.4%) were females and 32 (69.6%) were males, and the median age at diagnosis was 64.1 years. The median expression of FOXP3 was 84.9 positive cells/HPF. FOXP3 expression negatively correlated with Epstein-Barr virus-encoded small RNA positivity in tumour (p=0.041). The patients with low FOXP3 expression presented with aggressive clinical behaviour, including advance-staged diseases (p=0.043), splenomegaly (p=0.008), B symptoms (p=0.019) and extranodal involvement (p=0.019). The neutrophil-to-lymphocyte ratio was higher in the patients with low FOXP3 expression, compared with those with high FOXP3 expression. Low FOXP3 expression had an adverse effect on progression-free survival (PFS, p=0.033), and increased the risk of recurrence 2.320-fold (HR 2.320 (95% CI 1.109 to 4.856); p=0.025). CONCLUSIONS: Patients with AITL with low FOXP3 expression tend to have aggressive clinical presentation and shortened PFS. These findings may help with risk stratification and determination of new treatment strategy.

Combination of Sarcopenia and Anemia Predicts Worse Outcome in Elderly Patients With Diffuse Large B-Cell Lymphoma.

BACKGROUND/AIM: In diffuse large B-cell lymphoma (DLBCL), sarcopenia is associated with increased side-effects of chemotherapy and poor survival, especially in elderly patients. Anemia, a complex condition resulting from cancer itself and inflammation, might have a correlation with loss of muscle mass and might also indicate a worse outcome. In this study, we aimed to investigate the association of the skeletal muscle index (SMI) at the third lumbar vertebra (L3) with hemoglobin (Hb) levels and its predictive value for the outcome of DLBCL. PATIENTS AND METHODS: The study included patients, aged 70 or older, newly diagnosed with DLBCL who received immunochemotherapy. Sex-specific L3-SMI was measured by computed tomography, and Hb levels before treatment were recorded. The Kaplan-Meier method and Cox regression model were used to analyze survival and prognostic factors. RESULTS: Anemia was correlated with a low SMI. The presence of either low L3-SMI or anemia (Hb <10.5 g/l) indicated a poor prognosis for both progression-free and overall survival. A novel score combining L3-SMI, and Hb and lactate dehydrogenase levels as independent predictive factors was proposed for treatment response, progression-free and overall survival after adjusting for International Prognostic Index. CONCLUSION: This study highlights the importance of sarcopenia and anemia in patients with DLBCL, particularly in the elderly population. The proposed novel score combining L3-SMI, Hb, and lactate dehydrogenase may provide additional prognostic information for patients with DLBCL, aiding in treatment decisions and management.

Children with chronic myeloid leukaemia treated with front-line imatinib have a slower molecular response and comparable survival compared with adults: a multicenter experience in Taiwan.

BACKGROUND: The direct comparison of molecular responses of front-line imatinib (IM) monitored at the same laboratory between children and adults with chronic phase (CP) of chronic myeloid leukaemia (CML) had not been reported. In this multicenter study, we compared the landmark molecular responses and outcomes of paediatric and adult CML-CP cohorts treated with front-line IM in whom the BCR::ABL1 transcript levels were monitored at the same accredited laboratory in Taiwan. METHODS: Between June 2004 and July 2020, 55 newly diagnosed paediatric and 782 adult CML-CP patients, with molecular diagnosis and monitoring at the same reference laboratory in Taiwan, were enrolled. The criteria of 2020 European LeukemiaNet were applied to evaluate the molecular responses. RESULTS: By year 5, the cumulative incidences of IS <1%, MMR, MR4.0 and MR4.5 of paediatric patients were all significantly lower than those of adult patients (58 vs 75%, 48 vs 66%, 25 vs 44%, 16 vs 34%, respectively). The 10-year progression-free survival (PFS) (90%) and overall survival (OS) (94%) of paediatric patients did not differ from those (92%) of adult patients. CONCLUSIONS: We demonstrated the paediatric cohort had slower molecular responses to front-line IM and similar outcomes in 10-year PFS and OS in real-world practice.

Oral Chemotherapy Application in Elderly Patients With Diffuse Large B-Cell Lymphoma: An Alternative Regimen in Retrospective Analysis.

Background: A combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard treatment for diffuse large B-cell lymphoma (DLBCL). However, no standard treatment has been established for older patients (age ≥ 75 years). This study retrospectively analyzed different treatment strategies in older patients with DLBCL with different chemotherapy regimens and compared the survival rate of patients using oral or intravenous form cyclophosphamide and etoposide in a single center. Methods: We reviewed the records of older patients with DLBCL, aged ≥ 75 years, from January 2010 to August 2019. The different treatment combinations, clinical characteristics, response rates, and toxicity profiles were analyzed. The median overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier (KM) method. Cox regression model was used to identify the risk factors. Results: Eighty-four patients were included. One-quarter of the patients received cytoreduction treatment because of their poor medical condition at the time of diagnosis. Twenty-six percent of the patients were aged ≥ 85 at the time of diagnosis and 46.7% completed the treatment course. Patients receiving non-anthracycline-containing (non-ACR) treatment had worse Charlson comorbidity index, worse PFS, lower body mass index, or were older. The mean anthracycline accumulative dose in the anthracycline-containing (ACR) group was 134 mg/m2. The median OS was 17.2 months and median PFS was 7.7 months. The PFS of R-CHOP is better than R-mini-CHOP and R-CVOP without statistical significance, but OS of R-CHOP is not better than the other regimens. Conclusion: The toxicity, efficacy, and KM curve for OS and PFS in the non-ACR group were lower compared to ACR group, without statistical significance. R-CVOP had similar OS with R-mini-CHOP in our study. The result does not mean etoposide could totally substitute for anthracycline, but etoposide did have lower early progression rate (12.5%), and it may be an option for frail patients with comorbidity. Oral form cyclophosphamide and etoposide could be considered as a substitute for intravenous administration because of the similar effect and toxic profile.

Incidence and predictors of idiopathic pneumonia syndrome in hematopoietic stem cell transplant patients: a nationwide registry study.

Idiopathic pneumonia syndrome (IPS) is a rare but deadly complication of hematopoietic stem cell transplantation (HSCT). This study characterized the incidence and risk factors for IPS after HSCT in Taiwan. Data from January 2009 to February 2019 was collected from the Taiwan Society of BMT national registry. Forty-three (1.1%) of 3924 HSCT patients who developed IPS were identified. Incidence of IPS was lower in patients who received autologous HSCT than patients who received allogeneic HSCT (0.68% vs 1.44%, P = 0.022). Multivariate analysis showed that use of TBI and intravenous busulfan in the conditioning regimen were each independent predictor of IPS after HSCT. In addition, development of IPS was significantly associated with increased risk of death in the first 120 days post-HSCT (HR, 2.09; 95% CI, 1.08 to 4.05, P = 0.029) and 2 years post-HSCT (HR, 1.65; 95% CI, 1.07 to 2.542, P = 0.023), but not beyond 2 years post-HSCT. However, survival outcomes did not differ significantly between patients with IPS who received autologous versus allogeneic HSCT (P = 0.52). In conclusion, despite the relatively low incidence of post-HSCT IPS in Taiwan, mortality remains high. The results of this study will help to identify high-risk patients for early intervention and guide future therapeutic research.

Comparison of molecular responses and outcomes between BCR::ABL1 e14a2 and e13a2 transcripts in chronic myeloid leukemia.

Several studies have compared the molecular responses between e14a2 and e13a2 BCR::ABL1 transcripts in chronic myeloid leukemia (CML) patients treated with front-line imatinib, but there were very limited studies on nilotinib or dasatinib-treated patients. We retrospectively analyzed the molecular responses in 1124 CML patients with the e14a2 or e13a2 transcript receiving front-line imatinib, nilotinib or dasatinib treatment. Patients with the e14a2 transcript had higher optimal response rates than those with the e13a2 transcript at 12 months in the imatinib-treated group, and 6 and 12 months in the nilotinib-treated group. The optimal response rates were not significantly different between the two transcripts in the dasatinib-treated group at landmark molecular responses. With a median follow-up time of 48.4 months, higher cumulative incidences of BCR::ABL1 International Scale ≤1% and major molecular response were observed in patients with the e14a2 rather than the e13a2 transcript receiving front-line imatinib or nilotinib treatment, but not in dasatinib-treated patients. The progression-free survival and overall survival did not differ between the two transcripts in all three treatment groups. In view of the speed and depth of molecular responses, BCR::ABL1 transcript subtypes might provide helpful information in selecting a front-line tyrosine kinase inhibitor for individual young patients with future potential treatment-free remission.

NOVEL-1st: an observational study to assess the safety and efficacy of nilotinib in newly diagnosed patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase in Taiwan.

Nilotinib has been approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP). However, the real-world evidence of nilotinib in newly diagnosed untreated Ph+ CML-CP is limited in Taiwan. The NOVEL-1st study was a non-interventional, multi-center study collecting long-term safety and effectiveness data in patients with newly diagnosed and untreated Ph+ CML-CP receiving nilotinib. We enrolled 129 patients from 11 hospitals. Overall, 1,466 adverse events (AEs) were reported; among these, 151 were serious and 524 were nilotinib-related. Common hematological AEs were thrombocytopenia (31.0%), anemia (20.9%), and leukopenia (14.0%); common nilotinib-related AEs were thrombocytopenia (29.5%), anemia (14.7%), and leukopenia (12.4%). Early molecular response, defined as BCR-ABL ≤ 10% at Month 3, was seen in 87.6% of patients. By 36 months, the cumulative rates of complete hematologic response, complete cytogenetic response, major molecular response, molecular response 4.0-log reduction, and molecular response 4.5-log reduction were 98.5, 92.5, 85.8, 65.0, and 45.0%, respectively. Nilotinib is effective and well-tolerated in patients with newly diagnosed Ph+ CML-CP in the real-world setting. Long-term holistic care and a highly tolerable AE profile may contribute to good treatment outcomes in Ph+ CML-CP under first-line treatment with nilotinib.

Role of quantitative hepatitis B surface antibodies in preventing hepatitis B virus-related hepatitis in patients treated with rituximab.

Hepatitis B virus (HBV) reactivation is a well-known complication after rituximab-based chemotherapy in patients with B cell lymphoma (BCL) who have resolved HBV infection. This retrospective cohort study used electronic medical records from the Kaohsiung Chang Gung Memorial Hospital. There were 128 patients with BCL and resolved HBV infection treated with 1st-line rituximab-containing therapy from 2008 to 2013. No patient received antiviral prophylaxis. Patients with high pretreatment hepatitis B surface antibody (anti-HBs titer ≥100 mIU/mL), had significantly less HBV reactivation (2.0%, 1/49) than patients with low (10-100 mIU/mL, 10.8%, 4/37) or negative anti-HBs (<10 mIU/mL, 23.8%, 10/42) (p = 0.001). No patient in the high group vs. 1 (2.7%) low group vs. 6 (14.3%) negative group developed HBV-related hepatitis (p = 0.002). Patients with high pretreatment anti-HBs have a low risk of HBV-related complications and may not require antiviral prophylaxis. We propose an algorithm for the management of HBV reactivation risk in BCL.

A comprehensive retrospective cohort study of the journey of B-cell lymphoma in Taiwan.

Complete disease journey and risk factors for poor outcomes are needed to facilitate effectiveness evaluations of new therapies and clinical decision-making in B-cell Non-Hodgkin lymphoma (B-NHL), particularly in Asia where such data are lacking. This retrospective cohort study used electronic medical records from a regional medical centre in southern Taiwan to follow-up 441 patients newly diagnosed with common B-NHL subtypes: Diffuse Large B-cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma (CLL/SLL), Marginal Zone Lymphoma (MZL), Mantle Cell Lymphoma (MCL), and Waldenström macroglobulinemia (WM), between 01-Jan-2008 and 31-Dec-2013, until 31-Dec-2017. Treatment pathways were modelled using a Markov approach. Stage III/IV disease at diagnosis was frequent for patients with DLBCL, FL, MCL and WM. Hepatitis B surface antigen/hepatitis C virus seropositivity was 18.6%/12.3%. Clinical responses to 1st-line treatment were observed in 76.0% (DLBCL), 87.3% (FL), 86.0% (MZL), 60.0% (MCL), and 42.9% (WM) of patients. For DLBCL, disease control was achieved by ~ 50% after 1st-line, ~ 24% after 2nd-line, ~ 17% after 3rd-line. Patients with Stage III/IV DLBCL or age > 65 years at diagnosis had lower rates of active treatment, poorer disease control and higher mortality than patients with early stage disease or age ≤ 65 years. Disease flare < 6 months after 1st-line treatment was significantly associated with mortality. Despite good clinical response rates for some sub-types, survival remains poor. New treatments are needed to improve the outcome of B-NHL.

The status of jaw lesions and medication-related osteonecrosis of jaw in patients with multiple myeloma.

BACKGROUND/PURPOSE: Myeloma jaw lesions are not uncommon. The study aimed to investigate the status of jaw lesions and medication-related osteonecrosis of jaw (MRONJ) in multiple myeloma (MM) patients. METHODS: One hundred and twenty-two consecutive newly-diagnosed MM patients seeking dental care at a hospital of southern Taiwan was examined according to jaw lesions with complete follow-up data. RESULTS: Median age of the patients was 67.8 years, and 88.5% of patients were of DS stage III and 41.0% were of ISS stage III at diagnosis. Median survival was 37.9 months for 43 (35.2%) patients with jaw lesions and 57.4 months for 79 patients without jaw lesions. 1-year, 5-year and >7-year overall survival rates for patients with jaw lesions versus patients without jaw lesions were 94.9%, 67.2%, 56.7% vs 83.7%, 51.8%, 26.8% respectively. Patients with jaw lesions had the worse survival (P = 0.03). Neither age nor stage affected survival. Jaw lesions involved the mandible more often than the maxilla and stopped progressing during remission, but did not repair. Jaw lesions were the first evidence or recurrent sign of MM in six (4.9%) patients. Long-term monthly antiresorptive therapy changed the radiographic patterns of jawbones and induced MRONJ developing in 16.7% (8/48) of patients. Five (62.5%) MRONJ sites spontaneously occurred without local risk factors. CONCLUSION: Nearly one-third of MM patients develop osteolytic jaw lesions that seem to be associated with poorer survival. Jaw lesion is an independent prognostic predictor of survival in myeloma. Antiresorptive drugs at less frequent dosing regimen are crucial to minimize spontaneous MRONJ.

Intracoronary Injection of Autologous CD34+ Cells Improves One-Year Left Ventricular Systolic Function in Patients with Diffuse Coronary Artery Disease and Preserved Cardiac Performance-A Randomized, Open-Label, Controlled Phase II Clinical Trial.

This phase II randomized controlled trial tested whether intracoronary autologous CD34+ cell therapy could further improve left ventricular (LV) systolic function in patients with diffuse coronary artery disease (CAD) with relatively preserved LV ejection fraction (defined as LVEF >40%) unsuitable for coronary intervention. Between December 2013 and November 2017, 60 consecutive patients were randomly allocated into group 1 (CD34+ cells, 3.0 × 107/vessel/n = 30) and group 2 (optimal medical therapy; n = 30). All patients were followed for one year, and preclinical and clinical parameters were compared between two groups. Three-dimensional echocardiography demonstrated no significant difference in LVEF between groups 1 and 2 (54.9% vs. 51.0%, respectively, p = 0.295) at 12 months. However, compared with baseline, 12-month LVEF was significantly increased in group 1 (p < 0.001) but not in group 2 (p = 0.297). From baseline, there were gradual increases in LVEF in group 1 compared to those in group 2 at 1-month, 3-months, 6-months and 12 months (+1.6%, +2.2%, +2.9% and +4.6% in the group 1 vs. -1.6%, -1.5%, -1.4% and -0.9% in the group 2; all p < 0.05). Additionally, one-year angiogenesis (2.8 ± 0.9 vs. 1.3 ± 1.1), angina (0.4 ± 0.8 vs. 1.8 ± 0.9) and HF (0.7 ± 0.8 vs. 1.8 ± 0.6) scores were significantly improved in group 1 compared to those in group 2 (all p < 0.001). In conclusion, autologous CD34+ cell therapy gradually and effectively improved LV systolic function in patients with diffuse CAD and preserved LVEF who were non-candidates for coronary intervention (Trial registration: ISRCTN26002902 on the website of ISRCTN registry).

Human Umbilical Cord-Derived Mesenchymal Stem Cells for Acute Respiratory Distress Syndrome.

OBJECTIVES: To investigate the safety, feasibility, and possible adverse events of single-dose human umbilical cord-derived mesenchymal stem cells in patients with moderate-to-severe acute respiratory distress syndrome. DESIGN: Prospective phase I clinical trial. SETTING: Medical center in Kaohsiung, Taiwan. PATIENTS: Moderate-to-severe acute respiratory distress syndrome with a PaO2/FIO2 ratio less than 200. INTERVENTIONS: Scaling for doses was required by Taiwan Food and Drug Administration as follows: the first three patients received low-dose human umbilical cord-derived mesenchymal stem cells (1.0 × 10 cells/kg), the next three patients with intermediate dose (5.0 × 10 cells/kg), and the final three patients with high dose (1.0 × 10 cells/kg) between December 2017 and August 2019. MEASUREMENTS AND MAIN RESULTS: Nine consecutive patients were enrolled into the study. In-hospital mortality was 33.3% (3/9), including two with recurrent septic shock and one with ventilator-induced severe pneumomediastinum and subcutaneous emphysema. No serious prespecified cell infusion-associated or treatment-related adverse events was identified in any patient. Serial flow-cytometric analyses of circulating inflammatory biomarkers (CD14CD33/CD11b+CD16+/CD16+MPO+/CD11b+MPO+/CD14CD33+) and mesenchymal stem cell markers (CD26+CD45-/CD29+CD45-/CD34+CD45-/CD44+CD45-/CD73+CD45-/CD90+CD45-/CD105+CD45-/CD26+CD45-) were notably progressively reduced (p for trend < 0.001), whereas the immune cell markers (Helper-T-cell/Cytotoxity-T-cell/Regulatory-T-cell) were notably increased (p for trend < 0.001) after cell infusion. CONCLUSIONS: The result of this phase I clinical trial showed that a single-dose IV infusion of human umbilical cord-derived mesenchymal stem cells was safe with favorable outcome in nine acute respiratory distress syndrome patients.

Distinct immunoglobulin heavy chain variable region gene repertoire and lower frequency of del(11q) in Taiwanese patients with chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in Western countries but very rare in Asia. Peripheral blood or bone marrow mononuclear cells obtained at initial diagnosis from 194 patients with CLL were analysed to determine the ethnic difference in genetic abnormalities. Mutated IGHV was detected in 71·2% of Taiwanese CLL and IGHV3-23 was the most frequently used gene. Stereotyped BCR was present in 18·3% with subset 8 being the most frequent. All cases with subset 8 belonged to IGHV 4-39 and were exclusively associated with un-mutated IGHV and poor outcome. Mutation frequencies of SF3B1 (9·7%), NOTCH1 (8·6%), BIRC3 (1·1%), ATM (16·9%) or TP53 (8·1%), and frequencies of cytogenetic abnormalities including trisomy 12 (18·6%), del(17p) (10·4%), del(13q) (43·7%) and IGH translocation (10·1%) were comparable to those reported from Western countries, except del(11q) (6·9%) which was lower in our patients. Patients with un-mutated IGHV, subset 8, disrupted TP53, trisomy 12, and SF3B1 mutations had a worse outcome compared to patients without these mutations. In conclusion, IGHV3-23 usage, stereotyped subset 8 and lower frequency of del(11q) show an ethnicity-dependent association in Taiwanese CLL patients.

Intra-carotid arterial transfusion of autologous circulatory derived CD34+ cells for old ischemic stroke patients - a phase I clinical trial to evaluate safety and tolerability.

This phase I clinical trial tested the hypothesis that circulatory CD34+ cell therapy might be safe for old ischemic stroke (IS) (defined as IS>6 months) patients and also to evaluate the neurological function after the therapy. Nine old IS patients (with mean IS interval: 8.6 ± 6.4 years) were consecutively enrolled and received intra-carotid artery transfusion of circulatory-derived autologous CD34+ cells (3.0×107 cells/patient) into the ipsilateral brain infarct area at catheterization room by Catheter Looping Technique, after subcutaneous G-CSF injection (5 µg/kg twice a day for 4 days). The results showed that procedural safety was 100% with all patients uneventfully discharged. The circulating number of EPCs and angiogenesis (i.e., by Matrigel assay) were significantly higher at post than at prior to G-CSF treatment (all P<0.001). Time courses (0/5/10/30 minutes) of blood samplings from right-internal jugular vein exhibited significantly increased in levels of SDF-1α and EPCs numbers in time points of 5/10/30 minutes than in the baseline (0 minute) (all P<0.05). Barthel index was increased (defined as ≥5 scores) in 44.4% (4/9) and CASI score was notably improved (all P<0.01) at 6-month follow-up after the cell therapy as compared to the baseline. No recurrent IS or any tumorigenesis was found in these patients with a mean follow-up time interval of 16.5 ± 6.2 months. All of these patients remain survive and are followed up at outpatient department. In conclusion, CD34+ cell therapy is safe and might offer some benefit to old IS patients.

SIRT1 overexpression is an independent prognosticator for patients with esophageal squamous cell carcinoma.

BACKGROUND: Sirtuin 1 (SIRT1) regulates DNA repair and metabolism by deacetylating target proteins. SIRT1 may be oncogenic because its overexpression has been detected in many cancers. The aim of the present study was to clarify the prognostic role of SIRT1 in patients with esophageal squamous cell carcinoma (ESCC) and evaluate the effect of SIRT1 inhibitor in vitro. METHODS: The expression of SIRT1 was evaluated immunohistochemically in 155 surgically resected ESCC and the staining results were evaluated semiquantitatively by the Immunoreactive Scoring System. The clinical features and treatment outcome were analyzed. The effect of SIRT1 inhibitor, SIRT 1 inhibitor IV, (S)-35, was investigated in vitro on ESCC cell lines. RESULTS: The expression of SIRT1 on ESCC did not correlate with age, gender, tumor location, stage, T classification, N classification, surgical margin or histology. Univariate analysis showed that SIRT1 overexpression was associated with inferior overall survival (P = 0.004) and disease-free survival (P = 0.004). In multivariate comparison, SIRT1 overexpression remained independently associated with worse overall survival (P = 0.009, hazard ratio = 1.776) and disease-free survival (P = 0.017, hazard ratio = 1.642). In cell lines, SIRT1 inhibitor inhibited ESCC growth. CONCLUSIONS: Our study suggests that SIRT1 overexpression is an independent prognosticator for patients with ESCC and the SIRT1 inhibitor suppressed cell proliferation of ESCC cell lines. Our findings suggest that inhibition of SIRT1 signaling may be a promising novel target for ESCC.

Positive expression of Midkine predicts early recurrence and poor prognosis of initially resectable combined hepatocellular cholangiocarcinoma.

BACKGROUND: Post-surgical prognosis is usually poor for combined hepatocellular cholangiocarcinoma (CHCC-CC), a rare primary liver cancer. Although midkine (MK) is a prognostic biomarker for several known cancers, it is not known whether it can be used as such in resectable CHCC-CC. This study examined whether MK expression can predict recurrence and survival in patients with resectable CHCC-CC. METHODS: We retrospectively enrolled 52 patients with resectable CHCC-CC who had received curative hepatic resections. MK expression was assessed in post-surgical immunohistochemical studies of specimens in paraffin blocks. Clinical outcomes were analyzed from medical records. RESULTS: Two-year disease-free and three-year overall survival rates were 42.1% and 44.6%. MK was expressed in 30 patients. Univariate analysis showed patients positively expressing MK had a significantly poorer 2-year disease free and three-year overall survival. Multivariate analysis found positive MK expression independently predicted recurrence. CONCLUSIONS: Positive expression of MK predicts poor prognosis in patients with resectable CHCC-CC.

The Five-Year Clinical and Angiographic Follow-Up Outcomes of Intracoronary Transfusion of Circulation-Derived CD34+ Cells for Patients With End-Stage Diffuse Coronary Artery Disease Unsuitable for Coronary Intervention-Phase I Clinical Trial.

OBJECTIVES: This study investigated the clinical and angiographic long-term outcomes of intracoronary transfusion of circulation-derived CD34+ cells for patients with end-stage diffuse coronary artery disease unsuitable for coronary intervention. DESIGN AND SETTING: A single-center prospective randomized double-blinded phase I clinical trial. Thirty-eight patients undergoing CD34+ cell therapy were allocated into groups 1 (1.0 × 10 cells/each vessel; n = 18) and 2 (3.0 × 10 cells/each vessel; n = 20). PATIENTS: Those with end-stage diffuse coronary artery disease were unsuitable for percutaneous and surgical coronary revascularization. INTERVENTIONS: Intracoronary delivery of circulation-derived CD34+ cells. MEASUREMENTS AND MAIN RESULTS: We prospectively evaluated long-term clinical and echocardiographic/angiographic outcomes between survivors and nonsurvivors. By the end of 5-year follow-up, the survival rate and major adverse cardio/cerebrovascular event were 78.9% (30/38) and 36.8% (14/38), respectively. During follow-up period, 31.6% patients (12/38) received coronary stenting for reason of sufficient target vessel size grown-up after the treatment. Endothelial function was significantly reduced in the nonsurvivors than the survivors (p = 0.039). Wimasis image analysis of angiographic findings showed that the angiogenesis was significantly and progressively increased from baseline to 1 and 5 years (all p < 0.001). The 3D echocardiography showed left ventricular ejection fraction increased from baseline to 1 year and then remained stable up to 5 years, whereas left ventricular chamber diameter exhibited an opposite pattern to left ventricular ejection fraction among the survivors. The clinical scores for angina and heart failure were significantly progressively reduced from baseline to 1 and 5 years (all p < 0.001). CONCLUSIONS: CD34+ cell therapy for end-stage diffuse coronary artery disease patients might contribute to persistently long-term effects on improvement of left ventricular function, angina/heart failure, and amelioration of left ventricular remodeling.

Peritumoral SPARC expression and patient outcome with resectable intrahepatic cholangiocarcinoma.

BACKGROUND AND OBJECTIVES: Cholangiocarcinoma (CCA) affects thousands worldwide with increasing incidence. SPARC (secreted protein acidic and rich in cysteine) plays an important role in cellular matrix interactions, wound repair, and cellular migration, and has been reported to prevent malignancy from growth. SPARC undergoes epigenetic silencing in pancreatic malignancy, but is frequently expressed by stromal fibroblasts adjacent to infiltrating pancreatic adenocarcinomas. CCA is also a desmoplastic tumor, similar to pancreatic adenocarcinoma. SPARC's clinical influence on clinicopathological characteristics of mass-forming (MF)-CCA still remains unclear. In this study, we evaluate the expression of SPARC in tumor and stromal tissue to clarity its relation with prognosis. METHODS: Seventy-eight MF-CCA patients who underwent hepatectomy with curative intent were enrolled for an immunohistochemical study of SPARC. The expression of immunostaining of SPARC was characterized for both tumor and stromal tissues. We conducted survival analysis with 16 clinicopathological variables. The overall survival (OS) was analyzed by Kaplan-Meier analysis and Cox proportional hazards regression modeling. RESULTS: Thirty-three men and 45 women with MF-CCA were studied. Within total 78 subjects, 12 (15.4%) were classified as tumor negative/stroma negative, 37 (47.4%) as tumor positive/stroma negative, four (5.1%) as tumor negative/stroma positive, and 25 (32.1%) as tumor positive/stroma positive. With a median follow-up of 13.6 months, the 5-year OS was 14.9%. Cox proportional hazard analysis revealed that SPARC tumor positive and stromal negative immunostaining and curative hepatectomy predicted favorable OS in patients with MF-CCA after hepatectomy. CONCLUSION: MF-CCA patients with SPARC tumor positive and stromal negative expression may have favorable OS rates after curative hepatectomy.